review of literature on clinical pancreatology - The Pancreapedia

REVIEW OF LITERATURE ONCLINICAL PANCREATOLOGYScientific <strong>literature</strong> made available in 2009Selected and edited byÅke Andrén-Sandberg & Omid AzodiFrom the Department <strong>of</strong> Surgery, Karolinska Institutet at Karolinska UniversityHospital, Huddinge, S-141 86 Stockholm, Sweden

REVIEWER’S PREFACE (and SEARCH ALGORITM)The scientific <strong>literature</strong> also in small medical subjects like pancreatology is today enormous –and it is not possible to keep updated unless making very strong and focused efforts. Thepresent <strong>review</strong> is an attempt to make it easier for clinical pancreatologists to keep updated.From the beginning the consecutive quarterly <strong>review</strong>s were an effort to make the <strong>review</strong>ersupdated, but hopefully it can be used also <strong>of</strong> others with the same interest, i.e. clinicalpancreatology. However, it will still be a personal <strong>review</strong>, which means that the selection <strong>of</strong>presented articles have been up to the <strong>review</strong>ers, and other authors should probably havemade at least some other choises.There must be made some limitations, otherwise a <strong>review</strong> in this form should not be possibleto write due to lack <strong>of</strong> time and lack <strong>of</strong> brain capacity, and probably not possible to readeither. Regarding the limitations, first <strong>of</strong> all almost all <strong>of</strong> the articles have been read in theirfull length, but the writing here is based on their abstracts for practical reasons. This is also inline with the aim <strong>of</strong> the <strong>review</strong>: not to report all what has been published, but rather to give anintroductional sample that hopefully will make the reader eager to read the whole article orarticles: “a tast <strong>of</strong> pancreatology in 2009”.A second limitation is that most <strong>of</strong> the selections has been made through PubMed; a fewother sources (like the journals “Pancreas”, “Pancreatology” and “Journal <strong>of</strong> the Pancreas”)have also been scrutinized, but then more occasional and not systematically. The MeSHs inPubMed have been pancreas, pancreatic neoplasm, acute pancreatitis, chronic pancreatitis,pancreatic trauma and pancreatic pseudocysts. This will lead to a lack <strong>of</strong> some articles thatmight be <strong>of</strong> interest, e.g. in pancreatic physiology, but the border has to be set somewhere.Another limitation is that almost all articles dealing with purely transplantation and diabetes(and most <strong>of</strong> endocrine pankreas) issues have been dropped. Also, this is a clinical oriented<strong>review</strong> and the term human has been used in the search algorithm. Therefore almost all“preclinical” articles have been neglected; i.e. molecular biology, cell lines studies and wholeanimal studies are not included except exceptionally (when the authors could not resist thetemptation). This is not because the preclinical issues are not interesting, but because theyare so numerous, and because it is much more difficult to evaluate the importance <strong>of</strong> them.Some may seem to be <strong>of</strong> little importance today, but might be the first paper for a newparadigm – other may represent the reverse.One more thing, this <strong>review</strong> is not written in English and not even in Swedish but in the bestSwinglish the authors can present. Maybe some <strong>of</strong> the sentences and word make you smilea little, but remember than that our Swedish probably still is much better than your English …The plan is to follow this quarter by a new <strong>review</strong> next quartetr and next quarter and (it isthen the quarter when the <strong>review</strong> was made available through PubMed that counts, not themonth it was actually published). So, welcome with comments – and if the comments fail toappear, the next quarters and year will have the same disposition as the present. Welcomeback next quarter!Åke Andrén-Sandberg and Omid AzodiDepartment <strong>of</strong> Surgery (“Gastrocentrum Kirurgi”)Karolinska University Hospital at HuddingeSE-141 86 StockholmSwedenake.andren-sandberg@karolinska.se and sayed-omid.sadrazodi@ki.se

ABBREVIATIONAAPacute alcoholicABPacute biliary pancreatitisACLAMactivated leucocyte cell adhesion molecule (synonym CD166)ACPalcoholic chronic pancreatitisACPanaplastic carcinoma <strong>of</strong> the pancreasADAMTSa disintegrin and metalloprotease with thrombospondin motifsADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif, 9ADCapparent diffusion coefficientADIPOQadiponectin geneACPalcoholic chronic pancreatitisADMacinar-ductal metaplasiaAGAAmerican Gastroenterological AssociationaICAM-1anti-ICAM-1 monoclonal antibodyAIPautoimmune chronic pancreatitisAJCCAmerican Joint Committee on CancerAOSantioxidant statusALBalbuminALFacute liver failureALLacute lymphoblastic leukemiaALTalanine aminotransferaseAPACHEAcute Physiology and Chronic Health EvaluationAPACHE II Acute Physiology and Chronic Health Evaluation IIAPAPacetaminophenAPCactivated protein CAPC-PCIactivated protein C-protein C inhibitorASantisenseASTaspartate aminotransferaseAUROCarea under the receiver operator characteristicBDbiliary drainageBD-IPMNbranch duct intraductal papillary mucinous neoplasmsBMIbody mass indexBOFSBernard Organ Failure ScoreBPDIblunt pancreatoduodenal injuryCA 19-9 carbohydrate antigen 19-9CAPAPcarboxypeptidase B activation peptideCapCelcapecitabine and celecoxibCBDScommon bile duct stoneCCKcholecystokininCDK-2 cyclin-dependent kinase 2Ccrcreatinine clearanceCCRTchemotherapy and radiation therapyCEAcarcinoembryonic antigenCEACAMCEA-related cell adhesion moleculesCEUScontrast-enhanced ultrasonographyCFcystic fibrosisCFAcoefficient <strong>of</strong> fat absorptionCFRcase fatality rateCFTRcystic fibrosis transmembrane conductance regulatorCIconfidence intervalCOX-2cyclooxygenase-2CPB/Nceliac plexus block/neurolysisCPRcurved planar reformation

CRPC-reactive proteinCRTchemoradiotherapyCTcomputed tomographyCTLcytotoxic T lymphocyteCTRCchymotrypsin CCygb/STAP cytoglobin/stellate cell activation-associated protein2D2-dimensional3D3-dimensionalDBPdouble-bypass procedureDCdendritic celldCKdeoxycytidine kinaseDGEdelayed gastric emptyingDIGEdifference gel electrophoresisDLK1delta-like 1 homologDMdiabetes mellitusDMBA7,12-dimethylbenzanthraceneDPdistal pancreatectomyDPP-4dipeptidyl peptidase-4DSSdisease-specific survivalDTAdiphtheria toxin gene A chainDUduodenal ulcerDUPAN-2 Duke pancreatic monoclonal antigen type 2DUVRvitamin D-effective ultraviolet radiationDWIdiffusion-weighted imagingECMextracellular matrixEDendoscopic drainageEGelastographyEGDesophagogastroduodenoscopyEGFRepidermal growth factor receptoreGFRestimated glomerular filtration rateEG-UStranscutaneous ultrasonography elastographyELFelastic light scattering fingerprintingEMSself-expandable metallic stentEMTepithelial-mesenchymal transitionEORTCEuropean Organization for Research and Treatment <strong>of</strong> CancerERCPendoscopic retrograde cholangiopancreatographyERPendoscopic retrograde pancreatographyESembryonic stem cellsESWLextracorporeal shock wave lithotripsyETDPendoscopic transgastric distal pancreatectomyEUROPAC The European Registry <strong>of</strong> Hereditary Pancreatitis and FamilialPancreatic CancerEUSendoscopic ultrasoundEUS-CPendoscopic ultrasound-guided cholangiopancreatographyEUS-FNAendoscopic ultrasound-guided fine needle aspirationEUS-TCBendoscopic ultrasound-guided trucut biopsyFACSfluorescence activated cell scanningFAMMMfamilial atypical multiple mole melanomaFAPfamilial adenomatous polyposisFASTKFas-activated serine/threonine kinaseFDGfluorodeoxyglucoseFDG-PETfluorodeoxy glucose-positron emission tomographyFECfecal elastase-1 concentrationsFIfluorescence intensityFISHfluorescence in situ hybridization

FMF AIPfocal mass-forming autoimmune pancreatitisFNAfine-needle aspirationFPfocal pancreatitisFPCfamilial pancreatic cancerFRAPferric reducing ability <strong>of</strong> plasma5-FU5-fluorouracilFVLfactor V LeidenGELgranulocytic epithelial lesionsGEMgemcitabine hydrochlorideGemLipliposomal gemcitabineGEP-NETgastrointestinal and pancreatic neuroendocrine tumorsGIgastrointestinalGIPglucose-dependent insulinotropic polypeptideGISTgastrointestinal stromal tumorGLP-1glucagon-like peptide-1GSK-3beta glycogen synthase kinase 3betaGTglutamyltransferaseGUgastric ulcerHCAheterocyclic aminesHFhem<strong>of</strong>iltrationHIFhypoxia inducible factorh-IAPPhormone human islet amyloid polypeptidehIPChuman islet-derived precursor cellsHLPhyperlipoproteinemiaHMBG1 high-mobility group box 1HOMA-IRhomeostasis model assessment <strong>of</strong> insulin resistanceHPhereditary pancreatitishPSChuman pancreatic stellate cellHRQOLhealth-related quality <strong>of</strong> lifeHSP27 heat shock protein 27HThyperthermiaHuRHu antigen RIAPPamyloid polypeptideIATintraportal islet autotransplantationICAM-1intercellular adhesion molecule-1IC-IPMCinvasive carcinoma originating in intraductal papillary mucinousneoplasmICPidiopathic chronic pancreatitisICUintensive care unitIDCPidiopathic duct-centric chronic pancreatitisIFABPintestinal fatty acid binding proteinIgG4immunoglobulin G4IGF-1Rinsulin-like growth factor 1 receptorIHCimmunohistochemistryILinterleukinIL-10interleukin-10IL-13Ralpha2 interleukin-13 receptor alpha2IMTinflammatory my<strong>of</strong>ibroblastic tumorINGAPislet neogeneis-associated proteinIPMCintraductal papillary mucinous carcinomaIPMNintraductal papillary mucinous neoplasmIPMN-Brbranch duct intraductal papillary mucinous neoplasmIPNinfected pancreatic necrosisIPTinflammatory pseudotumorISinvasion score

ITNPintrathecal narcotics pumpJCGAIPJapanese clinical guidelines for autoimmune pancreatitisKOCK homology domain containing protein overexpresssed incancerL-aspL-asparaginaseLCMlaser-capture microdissectionLDLlow-density lipoproteinLEBSlow-coherence enhanced backscatteringLNlymph nodeLNMlymph node metastasisLNRlymph node ratioLPlaparoscopic distal pancreatectomyLPCliver perfusion chemotherapyLPSPlymphoplasmacytic sclerosing pancreatitisMABPmild acute biliary pancreatitisMCNmucinous cystic neoplasmMDCTmultidetector computer tomographyM3DDmaximum 3-dimensional diameterMD-IPMNmain duct pancreatic intraductal papillary-mucinous neoplasmmDNAmitochondrial DNAMEN-1 multiple endocrine neoplasia type 1MEN-2 multiple endocrine neoplasia syndrome type 2mFOLFOX 5-fluorouracil (5-FU), folinic acid, and oxaliplatinmFOLFOX.3 5-fluorouracil (5-FU), folinic acid, and irinotecanMIBGmetaiodobenzylguanidineMI-IPMCminimally invasive intraductal papillary mucinous neoplasmMm-MASTa score measuring alcohol addictionMMPmatrix metalloproteinaseMMRmismatch repairMnd-QDmanganese-doped quantum dotsMOFmultiple organMPDmain pancreatic ductMPRmultiplanar reformationMRCPmagnetic resonance cholangiopancreatographyMRImagnetic resonance imagemRNAmessenger RNAMSImicrosatellite instabilityMSTmedian survival timeMT-SP1matriptaseMTT3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromideNACRTneoadjuvant chemoradiation therapyNETneuroendocrine tumorsNEUROD1 neurogenic differentiation 1NEUROG3 neurogenin 3NF-kappaB nuclear factor-kappaBNGFnerve growth factorNIRnear-infraredNOFnon organ failureNOMnonoperative managementNOTESnatural orifice transluminal endoscopic surgeryNOxexcretion <strong>of</strong> nitric oxideNPnecrotizing pancreatitisNPMnucleophosminNPVnegative predictive valuesNSEneuron-specific enolase

ODPopen distal pancreatectomyOForgan failure25(OH)D25-hydroxyvitamin DORodds ratiosOSoverall survivalPACpancreatic adenocarcinomaPAFplatelet-activating factorPAI-1 plasminogen activator inhibitor type 1PAMprediction analysis for microarraysPanINpancreatic intraepithelial neoplasiaPAP-1 pancreatitis-associated protein 1PBPplasminogen-binding proteinPCpancreatic cancerPCDpercutaneous catheter drainagePCIprotein C inhibitorPDperitoneal dialysisPDpancreatoduodenectomyPDApancreatic ductal adenocarcinomasPDACpancreatic ductal adenocarcinomaPDI pancreatic ductal injury .PDX1 pancreatic duodenal homeobox factor 1PECApancreatic endocrine carcinomasPEGpolyethylene glycolsPENpancreatic endocrine neoplasmPETpancreatic endocrine tumorPETpositron emission tomographyPFprogression-freePFCpancreatic fluid collectionsPGpancreaticogastrostomyPGF1-alpha prostaglandin F1-alphaP4H-betaprolyl 4-hydroxylase-betaPIpancreatic injuryPJpancreaticojejunostomyPJSPeutz-Jeghers syndromepNETpancreatic neuroendocrine tumorsp-NPMphosphorylated nucleophosminPODpostoperative daysPOPFpostoperative pancreatic fistulaPOU3F4 POU class 3 homeobox 4PPpancreatic polypeptidePPARGperoxisome proliferator-activated receptor-gammaPPFpancreaticopleural fistulaPPHpostpancreatectomy hemorrhagePPPDpylorus-preserving pancreatoduodenectomyPRRTpeptide receptor radionuclide therapyPPVpositive predictive valuesPRprogesterone receptorPSCpancreatic stellate cellsPSCAprostate stem cell antigenPTCHmembrane receptor patchedPTFEpolytetrafluoroethylenePVRportal vein reconstructionQDquantum dotsQLQquality <strong>of</strong> lifeQoLquality <strong>of</strong> life

QSRquantitative systematic <strong>review</strong>reg Iregenerating gene IRCCrenal cell carcinomaRECISTresponse evaluation criteria in solid tumorsRPFretroperitoneal fibrosisRPL10ribosomal protein L10RRrelative riskRRGrenal rim gradeRTradiotherapyRT/CTradiochemotherapyRT-PCRreverse transcription polymerase chain reactionSAPsevere acute pancreatitisSCAserous cystadenomaSCPTsolid and cystic pseudopapillary tumorSDCTsingle-detector CTSEERSurveillance, Epidemiology, and End ResultsSHHsonic hedgehogSIRstandardised incidence ratiosSMAserous microcystic adenomaSMAsmooth muscle actinSMOsmoothened receptorSMPRsecretin-stimulated magnetic resonance pancreatographySMRstandardised mortality ratioSOsphincter <strong>of</strong> OddiSODsuperoxide dismutaseSOFsingle organ failureSORsummary odds ratioS1Psphingosine-1-phosphateSPDPspleen-preserving distal pancreatectomySPINK-1serine protease inhibitor Kazal type ISPNsolid-pseudopapillary neoplasmsSPTsolid pseudopapillary tumorsRAGEsoluble form <strong>of</strong> the receptor for advanced glycation end productsSSsenseSSAsomatostatin analogssst2 somatostatin receptor subtype 2sTNFRsoluble tumor necrosis factor receptorsSUVstandardized uptake valueTAPtrypsinogen activation peptideTBtuberculosisTBARSthiobarbituric acid reactive substancesTCtotal cholesterolTGF-betatransforming growth factor-betaTIMP-1tissue inhibitor <strong>of</strong> metalloproteinase-1TKtyrosine kinaseTregregulatory T cellsTRHthyrotropin-releasing hormoneTRHRthyrotropin-releasing hormone receptorTrkAtyrosine kinase receptor ATSP-1thrombospondin-1TTPtime to progressionUFTuracil-tegafuruPAurokinase-type plasminogen activatoruPARurokinase-type plasminogen activator receptorUBR2 ubiquitin-protein ligase E3 component n-recognin 2

USUTDTVESDVTEZESWHOXIAPUnited Statesurinary trypsinogen-2 dipstick testvolume equivalent sphere diametervenous thromboembolismZollinger-Ellison syndromeWorld Health OrganisationX-linked inhibitor <strong>of</strong> apoptosis protein

CONTENTREVIEWER’S PREFACE (and SEARCH ALGORITM)ABBREVIATIONSPANCREATIC HISTORYEarly conceptsPancreatic anatomyPancreatic physiologyEarly thoughts on pancreatic diseaseReinier de GraafAcute pancreatitisNicholaes TulpA new interest in pancreatitisReginald FitzTwo types <strong>of</strong> pancreatitisNicholas SennPancreatitis patophysiologyOpie’s common channel hypothesisAlcoholic pancreatitisBiochemical diagnosisClassification <strong>of</strong> acute pancreatitisAttempts to treat acute pancreatitisGallstone pancreatitisJohn BeardPancreatic surgeryPancreatic cystsFirst pancreatic resectionsEnucleationBillroth, Codivilla and HalstedtBiliary-enteric anastomosisManaging the pancreatic remnantKausch and HirschelWhipple and BraunschweigRockey and PriestlyPancreatic duct drainage in chronic pancreatitis and pancreatic cancerPancreatic transplantationModern pancreatic historyHoward ReberJohn HowardKatsusuke SatakePANCREATIC DEVELOPMENT, EMBRYOLOGY and ANATOMYFactors influencing developmentRegenerating gene ITransforming growth factor-beta (TGF-beta)Islet neogenesis-associated proteinConnexinsDiphtheria toxin gene A chain (DTA)Cell-surface markersOxygenThyrotropin-releasing hormonePancreatic anatomy and malformations

Ectopic pancreasCircumportal annularePancreas annularePolyspleni and short pancreasDouble common bile ductAnomal pancreatic duct systemAgenesia <strong>of</strong> the dorsal pancreatic neck, body and tailFatty pancreasSpleno-pancreatic fusionPANCREATIC PHYSIOLOGYSphincter <strong>of</strong> OddiFeedingStudies <strong>of</strong> pancreatic duct secretionCholecystokininPancreatic function in the elderlyEthanol metabolismIAPPGlucose metabolismDiabetic overviewIncretin mimeticsStem cell therapyHISTOPATHOLOGYTransplanting pancreatic isletsACUTE PANCREATITISOverall resultsMortalityEpidemiology and demographyAn increased incidenceRisk factors in the USGermanyIndiaEtiologic factors and factors <strong>of</strong> importance for development <strong>of</strong> pancreatitisCytokinesZinc and copperProp<strong>of</strong>olGenetic polymorphismOxidative stressHemoconcentrationCaboxypeptidase BObesityDyslipedemiaDominant dorsal duct syndromeClassification and prediction <strong>of</strong> severityScoring systemsSingle factorsHigh- versus low-volume hospitalsAcute pancreatitisCholecystectomyDiagnostics in acute pancreatitisSymptomsUrinary trypsinogen-2Dip-slide diagnosis

HyperamylasemiaHyperlipedemiad-DimerCTMREconomical aspectsDifferential diagnosisAcute pancreatitis in childrenEpidemiologyAcute pancreatitis in pediatric acute lymphoblastic leukemiaSpecific injuriesPulmonary injuryOsteonecrosisAbdominal aortic aneurysm following acute pancreatitisColonic obstruction in acute pancreatitisPancreatitis in anorexia nervosaSubgroups <strong>of</strong> acute forms <strong>of</strong> pancreatitisGallstone-induced pancreatitisHypercalcemia-induced pancreatitisAlcohol-induced pancreatitisPost-ERCP-pancreatitisIschemic pancreatitisDrug-induced pancreatitisInfective pancreatitisAttempts to non-surgical treatmentEnteral nutritionPlasmapheresis <strong>of</strong> triglyceridesIntravenous protease inhibitorsDialysis as a treatment for acute pancreatitisPeritoneal lavageProbioticsAntibioticsNecrosectomyMinimal invasive methodsIntraparenchymal pancreatic airIntrahepatic fluid collectionsEndoscopic treatmentRadiologic interventionsQuality <strong>of</strong> life after acute pancreatitisExperimentalCHRONIC PANCREATITISEpidemiology and demographyChinaIndiaRisk <strong>of</strong> cancerGeneticsCFTRChymotrypsin CSpainPossible etiological factorsHomocysteinemiaChanges in neurohormonesAmino acidsDiagnostics

SymptomsEndocopic ultrasography (EUS)ERCP in childrenBreath testsAssociation with liver diseaseAlcohol-induced chronic pancreatitisGroove pancreatitisPainTheories on investigations <strong>of</strong> pain in patients with chronic pancreatitisTypes <strong>of</strong> painMedical pain treatmentPancreatic enzymes as treatment for painSafety <strong>of</strong> pancreatic enzyme supplementationSurgical interventionsOutcome <strong>of</strong> pancreatoduodenectomyPancreatogastrostomyLongitudinal pancreatodjejunostomyIslet transplantationOther interventions agains painPancreatic duct stentingPlexus blockRadiotherapyHal<strong>of</strong>unginol as prevention <strong>of</strong> fibrosisPancreatopleural fistulaeMaldigestion and nutritionVitaminsNutritional supportInfluence <strong>of</strong> colostrumsDiabetes in chronic pancreatitisFunction in diabetes mellitusPancreas divisumPancreatic stellate cellsPancreatic duct stonesDuodenal dystrophyCystic fibrosisAUTOIMMUNE PANCREATITISPathogenesisAssociation with Helicobacter pyloriAssociation with eosinophiliaDefinitions and differential diagnosisA new antibodyPossible etiological factorsK-rasTGF-beta1Extrapancreatic manifestationsMikulicz diseaseSclerosing cholangitisRetroperitoneal fibrosisDiagnosticsCTPET-CT for differential diagnosisPositrone emission tomographyMissdiagnosisConcomittant cancer

Case reportsHEREDITARY PANCREATITISCase reportPANCREATIC CANCERClassification <strong>of</strong> pancreatic tumorsDemography and epidemiologyStatistics in theoryImportance <strong>of</strong> raceSwedenDanmarkFranceKoreaArctic pancreatic cancerPancreatic compared to peripancreatic cancersDeath at homeEtiological factorsRead meat and risk <strong>of</strong> cancerSmokingAlcohol and smokingLife-style factorsCarbohydrate intakeFructoseCitrus fruitsPollutionRadonVitamine DTocopherolsNitrate in drinking waterPerfluorooctanoatePsoriasisGenetic aspectsScreeningLynch syndromeMolecular biologyMethodologyACLAMActinin-4ADAMTSAnnexin A5Basement membrane proteinsBCRA1B7 ligand familyCiliogenesisCOX-2CTNNB1CytokinesCytokine polymorphismDoxycyclinsEpidermal growth factor receptorEpithelial-mesenchymal transitionFibrinogenGlycogen synthas kinase inhibitorHedgehog pathway

HSP27HuRIGF-1 receptorIntegrinesInterleukin-13 receptorK-rasMatriptaseMitochondrial DNANF-kappaBOsteopontinp21/p27p53Pain and nerve growth factorPPARGPlasminogen activatorREG4RosiglitazoneSomatostatin receptor subtype 2SphingolipidsSynuclein-gammaTyrosine kinasesUrokinase-type plasminogen activatorVitamin DProteomicsProteomics from lymph node metastasesFamilial pancreatic cancerHistologic precursorsExperimental pancreatic cancerEarly pancreatic cancerStagingPrognostic factorsPancreatic cancer diagnosing and stagingAlgorithmTumor markersContrast-enhanced ultrasonographyEndoscopic ultrasonographyEndoscopic ultrasound-guided fine-needle aspiration biopsiEndoscopic ultrasound-guided trucut biopsyComputed tomographyPET-CTMagnetic resonance imaging (MRI)ElastographMetabolomicsOptical markersQuantum dotsDifferential diagnosisBronchogenic carcinomaHydatide cystGISTChronic pancreatitisPseudotumorSpecial symptoms and signsHemosuccus pancreaticusVenous tromboembolismObesity

Diabetes in pancreatic cancerCoeliac axis stenosisPreoperative biliary drainageExperimentalPancreatic cancer cachexiaEffect <strong>of</strong> age on outcomeSurgical techniquesPancreatojejunostomyBioabsorbable staple line-reinforcementTotal pancreatectomyPortal vein reconstructionArterial reconstruction at pancreatic resectionExtended lymphadenectomyCryosurgeryPostoperative complicationsSurgical resultsLong-term survivalBody and tail tumorsDistal pancreatectomyLaparoscopic distal pancreatectomySpleen-preserving laparoscopicallyNOTESRenal function at pancreatoduodenectomyGlucose monitoringPeroperativelyGlucos metabolism after pancreatectomyPalliationPalliative stentingPrediction <strong>of</strong> survivalQuality <strong>of</strong> lifeQuality <strong>of</strong> careOrganizationChemotherapyAdjuvants and neoadjuvantsPalliative cytotoxic treatmentStem cell transplantationBetulinCurcuminAloeGinsengMORE UNUSUAL TUMORS OF THE PANCREASAnaplastic carcinoma <strong>of</strong> the pancreasCystic pancreatic tumorsIntraductal papillary mucinous neoplasm (IPMN)Growth rateWays <strong>of</strong> detectionRisk <strong>of</strong> cancerMolecular biologyImagingDifferential diagnosesExtrapancreatic tumorsPredictive factorsIn immune suppressed patientsFrozen section at operation

HemodialysisSerous cystadenomasSerous microcystic adenomaMucinous adenomaSolid and pseudopapillary tumor (Frantz's tumor)DiagnosisDifferential diagnosisSolid and cystic pseudopapillary tumorsIntraductal tubular carcinomaAdenosquamous carcinomaPancreatic lymphomaSmall cell carcinoma <strong>of</strong> the pancreasNon pancreatic periampullary tumorsPapilla <strong>of</strong> Vater tumorsDuodenal tumorsLocal excisionMetastases to pancreasRenal cell carcinomaColorectal carcinomaBronchial carcinomaDiffuse retroperitoneal cystic abdominal lymphangiomatosisMerkel cell carcinomaPancreatic tuberculosisPANCREATIC PSEUDOCYSTS and ANEURYSMSPancreatic pseudocystsDiagnosticsCase reportHemosuccus pancreaticusPancreatic aneurysmPANCREATIC TRAUMAENDOCRINE PANCREATIC TUMORSHistoryGeneticsFamilial endocrinopathiasMultiple endocrine neoplasiaDiagnosticsSomatostatinomaVIPomaZollinger-Ellison syndromeInsulinomasNon-functioning tumorTumors <strong>of</strong> the papilla <strong>of</strong> VaterSurgeryMedical treatmentCytotoxic treatmentMetastatic endocrine cancersPanniculitisOverall survivalQuality <strong>of</strong> lifeREFERENCES

ABBREVIATIONAAPacute alcoholicABPacute biliary pancreatitisACLAMactivated leucocyte cell adhesion molecule (synonym CD166)ACPalcoholic chronic pancreatitisACPanaplastic carcinoma <strong>of</strong> the pancreasADAMTSa disintegrin and metalloprotease with thrombospondin motifsADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif, 9ADCapparent diffusion coefficientADIPOQadiponectin geneACPalcoholic chronic pancreatitisADMacinar-ductal metaplasiaAGAAmerican Gastroenterological AssociationaICAM-1anti-ICAM-1 monoclonal antibodyAIPautoimmune chronic pancreatitisAJCCAmerican Joint Committee on CancerAOSantioxidant statusALBalbuminALFacute liver failureALLacute lymphoblastic leukemiaALTalanine aminotransferaseAPACHEAcute Physiology and Chronic Health EvaluationAPACHE II Acute Physiology and Chronic Health Evaluation IIAPAPacetaminophenAPCactivated protein CAPC-PCIactivated protein C-protein C inhibitorASantisenseASTaspartate aminotransferaseAUROCarea under the receiver operator characteristicBDbiliary drainageBD-IPMNbranch duct intraductal papillary mucinous neoplasmsBMIbody mass indexBOFSBernard Organ Failure ScoreBPDIblunt pancreatoduodenal injuryCA 19-9 carbohydrate antigen 19-9CAPAPcarboxypeptidase B activation peptideCapCelcapecitabine and celecoxibCBDScommon bile duct stoneCCKcholecystokininCDK-2 cyclin-dependent kinase 2Ccrcreatinine clearanceCCRTchemotherapy and radiation therapyCEAcarcinoembryonic antigenCEACAMCEA-related cell adhesion moleculesCEUScontrast-enhanced ultrasonographyCFcystic fibrosisCFAcoefficient <strong>of</strong> fat absorptionCFRcase fatality rateCFTRcystic fibrosis transmembrane conductance regulatorCIconfidence intervalCOX-2cyclooxygenase-2CPB/Nceliac plexus block/neurolysisCPRcurved planar reformation

CRPC-reactive proteinCRTchemoradiotherapyCTcomputed tomographyCTLcytotoxic T lymphocyteCTRCchymotrypsin CCygb/STAP cytoglobin/stellate cell activation-associated protein2D2-dimensional3D3-dimensionalDBPdouble-bypass procedureDCdendritic celldCKdeoxycytidine kinaseDGEdelayed gastric emptyingDIGEdifference gel electrophoresisDLK1delta-like 1 homologDMdiabetes mellitusDMBA7,12-dimethylbenzanthraceneDPdistal pancreatectomyDPP-4dipeptidyl peptidase-4DSSdisease-specific survivalDTAdiphtheria toxin gene A chainDUduodenal ulcerDUPAN-2 Duke pancreatic monoclonal antigen type 2DUVRvitamin D-effective ultraviolet radiationDWIdiffusion-weighted imagingECMextracellular matrixEDendoscopic drainageEGelastographyEGDesophagogastroduodenoscopyEGFRepidermal growth factor receptoreGFRestimated glomerular filtration rateEG-UStranscutaneous ultrasonography elastographyELFelastic light scattering fingerprintingEMSself-expandable metallic stentEMTepithelial-mesenchymal transitionEORTCEuropean Organization for Research and Treatment <strong>of</strong> CancerERCPendoscopic retrograde cholangiopancreatographyERPendoscopic retrograde pancreatographyESembryonic stem cellsESWLextracorporeal shock wave lithotripsyETDPendoscopic transgastric distal pancreatectomyEUROPAC The European Registry <strong>of</strong> Hereditary Pancreatitis and FamilialPancreatic CancerEUSendoscopic ultrasoundEUS-CPendoscopic ultrasound-guided cholangiopancreatographyEUS-FNAendoscopic ultrasound-guided fine needle aspirationEUS-TCBendoscopic ultrasound-guided trucut biopsyFACSfluorescence activated cell scanningFAMMMfamilial atypical multiple mole melanomaFAPfamilial adenomatous polyposisFASTKFas-activated serine/threonine kinaseFDGfluorodeoxyglucoseFDG-PETfluorodeoxy glucose-positron emission tomographyFECfecal elastase-1 concentrationsFIfluorescence intensityFISHfluorescence in situ hybridization

FMF AIPfocal mass-forming autoimmune pancreatitisFNAfine-needle aspirationFPfocal pancreatitisFPCfamilial pancreatic cancerFRAPferric reducing ability <strong>of</strong> plasma5-FU5-fluorouracilFVLfactor V LeidenGELgranulocytic epithelial lesionsGEMgemcitabine hydrochlorideGemLipliposomal gemcitabineGEP-NETgastrointestinal and pancreatic neuroendocrine tumorsGIgastrointestinalGIPglucose-dependent insulinotropic polypeptideGISTgastrointestinal stromal tumorGLP-1glucagon-like peptide-1GSK-3beta glycogen synthase kinase 3betaGTglutamyltransferaseGUgastric ulcerHCAheterocyclic aminesHFhem<strong>of</strong>iltrationHIFhypoxia inducible factorh-IAPPhormone human islet amyloid polypeptidehIPChuman islet-derived precursor cellsHLPhyperlipoproteinemiaHMBG1 high-mobility group box 1HOMA-IRhomeostasis model assessment <strong>of</strong> insulin resistanceHPhereditary pancreatitishPSChuman pancreatic stellate cellHRQOLhealth-related quality <strong>of</strong> lifeHSP27 heat shock protein 27HThyperthermiaHuRHu antigen RIAPPamyloid polypeptideIATintraportal islet autotransplantationICAM-1intercellular adhesion molecule-1IC-IPMCinvasive carcinoma originating in intraductal papillary mucinousneoplasmICPidiopathic chronic pancreatitisICUintensive care unitIDCPidiopathic duct-centric chronic pancreatitisIFABPintestinal fatty acid binding proteinIgG4immunoglobulin G4IGF-1Rinsulin-like growth factor 1 receptorIHCimmunohistochemistryILinterleukinIL-10interleukin-10IL-13Ralpha2 interleukin-13 receptor alpha2IMTinflammatory my<strong>of</strong>ibroblastic tumorINGAPislet neogeneis-associated proteinIPMCintraductal papillary mucinous carcinomaIPMNintraductal papillary mucinous neoplasmIPMN-Brbranch duct intraductal papillary mucinous neoplasmIPNinfected pancreatic necrosisIPTinflammatory pseudotumorISinvasion score

ITNPintrathecal narcotics pumpJCGAIPJapanese clinical guidelines for autoimmune pancreatitisKOCK homology domain containing protein overexpresssed incancerL-aspL-asparaginaseLCMlaser-capture microdissectionLDLlow-density lipoproteinLEBSlow-coherence enhanced backscatteringLNlymph nodeLNMlymph node metastasisLNRlymph node ratioLPlaparoscopic distal pancreatectomyLPCliver perfusion chemotherapyLPSPlymphoplasmacytic sclerosing pancreatitisMABPmild acute biliary pancreatitisMCNmucinous cystic neoplasmMDCTmultidetector computer tomographyM3DDmaximum 3-dimensional diameterMD-IPMNmain duct pancreatic intraductal papillary-mucinous neoplasmmDNAmitochondrial DNAMEN-1 multiple endocrine neoplasia type 1MEN-2 multiple endocrine neoplasia syndrome type 2mFOLFOX 5-fluorouracil (5-FU), folinic acid, and oxaliplatinmFOLFOX.3 5-fluorouracil (5-FU), folinic acid, and irinotecanMIBGmetaiodobenzylguanidineMI-IPMCminimally invasive intraductal papillary mucinous neoplasmMm-MASTa score measuring alcohol addictionMMPmatrix metalloproteinaseMMRmismatch repairMnd-QDmanganese-doped quantum dotsMOFmultiple organMPDmain pancreatic ductMPRmultiplanar reformationMRCPmagnetic resonance cholangiopancreatographyMRImagnetic resonance imagemRNAmessenger RNAMSImicrosatellite instabilityMSTmedian survival timeMT-SP1matriptaseMTT3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromideNACRTneoadjuvant chemoradiation therapyNETneuroendocrine tumorsNEUROD1 neurogenic differentiation 1NEUROG3 neurogenin 3NF-kappaB nuclear factor-kappaBNGFnerve growth factorNIRnear-infraredNOFnon organ failureNOMnonoperative managementNOTESnatural orifice transluminal endoscopic surgeryNOxexcretion <strong>of</strong> nitric oxideNPnecrotizing pancreatitisNPMnucleophosminNPVnegative predictive valuesNSEneuron-specific enolase

ODPopen distal pancreatectomyOForgan failure25(OH)D25-hydroxyvitamin DORodds ratiosOSoverall survivalPACpancreatic adenocarcinomaPAFplatelet-activating factorPAI-1 plasminogen activator inhibitor type 1PAMprediction analysis for microarraysPanINpancreatic intraepithelial neoplasiaPAP-1 pancreatitis-associated protein 1PBPplasminogen-binding proteinPCpancreatic cancerPCDpercutaneous catheter drainagePCIprotein C inhibitorPDperitoneal dialysisPDpancreatoduodenectomyPDApancreatic ductal adenocarcinomasPDACpancreatic ductal adenocarcinomaPDI pancreatic ductal injury .PDX1 pancreatic duodenal homeobox factor 1PECApancreatic endocrine carcinomasPEGpolyethylene glycolsPENpancreatic endocrine neoplasmPETpancreatic endocrine tumorPETpositron emission tomographyPFprogression-freePFCpancreatic fluid collectionsPGpancreaticogastrostomyPGF1-alpha prostaglandin F1-alphaP4H-betaprolyl 4-hydroxylase-betaPIpancreatic injuryPJpancreaticojejunostomyPJSPeutz-Jeghers syndromepNETpancreatic neuroendocrine tumorsp-NPMphosphorylated nucleophosminPODpostoperative daysPOPFpostoperative pancreatic fistulaPOU3F4 POU class 3 homeobox 4PPpancreatic polypeptidePPARGperoxisome proliferator-activated receptor-gammaPPFpancreaticopleural fistulaPPHpostpancreatectomy hemorrhagePPPDpylorus-preserving pancreatoduodenectomyPRRTpeptide receptor radionuclide therapyPPVpositive predictive valuesPRprogesterone receptorPSCpancreatic stellate cellsPSCAprostate stem cell antigenPTCHmembrane receptor patchedPTFEpolytetrafluoroethylenePVRportal vein reconstructionQDquantum dotsQLQquality <strong>of</strong> lifeQoLquality <strong>of</strong> life

QSRquantitative systematic <strong>review</strong>reg Iregenerating gene IRCCrenal cell carcinomaRECISTresponse evaluation criteria in solid tumorsRPFretroperitoneal fibrosisRPL10ribosomal protein L10RRrelative riskRRGrenal rim gradeRTradiotherapyRT/CTradiochemotherapyRT-PCRreverse transcription polymerase chain reactionSAPsevere acute pancreatitisSCAserous cystadenomaSCPTsolid and cystic pseudopapillary tumorSDCTsingle-detector CTSEERSurveillance, Epidemiology, and End ResultsSHHsonic hedgehogSIRstandardised incidence ratiosSMAserous microcystic adenomaSMAsmooth muscle actinSMOsmoothened receptorSMPRsecretin-stimulated magnetic resonance pancreatographySMRstandardised mortality ratioSOsphincter <strong>of</strong> OddiSODsuperoxide dismutaseSOFsingle organ failureSORsummary odds ratioS1Psphingosine-1-phosphateSPDPspleen-preserving distal pancreatectomySPINK-1serine protease inhibitor Kazal type ISPNsolid-pseudopapillary neoplasmsSPTsolid pseudopapillary tumorsRAGEsoluble form <strong>of</strong> the receptor for advanced glycation end productsSSsenseSSAsomatostatin analogssst2 somatostatin receptor subtype 2sTNFRsoluble tumor necrosis factor receptorsSUVstandardized uptake valueTAPtrypsinogen activation peptideTBtuberculosisTBARSthiobarbituric acid reactive substancesTCtotal cholesterolTGF-betatransforming growth factor-betaTIMP-1tissue inhibitor <strong>of</strong> metalloproteinase-1TKtyrosine kinaseTregregulatory T cellsTRHthyrotropin-releasing hormoneTRHRthyrotropin-releasing hormone receptorTrkAtyrosine kinase receptor ATSP-1thrombospondin-1TTPtime to progressionUFTuracil-tegafuruPAurokinase-type plasminogen activatoruPARurokinase-type plasminogen activator receptorUBR2 ubiquitin-protein ligase E3 component n-recognin 2

USUTDTVESDVTEZESWHOXIAPUnited Statesurinary trypsinogen-2 dipstick testvolume equivalent sphere diametervenous thromboembolismZollinger-Ellison syndromeWorld Health OrganisationX-linked inhibitor <strong>of</strong> apoptosis protein

PANCREATIC HISTORYEarly conceptsPancreatic anatomyThe earliest observations on the pancreas were probably made by rabbis in the BabylonianTalmud who refer to a "finger <strong>of</strong> the liver" [001]. The initial anatomical descriptions <strong>of</strong> thepancreas are generally considered to have originated from the Alexandrians Herophilus,Erasistratos, and Eudemus in the third century BC [002, 003]. Although Galen provided amodest anatomical description, neither he, Hippocrates, Erasistratus, nor Herophilus wereable to identify any relationship to disease. These ancient quasi anatomophysiologistsregarded the pancreas as unusual, given that it had no cartilage or bone. This observationled Ruphos <strong>of</strong> Ephesus (c. 100 BC) to name the organ "pancreas" (Greek pan: all, + kreas:flesh or meat) [004, 005].Andreas Vesalius (1513-1564) referred to the pancreas in the fifth book <strong>of</strong> his opus (Dehumani corporis fabrica) as a "glandulous organ or kannelly body <strong>of</strong> substance growing in theneather pannicle <strong>of</strong> the caule (omentum)" and postulated that the pancreas exerts aprotective effect on the stomach by serving as a cushion (Schutzorgan) on which it rested[006].In 1642, in an anatomical dissection <strong>of</strong> an executed criminal, Johann Wirsüng (1589-1643)described the main pancreatic duct, but neither he nor his contemporaries could decipher thefunction <strong>of</strong> the gland [007]. Giovanni Domenico Santorini (1681-1737) is credited with thediscovery <strong>of</strong> the accessory pancreatic duct, although several other contemporary anatomistsalso reported on the existence <strong>of</strong> the accessory duct [008].In 1720, Abraham Vater (1684-1751) presented his description <strong>of</strong> the duodenal ampulla[008], whereas Ruggero Oddi, as a fourth year medical student in 1887, demonstrated theexistence <strong>of</strong> the sphincter, which bears his name [009]. The dubious history <strong>of</strong> this sphincteris recapitulated in Oddi's precipitous fall from scientific grace and his ignominious demise asa member <strong>of</strong> the French Foreign legion in an unknown grave in Tunisia [010].Pancreatic physiologyDespite knowledge <strong>of</strong> the existence <strong>of</strong> the pancreas, there was little effort to investigate thephysiological role <strong>of</strong> the gland until the late 17th century when Franciscus de le Boe Sylvius(1614-1672) <strong>of</strong> Amsterdam proposed that digestion was a multistep process starting withfermentation by saliva in the mouth and the stomach, a second phase involving thepancreas, followed by the passage <strong>of</strong> chyle into lymphatics, the venous system, andeventually, the right side <strong>of</strong> the heart [011]. His pupil, Regnier de Graaf (1641-1673),ingeniously developed a method for the direct investigation <strong>of</strong> the nature <strong>of</strong> pancreatic juiceby creating canine pancreatic fistulae through which he inserted feather quills into thepancreatic ductal orifices to obtain succus pancreaticus [012]. However, his investigationsinto the nature <strong>of</strong> the succus pancreaticus resulted in his erroneous conclusion that it wasacidic in nature (he had sampled the pyloric antra <strong>of</strong> his piscine models) [010].These innovative theories on digestion were subsequently modified by John Conrad Brunner(1653-1727) whose experiments in pancreatectomized dogs led him to propose thatspecialized duodenal glands (which are named after him) were the major source <strong>of</strong> digestivejuice secretion and that the pancreas was not vital either for digestion or for life [002, 013]. In1682, Peyer described the lymphatic nodules located in the walls <strong>of</strong> the ileum and proposedthat both Brunner glands and his own "patches" were adjuncts to digestion, producing a

fortifying secretion for the pancreatic juice [014]. This reductionist viewpoint sadly hinderedpancreatic investigation for years by concluding that the pancreas was a minor contributor todigestion and the gland languished while scientists probed the stomach and liver as the keyagents <strong>of</strong> digestion [010].Further elucidation <strong>of</strong> pancreatic physiology was provided by Willy Kuhne (1837-1900) <strong>of</strong>Germany, who identified trypsin and evaluated its role in the digestion <strong>of</strong> protein, and byAlexander Marcet [011] (1770-1822), who identified lipase in 1815. Claude Bernard (1813-1878) <strong>of</strong> Paris demonstrated that gastric digestion "is only a preparation act" and thatpancreatic juice emulsified fatty foods by splitting them into glycerin and fatty acids [015]. Inaddition, he demonstrated the role <strong>of</strong> the pancreas in the conversion <strong>of</strong> starch into sugar andits solvent action on the "proteides that have not been cleaved in the stomach." Further workby Eberle in 1843 demonstrated that pancreatic juice emulsified fat, and a year later, Valentindemonstrated its activity on starch [011].The concept <strong>of</strong> the regulation <strong>of</strong> pancreatic secretion was initially addressed by Ivan Pavlov(1849-1936) and his pupils who proposed a dominant role <strong>of</strong> the vagus nerve in the neuralregulation <strong>of</strong> pancreatic secretion. In 1902, William Bayliss (1860-1924) and Ernest Starling(1866-1927) <strong>of</strong> University College, London, demonstrated that this phenomenon was in factnot only a neural reflex but also the effect <strong>of</strong> a chemical messenger, which led them tointroduce the word "hormone" (derived from the Greek hormonos: I arouse to excitement)and name the putative agent "secretin" [016]. Further developments in this field included thediscovery <strong>of</strong> cholecystokinin by A. C. Ivy (1893-1978) and E. Oldberg (1901-1986) [017] andthe understanding that a number <strong>of</strong> chemical messengers influenced different aspects(protein and water, bicarbonate) <strong>of</strong> pancreatic secretion [010].Early thoughts on pancreatic diseaseAlthough Galen (130-201 AC) was aware <strong>of</strong> pancreatic problems [018] the pancreasremained in virtual obscurity as a seat <strong>of</strong> disease until the late 16th century when there was arenaissance in the study <strong>of</strong> the gland largely initiated by the experiments <strong>of</strong> Franciscus de laBoe Sylvius (1614-1672) and his protégé, Regnier de Graaf (1641-1673) [011]. This renewedinterest led to the pancreas being blamed for a variety <strong>of</strong> maladies. In 1835, JJ Bigsby (1792-1881) published a <strong>review</strong> <strong>of</strong> the existing <strong>literature</strong> on the pancreas [019]. He noted that one<strong>of</strong> the earliest mentions <strong>of</strong> pancreatic disease was by Jean Fernel (1509-1558), who, in1542, believed that the pancreas was the origin <strong>of</strong> intermittent fevers and melancholy. Nearlya century later, Nathanael Highmore (1613-1687) ascribed apoplexy, palsy, and hysteria toaffliction <strong>of</strong> the pancreas. In a <strong>review</strong> <strong>of</strong> 45 patients with acute pancreatitis, HeinrichClaessen, as late as 1842, remarked that pancreatic disease was rare and that it was difficultto obtain information about this organ that was deep-seated, had limited relationships toother organs <strong>of</strong> the body, and was purely an organ <strong>of</strong> excretion [020]. Interest in pancreaticdiseases also waned after Brunner's experiment on the survival <strong>of</strong> pancreatectomized dogs,which led him to postulate that the pancreas was not a vital organ [003].Reinier de GraafIn the late seventeenth century, traditions in anatomy and chemistry came together to groundnew theoretical and experimental approaches to understanding the animal body. Theresearches <strong>of</strong> Dutch experimenters Reinier de Graaf and his mentor Franciscus Sylviusprovide keen insight into the ways experiments were constructed, negotiated, and thoughtabout by leading anatomists and physicians <strong>of</strong> the time. The objects and approaches deGraaf used in the laboratory – ligature, inflation, injection, tubes, vessels, tasting – were

derived from broadly Harveian anatomical and Helmontian chymical traditions. Experimentaltraditions and a comprehensive and materialistic chymical theory <strong>of</strong> acid-alkali interactionsunified the artificial and the natural and allowed de Graaf to create and use hybrid animalapparatusconstructions as tools to collect and assay the key ingredients <strong>of</strong> digestion anddisease [021].Acute pancreatitisThe death <strong>of</strong> Alexander the Great (356-323 BC) at the age <strong>of</strong> 33 has been ascribed to acutenecrotizing pancreatitis secondary to rich food and heavy alcohol consumption [022].Among the various pancreatic disorders, the pace <strong>of</strong> scientific discovery in acute pancreatitishas been particularly slow. A clinical description <strong>of</strong> acute pancreatitis was first presented in1652 by the Dutch anatomist Nicholas Tulp, and despite the nearly 350 years that havepassed, there continue to be many unanswered questions. In the late 19th and early 20thcentury, Reginald Fitz, Nicholas Senn, Eugene Opie, and others made seminal contributionsthat continue to influence our present understanding <strong>of</strong> acute pancreatitis [023].Nicholaes TulpThe first clinical description <strong>of</strong> acute pancreatitis is believed to have been published in 1652by the Dutch anatomist Nicholaes Tulp (1593-1674) [005, 024]. Tulp, who is alsoremembered for discovering the ileocecal valve, reported the case <strong>of</strong> a young man whosuccumbed to an illness characterized by incessant fevers and much distress. On autopsy,the pancreas was "swollen with dirty pus and filled with an excess <strong>of</strong> viscous mucus" [024].He speculated that the pancreas was "the origin <strong>of</strong> protracted and complicated diseases,such as consumption <strong>of</strong> the spine, continuous fever, cancer, abscesses, growths, vomiting,restlessness, sleeplessness, and other most dangerous affections, which from this source,like Pandora's box, frequently originate to the detriment <strong>of</strong> the human race." Tulp was a wellknownphysician and anatomist in Amsterdam and the praelector (lecturer) in Anatomy <strong>of</strong> theSurgeon's Guild from 1628 to 1653. In addition to being immortalized as the central figure inthe Rembrandt painting, "Lesson in anatomy," Tulp published a considerable amount <strong>of</strong> hisanatomical observations under the title "Observationum Medicarum Libri Tres” [025]. He wasthe chief editor <strong>of</strong> the Amsterdam Pharmacopoeia, and provided the first systematic catalog<strong>of</strong> medications in the Netherlands. Indeed, he was held in such public esteem that he waselected Burgermaster <strong>of</strong> Amsterdam four times. After Tulp's description, Théophile Bonet(1629-1689) [026] and JG Griesel [027] also reported on cases where the pancreas wasnecrotic on autopsy. Nearly a century later, Morgagni, in 1761, reported a clinical syndrome<strong>of</strong> severe upper abdominal pain, vomiting, and collapse in a patient whose autopsy revealedthat the "pancreas was enlarged and totally filled with knots, rather large, unequal and <strong>of</strong> theconsistency <strong>of</strong> cartilage" [010, 028].A new interest in pancreatitisThese early descriptions <strong>of</strong> pancreatic disease failed to discriminate between acute andchronic pancreatitis, presented little insight into the pathological features <strong>of</strong> the pancreas onautopsy, and were highly speculative with regard to causes and clinical symptoms <strong>of</strong>pancreatitis. Antoine Portal (1742-1832), who was pr<strong>of</strong>essor <strong>of</strong> medicine at the Collège deFrance, described the various pathological manifestations <strong>of</strong> pancreatic disease such asedema, hemorrhage, necrosis, and gangrene [029], although he considered thesemanifestations as different disease entities. Portal also reported recurring acute pancreatitispresenting with repeated bouts <strong>of</strong> intense pain that led to the eventual death <strong>of</strong> the patientfrom gangrene <strong>of</strong> the pancreas. Augustin-Nicolas Gendrin (1796-1890) also made

observations on acute pancreatitis which were similar to those <strong>of</strong> Portal [030]. Interestingly,these early authors noted an association between swelling <strong>of</strong> the salivary glands andinflammation <strong>of</strong> the pancreas. Théodoric Lerminier (1770-1836) observed that there was ananalogy between the state <strong>of</strong> the pancreas and the parotid in severe fevers [031] and S.Neumann (1819-1908) and JT Mondière both proposed that inflammation could rapidlyspread from the salivary glands to the pancreas resulting in the death <strong>of</strong> the patient [010,032]. It was only in 1899 that HF Harris <strong>of</strong> Boston was convincingly able to link mumps andpancreatitis [033].The etiology <strong>of</strong> pancreatic inflammation was a matter <strong>of</strong> intense speculation. Some <strong>of</strong> theproposed causative factors included mercury, which was used to treat syphilis at that time[003, 034], gastritis and continuous vomiting (Claessen, 1842) [020], chronic hepatic disease(Portal, 1803) [029], excessive masturbation (A von Störck, 1799) [035], migration <strong>of</strong> a wormfrom the duodenum to the pancreatic duct (Shea [036] and Lieutaud [037]), perforated gastriculcer causing penetration <strong>of</strong> the pancreas (Andral) [031] and compression <strong>of</strong> the bile ductleading to pancreatitis with jaundice (Crampton, 1818) [038].Karl von Rokitansky (1804-1878), chair <strong>of</strong> pathology at the Wiener AllgemeinesKrankenhaus, was the first in 1842 to recognize acute hemorrhagic pancreatitis [039]followed by Theodor Albrecht Edwin Klebs (1834-1913) <strong>of</strong> Berne, who, in 1870, noted thathemorrhagic inflammation <strong>of</strong> the gland resulted in "purulent peripancreatitis with partialsequestration <strong>of</strong> the gland" [040]. TS Cullen (1867-1948) <strong>of</strong> Edinburgh describedperiumbilical discoloration in a patient with ectopic pregnancy, and this later came to berecognized as a sign <strong>of</strong> severe acute pancreatitis [041], whereas G Gray-Turner (1877-1951)<strong>of</strong> London, in 1920, reported flank discoloration associated with hemorrhagic pancreatitis[042].In 1856, the great French physiologist Claude Bernard (1813-1878) demonstrated thecapacity <strong>of</strong> pancreatic secretions to digest proteins, carbohydrate and fat. Bernard initiallydemonstrated fat necrosis in dogs in 1856 but failed to elucidate on his finding. He wasfollowed by Julius Klob, an assistant <strong>of</strong> Rokitansky, who identified fat necrosis in humans in1860. In 1882, F Balser described the process <strong>of</strong> fat necrosis in more detail but felt that thiswas a separate event from pancreatic inflammation. W Dettner, who, in 1894, proposed apancreatic ferment as the cause, and H Chiari (1851-1916), who considered it to be due topancreatic degeneration (1896), contested this. Further controversy was excited by ReginaldFitz (1843-1913), who thought the origin was bacterial infection and HD Rolleston whoproposed it to be a solar plexus-related event. Robert Langerhans postulated that it waspancreatic ferment that resulted in necrosis <strong>of</strong> fat tissue, and Simon Flexner, in 1897,suggested that this ferment was lipase [010].Reginald FitzIn a seminal article published in 1889, Reginald Huber Fitz (1843-1913) <strong>of</strong> Boston presentedthe first systematic analyses <strong>of</strong> acute pancreatitis [032]. Fitz was born in Chelsea,Massachusets, and entered Harvard College in 1858 but left in his junior year to work in acopper mine [043]. He returned in 1862 to complete BA and MD degrees and thenproceeded to Europe, where he acquired a unique blend <strong>of</strong> training in both clinical medicineand pathology under the guidance <strong>of</strong> such illustrious scientists as Rokitansky, Skoda, andBillroth. Fitz also worked in the laboratory <strong>of</strong> Rudolf Virchow (1821-1902), where he becamean expert in microscopy and also brought to the United States Virchow's teaching thatdisease is an expression <strong>of</strong> aberration in normal cellular function. Having returned toMassachusetts, as an instructor in Pathology and later as Shattuck Pr<strong>of</strong>essor <strong>of</strong> PathologicAnatomy, he pioneered integration <strong>of</strong> clinical information with pathologic findings, and hisperspicacity led to significant advances in surgical pathology including characterization <strong>of</strong>

acute appendicitis, intestinal obstruction, complications <strong>of</strong> Meckel diverticulum, and acutepancreatitis [010].In 1889, at the New York Pathological Society's Middleton-Goldsmith lecture, Fitz presentedhis article entitled "Acute pancreatitis: a consideration <strong>of</strong> hemorrhage, hemorrhagic,suppurative, and gangrenous pancreatitis, and <strong>of</strong> disseminated fat necrosis" in which hesystematically <strong>review</strong>ed the clinical symptoms in 53 cases <strong>of</strong> pathologically documentedacute pancreatitis [043]. In addition, he detailed the various hemorrhagic, suppurative, andgangrenous changes in acute pancreatitis and their pathological differentiation. He furthercommented on various etiologies such as gall stones, alcohol, perforating gastric ulcer, andtrauma. Quite remarkably, Fitz also described pancreatic abscess, splenic vein thrombosis,and a likely pseudocyst <strong>of</strong> the pancreas as associated complications <strong>of</strong> acute pancreatitis. Inthis paper, Fitz also proposed a relationship between pancreatic hemorrhage andpancreatitis and a causal link between disseminated fat necrosis and acute pancreatitis[010].By his systematic analysis <strong>of</strong> the various facets <strong>of</strong> acute pancreatitis, Fitz laid the foundationfor antemortem diagnosis <strong>of</strong> this disease and greatly facilitated subsequent pancreaticresearch at the turn <strong>of</strong> the 20th century. Interestingly, Fitz initially advocated a conservativeapproach to the surgical management <strong>of</strong> patients with acute pancreatitis, noting that "anoperation… in the early stages <strong>of</strong> this disease, is extremely hazardous" [044]. However, hisrecommendation later changed to early laparotomy as performed for other causes <strong>of</strong> acuteabdomen [010].Two types <strong>of</strong> pancreatitisDespite the accumulating knowledge on pancreatitis, it was not until the middle <strong>of</strong> the 20thcentury that an understanding <strong>of</strong> the differences between acute and chronic pancreatitis wasappreciated. However, there were multiple descriptions <strong>of</strong> pancreatic concretions in the 18thand 19th centuries. In 1678, de Graaf recounted previous reports <strong>of</strong> pancreatic stones by hiscontemporaries. After this, there were also numerous reports <strong>of</strong> pancreatic lithiasis at thetime <strong>of</strong> autopsy by various authors including Bonet, Morgagni, and Johann Friedrich Meckel(1724-1774) [010]. In 1799, Matthew Baillie (1761-1823) <strong>of</strong> London published plates thatclearly depicted pancreatic ductal concretions, ductal dilatation, and changes <strong>of</strong> chronicpancreatitis [045]. At the turn <strong>of</strong> the 19th century, Sir Arthur Mayo Robson (1853-1933) <strong>of</strong>Leeds presumed the etiology to be <strong>of</strong> bacterial infection; however, the distinction amongacute, subacute, and chronic was still controversial [046, 047]. In 1946, Comfort [048], at theMayo Clinic, provided a significant analysis <strong>of</strong> the clinical entity <strong>of</strong> chronic pancreatitis and, inso doing, produced the seminal manuscript on the subject that has, for 50 years, remainedthe critical commentary on the disease.Nicholas SennOne <strong>of</strong> the contemporaries <strong>of</strong> Reginald Fitz who contributed extensively to the advancement<strong>of</strong> our knowledge <strong>of</strong> the pancreas was Nicholas Senn (1844-1908), a surgeon who was bornin Sweden but later moved to the United States and attended the Chicago Medical School[005]. He initially worked at the Cook County Hospital in Chicago and Milwaukee (Wisconsin)Hospital before proceeding to Munich for further training in surgery before finally returning toRush Medical College as pr<strong>of</strong>essor <strong>of</strong> surgery [010]. In 1886, Senn presented an extensiveaccount <strong>of</strong> his surgical experiments on the pancreas at the meeting <strong>of</strong> the American SurgicalAssociation as an article entitled "Surgery <strong>of</strong> the pancreas, as based upon experiments andclinical researches" [005, 049]. Starting with a <strong>review</strong> <strong>of</strong> the available surgical <strong>literature</strong> onthe pancreas, Senn noted that the only operations available were either excision <strong>of</strong> retentioncysts or formation <strong>of</strong> external pancreatic fistulas to drain such cysts [049]. He detailed a

series <strong>of</strong> animal experiments, <strong>of</strong> which one was transection <strong>of</strong> the pancreas followed bysuturing to prevent hemorrhage. In this experiment, Senn concluded that the contiguousportion <strong>of</strong> the pancreas continued to secrete digestive juices and that extravasation <strong>of</strong> thepancreatic juice from the distal end <strong>of</strong> the gland into peritoneum did not have adverseconsequences. He also disproved the prevailing notion <strong>of</strong> dead pancreatic tissue being ahighly putrescible substance leading to infection by crushing a segment <strong>of</strong> the pancreaticglands <strong>of</strong> two cats under aseptic conditions. He concluded that the affected part <strong>of</strong> the glandis absorbed and replaced by connective tissue while the rest <strong>of</strong> the gland functions normally.Presciently, he also noted that if the outlet <strong>of</strong> the pancreas is affected, it leads to ductalobstruction from scarring and destruction <strong>of</strong> the gland [010].His other experiments dealt with partial and total pancreatectomy, effects <strong>of</strong> the introduction<strong>of</strong> pancreatic juice into the peritoneal cavity, and the circulation, pancreatic fistulae, andgangrene <strong>of</strong> the pancreas. His observations on total pancreatectomy led him to cautionagainst this operation because it could lead to "damage or necrosis <strong>of</strong> the duodenum." Sennrecommended operative debridement <strong>of</strong> the gangrenous pancreas extrapolating casereports, which noted spontaneous recovery from gangrene <strong>of</strong> the pancreas by sloughing <strong>of</strong>the gland through the duodenum. Indeed, his experiments laid the foundation for futureexperimental work in pancreatic diseases, provided guiding principles for pancreatic surgery,and led him to being recognized as the "father <strong>of</strong> experimental pancreatology" [005].Pancreatitis patophysiologyIn 1896, Hans Chiari invoked a role for pancreatic enzymes in the pathogenesis <strong>of</strong> pancreaticnecrosis and proposed a theory <strong>of</strong> tryptic autodigestion initiated by activation by bile asinitially proposed by Claude Bernard or alternatively by enterokinase as had been suggestedby Nicholas Petrovich Shepovalnikov in 1889 [050]. Gerhard Katsch (1887-1961), in 1939,expanded this concept based on Heidenhein's original 1875 recognition <strong>of</strong> the inactive forms<strong>of</strong> enzymes in pancreatic cells. He described the phenomenon <strong>of</strong> Fermentengleisung(derailment <strong>of</strong> enzymes) whereby circulating activated pancreatic enzymes resulted indamage to the lungs, kidneys, and capillaries. Similar explanations for hypocalcemia, fatnecrosis, capillary permeability, pulmonary surfactant damage, and myocardial depressionwere considered by a variety <strong>of</strong> investigators between 1944 and 1970. None has proved tobe more persuasive than the role <strong>of</strong> superimposed infection that Sir Berkeley Moynihan(1856-1936) had emphasized as early as 1925 [051].Opie’s common channel hypothesisIt was only in the late 19th and the first part <strong>of</strong> the 20th century that the link betweengallstones and pancreatitis was explored. Körte [052] and Oser [053] noted an associationbetween diseases <strong>of</strong> the bile passages, especially cholelithiasis, and lesions <strong>of</strong> the pancreasand felt that inflammation can extend from the bile duct to the pancreas. Lancereaux [054]reported that a gallstone lodged in the common bile duct may occlude the pancreatic ductand produce conditions favorable to the penetration <strong>of</strong> microorganisms into the pancreas.In 1901, Eugene L. Opie (1873-1971), a pathologist at Johns Hopkins Hospital, proposed the"common channel hypothesis" based on his observations at autopsy <strong>of</strong> cases <strong>of</strong> acutehemorrhagic pancreatitis [055-057]. In one case, he noticed a 7-mm stone in the distalcommon bile duct, which was dilated without associated dilatation <strong>of</strong> the pancreatic duct. Heopined that the concretion created a common channel between the bile and pancreatic ductsresulting in reflux <strong>of</strong> bile into the pancreatic duct. To substantiate his hypothesis, heperformed various animal experiments where he infused bile into the pancreatic duct andinduced hemorrhagic pancreatitis. Opie also postulated that stones could affect the opening<strong>of</strong> the pancreatic duct and cause obstruction leading to pancreatitis. The common channel

dogma and its implied presence <strong>of</strong> cholecystitis and cholelithiasis has continued to dominatethinking despite the fact that only a fraction <strong>of</strong> patients with or without pancreatic diseasepossess a common channel and that in autopsies <strong>of</strong> many patients with acute pancreatitis,there are no gallstones obstructing the pancreatic duct. Similarly, animal experiments inwhich anastomosis <strong>of</strong> bile duct to pancreatic duct does not produce pancreatitis have failedto alter the firm belief that bile is in some way responsible for acute pancreatitis [003].Alcoholic pancreatitisIn the late 18th and early 19th century alcohol for the first time was suspected as an etiologicfactor in pancreatitis. Fleischmann, in 1815, described the case <strong>of</strong> a young alcoholic whodeveloped repeated bouts <strong>of</strong> abdominal pain, nausea, and vomiting, an affliction to which heeventually succumbed. At autopsy, he was noted to have a scirrhous pancreas suggestingrecurrent attacks <strong>of</strong> pancreatitis eventually leading to chronic pancreatitis [058]. The term"drunkard's pancreas" was coined by Friedreich in 1887, noting that "general, chronicinterstitial pancreatitis may result from excessive alcoholism" [059]. Symmers [060]performed autopsies on 31 alcoholic patients who died suddenly and noted acutepancreatitis in the absence <strong>of</strong> gallstones. Nearly half a century later, Owens and Howard[061] clearly made the distinction between gallstone and alcoholic pancreatitis and describedpancreatic calcifications in chronic alcoholic pancreatitis.Despite the prevalence <strong>of</strong> alcohol-induced pancreatitis, the pathogenesis remains to beelucidated. Clinical observations <strong>of</strong> chronic pancreatitis in alcoholics were substantiated byexperimental work in dogs by Sarles et al [062] where single exposure to alcohol did littledamage to the gland, but chronic exposure resulted in changes <strong>of</strong> chronic pancreatitis [063].However, further autopsy studies in humans have identified patients who had severe alcoholinducedacute pancreatitis with no underlying features <strong>of</strong> chronic pancreatitis, suggestingthat, at least in a minority <strong>of</strong> patients, alcohol induces acute pancreatitis [064, 065]. Lateranimal studies have demonstrated that alcohol increases the sensitivity <strong>of</strong> the pancreas tohyperstimulation-induced zymogen activation and, consequently, pancreatitis [066, 067].However, an understanding <strong>of</strong> the acute effects <strong>of</strong> alcohol on the acinar cell, the adaptiveresponses to chronic alcohol consumption, and the inciting factors that lead to recurrentacute pancreatitis and factors that predispose certain alcoholics to develop chronicpancreatitis remains limited [068]. In addition, hyperlipidemia, which is frequently present inthe setting <strong>of</strong> alcoholism, may play a part in the pathogenesis <strong>of</strong> alcoholic pancreatitis [069].Biochemical diagnosisUp until the early 20th century, the diagnosis <strong>of</strong> acute pancreatitis was made either clinicallyor at autopsy. In 1908, Julius Wohlgemuth [070] from the Institute <strong>of</strong> Pathology at the RoyalUniversity <strong>of</strong> Berlin introduced a biochemical method for quantitative determination <strong>of</strong> thepancreatic enzyme diastase (amylase) in the serum. In 1929, Robert Elman, from St Louis,reported in 8 patients the correlation between acute epigastric pain secondary to pancreaticdisease and elevation <strong>of</strong> blood amylase and subsequent relief <strong>of</strong> symptoms and acorresponding normalization <strong>of</strong> the serum amylase values thereby establishing the use <strong>of</strong>serum amylase as a marker for pancreatic inflammation [071]. Despite multipleimprovements in technique, measurement <strong>of</strong> serum amylase to diagnose acute pancreatitishas continued to have significant limitations because there are multiple nonpancreaticcauses <strong>of</strong> hyperamylasemia and because <strong>of</strong> the short-lived nature <strong>of</strong> amylase elevations inacute pancreatitis. The ability to measure pancreatic isoamylase [072] and macroamylase[073] has increased the specificity <strong>of</strong> amylase measurement in the diagnosis <strong>of</strong> acutepancreatitis. Determination <strong>of</strong> lipase, a more specific enzyme, was introduced by Cherry andCrandall [074] in 1932, and Comfort [075], in 1935, reported elevations <strong>of</strong> blood lipase in 17<strong>of</strong> 20 patients with acute pancreatic disease. It was soon apparent that although amylase

and lipase were useful diagnostic tests, they had little utility in determining the severity ornatural history <strong>of</strong> an attack <strong>of</strong> acute pancreatitis [076]. The measurement <strong>of</strong> various enzymessuch as trypsin [077, 078], elastase [079], carboxypeptidase [080], and many others hasbeen proposed, but to date, an accurate biochemical determination <strong>of</strong> the diagnosis andseverity <strong>of</strong> acute pancreatitis remains elusive and successive generations <strong>of</strong> physicians havehad to continue to rely on their clinical acumen in diagnosing and managing this disease.Classification <strong>of</strong> acute pancreatitisEarly attempts to classify pancreatitis were primarily descriptive <strong>of</strong> the clinical andpathological features. Classification efforts such as those by Joske, Howard, and Dreiling,and Blumenthal and Probstein focused on the etiology <strong>of</strong> pancreatitis but were not widelyapplicable to clinical practice [081].Beginning in 1974, John HC Ranson and surgical colleagues at New York University MedicalCenter proposed a set <strong>of</strong> objective criteria, which came to be referred to eponymously as theRanson criteria, based on clinical and biochemical variables at presentation and 48 hourslater [082, 083]. These criteria were widely adopted and the initial criteria were modified byvarious investigators, but the primary shortcomings <strong>of</strong> a 48-hour delay and the need forvarious laboratory tests to estimate the clinical course <strong>of</strong> a patient could not be improved[084]. Although later scores were an advance over the Ranson criteria in an objectiveassessment <strong>of</strong> severity and organ dysfunction, clinical applicability has been limited giventhat derivation <strong>of</strong> these scores is relatively complicated.In addition to the various clinical prognostic and severity criteria, there have been efforts toestablish a clinically based classification system for the protean manifestations <strong>of</strong> acutepancreatitis. A classification based on morphology was proposed in 1963 by a panel <strong>of</strong>experts who met in Marseille, and they primarily distinguished attacks <strong>of</strong> acute pancreatitisfrom chronic pancreatitis [085]. This classification was revised twice thereafter, but the focus<strong>of</strong> the changes was on classifying the various forms <strong>of</strong> chronic pancreatitis [086]. The firstmajor effort to classify the various manifestations and outcomes <strong>of</strong> acute pancreatitis was theAtlanta classification proposed at an international symposium [087] in 1992. Criteria wereproposed for severe acute pancreatitis, and these incorporated organ failure as a centraldeterminant underscoring the improved understanding <strong>of</strong> the systemic burden <strong>of</strong> acutepancreatitis. Definitions were also proposed for interstitial pancreatitis, necrotizingpancreatitis, pseudocyst, and infected pancreatic necrosis.The rapid advances in contrast-enhanced computed tomography (CT) have been critical inevaluating pancreatic necrosis and peripancreatic complications. In 1985, a grading systembased on CT appearance <strong>of</strong> the pancreas and peripancreatic fluid collections was proposedby Balthazar et al [088] from John Ranson's group at the New York University MedicalCenter, and this remains the only widely applied radiologic grading system to date.Attempts to treat acute pancreatitisThe limited recognition and understanding <strong>of</strong> pancreatic diseases up until the late 19thcentury meant that various empiric remedies were used in the treatment <strong>of</strong> these diseases.In his treatise on pancreatic diseases published in 1835, JJ Bigsby [019] noted that"inflammatory diseases <strong>of</strong> this organ do not run their course rapidly" and recommendedlimited bleeding to be achieved by the placement <strong>of</strong> a "dozen leeches to the abdominalparietes immediately over the seat <strong>of</strong> the pancreas." He advised against the use <strong>of</strong>stimulants such as mercury, noting somewhat presciently that "if the secretion <strong>of</strong> the inflamedorgan be increased, while the canal for its discharge is closed up, nothing but mischief canresult."

In the late 19th century, exploratory laparotomy gained momentum both to make a diagnosis<strong>of</strong> acute pancreatitis and to drain pancreatic abscesses and, in some instances, debridenecrotic tissue. Proponents <strong>of</strong> early surgical intervention including Senn, Körte, andMoynihan, although during the same period, were no less authorities than Fitz and Mikulicz,advocated conservative management [003, 089].The fervor for early surgical intervention was reversed after Gerhard Katsch’s (1887-1961)report, that during World War I and, subsequently, thereafter, that the number <strong>of</strong> patients withacute pancreatitis declined, and he attributed this to the starvation prevalent around this time[003]. The introduction <strong>of</strong> the assay for amylase also led to the recognition <strong>of</strong> milder forms <strong>of</strong>the disease and the spontaneous recovery <strong>of</strong> many patients with acute pancreatitis.Conservative treatment became established after Paxton and Payne reported, in a series <strong>of</strong>more than 300 patients, a mortality rate <strong>of</strong> nearly 45 percent in patients treated surgicallycompared with 23 percent in those patients treated conservatively [090].Beginning in the 1950s, the tide again turned to operative management as a means to treatpatients with severe acute pancreatitis. Both in Europe and in the United States, pancreaticresection was routinely performed early in the course <strong>of</strong> patients with severe acutepancreatitis to remove necrotic material despite mortality rates <strong>of</strong> 60-70 percent after suchtreatment. Indeed, in 1963, George Watts, a surgeon in Birmingham, successfully treated apatient experiencing "fulminant pancreatitis" and in shock with a total pancreatectomy.Although this operation initially gained support and was widely used, the appalling mortalityrate soon became evident and gave way to more cautious approaches in the late 1980s[010].The most noteworthy achievements in the treatment <strong>of</strong> acute pancreatitis have been theadvancements in supportive care including nutritional support, intensive care, andmanagement <strong>of</strong> shock and organ failure. The introduction <strong>of</strong> total parenteral nutrition (TPN)by Dudrick et al [091] vastly improved the ability to sustain critically ill patients, and TPNrapidly became a standard approach in patients with severe acute pancreatitis. Morerecently, the focus has shifted to enteral nutrition because there is increasing evidence tosuggest that it is safer, easier, as effective, and less expensive compared with TPN [092].However, the issue <strong>of</strong> "resting the gland" is still to be resolved, and there continues to bedebate about the relative merits <strong>of</strong> nasojejunal versus nasogastric feeding and the use <strong>of</strong>elemental formulas to minimize stimulation <strong>of</strong> the pancreas [010].The history <strong>of</strong> pharmacological approaches to treat acute pancreatitis and its complications iscomposed <strong>of</strong> a litany <strong>of</strong> failed trials dating back to the 1920s starting with the use <strong>of</strong> enzymeinhibitors such as quinine. Other medications that have been studied include aprotinin, whichwas even marketed commercially but eventually shown to have no benefit [093]antifibrinolytics [094], anticholinergics including atropine, H 2 -receptor antagonists, protonpump inhibitors, somatostatin, and octreotide [010]. Of these, somatostatin and octreotidewere extensively studied, but controlled trials have indicated little or no benefit [095, 096].Protease inhibition has also been investigated, and although gabexate mesylate, anantiprotease drug, has shown some promise in decreasing complication rates, clinical use <strong>of</strong>this drug is limited [096].Gallstone pancreatitisThe report <strong>of</strong> Classen et al [097] on elective endoscopic papillotomy and removal <strong>of</strong> commonbile duct stones opened up new frontiers in the treatment <strong>of</strong> gallstone pancreatitis andprovided an alternative to surgery. Safrany and Cotton [098] popularized emergentendoscopic sphincterotomy and stone extraction to treat acute gallstone pancreatitis. The

first randomized trial evaluating the role <strong>of</strong> endoscopic sphincterotomy was performed byNeoptolemos et al [099] and reported an overall reduction in the complication rate in thegroup randomized to endoscopic treatment. Several studies followed, and it graduallybecame clear that not all patients with biliary pancreatitis need emergent endoscopicsphincterotomy, and currently, this approach is advocated for patients with concomitantcholangitis, biliary obstruction, or severe organ dysfunction [010].John BeardThe British developmental biologist John Beard, DSc (1858-1924) is little remembered today.Yet, he made outstanding contributions to the life sciences. Beard deserves to be includedamong the leading biologists <strong>of</strong> the late 19th and early 20th century. He has been hailed as aforerunner <strong>of</strong> the present-day theory <strong>of</strong> the cancer stem cell. He was the first to point to theparallels between cancer and the trophoblastic cells that envelop and nourish the embryo,characterizing cancer as "irresponsible trophoblast." He pointed out that the initiation <strong>of</strong> fetalpancreatic function coincided with a reduction in the invasiveness <strong>of</strong> trophoblast, whichotherwise might progress to clinical cancer (i.e. choriocarcinoma). Based on the abovepropositions, he recommended the therapeutic use <strong>of</strong> pancreatic enzymes in treating cancerand other diseases. This therapy created a worldwide controversy, and although rejected inhis day, persists in the world <strong>of</strong> complementary and alternative medicine today [100].In the early 20th century, advocacy <strong>of</strong> the enzyme therapy <strong>of</strong> cancer was primarily the work<strong>of</strong> one man, John Beard, DSc (1858-1924). He and his collaborators made a determinedeffort to establish this mode <strong>of</strong> therapy, especially in the years 1905 to 1911. Despite a briefflowering <strong>of</strong> international interest, Beard's efforts came to naught. During the 20th century,there was a succession <strong>of</strong> American researchers who continued to investigate this topic. Thisincluded Marshall William McDuffie, MD (1882-1945), Frank LeForest Morse, MD (1876-1953), Franklin Lloyd Shively, MD (1887-1971), and William Donald Kelley (1926-2005). Incentral Europe, India, and other parts <strong>of</strong> the globe, the use <strong>of</strong> pancreatic enzymes as anadjuvant treatment for cancer has become a fairly routine practice, at least among thosedoctors who utilize complementary and alternative medicine (CAM). It is also a wellestablishedmethod for reducing inflammation and mitigating the adverse effects <strong>of</strong> cytotoxictreatment [101].Pancreatic surgeryThe first reliable report <strong>of</strong> pancreatic surgery in man and the cases that followed for the nextyears thereafter were confined to treatment <strong>of</strong> large pancreatic cysts with the usualpreoperative misdiagnosis <strong>of</strong> the underlying disease. Fiedrich Wilhelm Wandesleben, ageneral physician in Stromberg, German, reporter a previous healthy 28 year old male whosuffered blunt trauma to the abdomen in November 1844. The patient seemed to recoverwith the existing treatment, however, developed a palpable abdominal mass in two weeks.On December 4, 1844, an incision was made into the mass through the abdominal wall. Afterinitial evacuation <strong>of</strong> pus, a clear watery substance welled up from the wound. Probingsuggested a narrow channel trackning deep into the body cavity. Over the next 5 monthsclear fluid continued to exit from the wound. The fistulous tract started to close, but thepatient developed malaise and died eventually <strong>of</strong> respiratory failure. Examination <strong>of</strong> theabdominal cavity demonstrated a smooth surfaced cavity within the head <strong>of</strong> pancreas with anarrow tract to the abdominal incision site.Between 1860 and 1880, with the availability <strong>of</strong> ether anesthesia and Lister antisepsis, moreabdominal operations in general and few incidental operations on the pancreas were

performed. In 1880, Carl Thiersch <strong>of</strong> Leipzig, Germany, reported the first possible survivor <strong>of</strong>pancreatic surgery. A 38 year old male after initial operation for a presumed abdominal wallabscess by an unnamed physician, underwent delayed operative drainage <strong>of</strong> 3 liter <strong>of</strong> dark,chocolate-colored fluid. A persistent fistula with drainage <strong>of</strong> clear fluid followed thereafter.Thiersch’s probing and dilatation <strong>of</strong> the fistula demonstrated a tract heading toward theregion <strong>of</strong> the pancreatic tail.The first case <strong>of</strong> chemical diagnosis <strong>of</strong> pancreatic fistula in humans was published byDiedrich Kulenkampff <strong>of</strong> Bremen, Germany. He performed a trocar drainage <strong>of</strong> a presumedecchinococcal cysta <strong>of</strong> the liver in 1881. The resultant persistent fistula caused maceration <strong>of</strong>the skin. Chemical analysis revealed alkaline character with an albumin precipitate onheating. The fluid was able to breakdown starch, protein and fat and in the absence <strong>of</strong> thebile led to the relatively confident diagnosis <strong>of</strong> pancreatic juice.Pancreatic cystsThe resection <strong>of</strong> pancreatic cysts was apparently not considered feasible until Karl vonRokitansky, a gynecologic surgeon in Vienna, attempted a cystectomy in 1881. Duringpartival resection <strong>of</strong> a pancreatic cyst in the lesser sac there was intraoperative disruption <strong>of</strong>transverse colon, spillage <strong>of</strong> fluid into the peritoneal cavity and major hemorrhage. The cystawas eventually removed, but the patient died <strong>of</strong> sepsis ten days later. The autopsy showedthat the cyst originated from the head <strong>of</strong> pancreas.On December 2, 1881, Nathan Bozeman operated on a 41 year old femal admitted toWomen’s Hospital in New York with the presumed diagnosis <strong>of</strong> a large ovarian cyst. Fiveliters <strong>of</strong> light brownish fluid was drained intraoperatively from the cyst. The cyst was found tobe mobile within the abdominal cavity with a pedicle connecting to the tail <strong>of</strong> pancreas. Thepedicle was ligated and the cyst excised. Postoperative pain was controlled with rectaladministration <strong>of</strong> tinctures <strong>of</strong> quinine, beer-juice, opium and brandy. The early postoperativecourse was unremarkable but the long term outcome after discharge is unknown.The world’s first planned pancreatic surgery was performed by Karl Gussenbauer <strong>of</strong> Pragueon December 22, 1882. The patient was a 40 year old male who developed epigastric painand a large palpable mass after extensive consumption <strong>of</strong> alcohol. Air inflation <strong>of</strong> thestomach and colon showed that the tumor was located behind both organs. This observationled Gussenbauer to the assumption that the tumor was likely caused by a pancreatic cysta.Due to the detoriorating condition <strong>of</strong> the patient, Gussenbauer performed marsupialization <strong>of</strong>the cyst wall to the abdominal wall with placement <strong>of</strong> a large drain and packning into thecavity. The pancreatic healed gradually and the patient remained well for at least 8 yearsafter surgery. During his career, Gussenbauer operated on at least three smilar patients withpancreatic cysts.After Gussenbauer’s publication, the number <strong>of</strong> operations for pancreatic cysts increasedrapidly. Kuster was able to collect 13 published cases reported within 5 years afterGussenbauer’s initial presentation. By 1900, there were 149 reported cases which includenot only pseudocysts, but also retention and proliferative cysts. At that time mortality for cystexcision was close to 19 percent and for external marsupialization was 3 percent.Procedures such as cystoduodenostomy by Louis Ombredanne in 1911, cystogastrostomyby Rudolf Jedlicka 1921, cystjejunostomy by Adolf Henle in 1923 (but first reported by OttoHahn in 1927) introduced new standards in pancreatic surgery.First pancreatic resectionsThe first true pancreatic resection in humans was not performed until 1882. Prior to that, only

anecdotal reports <strong>of</strong> pancreatic resection for pancreatic protrusion after penetratingabdominal trauma were reported. Distal pancreatectomy was the first reported anatomicresection <strong>of</strong> pancreatic parenchyma in humans by Friedrich Trendelenburg <strong>of</strong> Bonn,Germany, on July 16, 1882. The patient was a 44 year old female with a giant mass in theleft upper quadrant. Trendelenburg resected the retroperitoneal mass along with thepancreatic tail from which the mass seemed to originate. The operation was complicated bya splenic injury requiring splenectomy. The proximal pancreatic remnant was closed withsuture ligature. Histology revealed a spindel cell carcinoma. The postoperative course wascomplicated by wound infection and malnutrition. The patient insisted on going home butdied there later <strong>of</strong> respiratory failure. By 1910, distal pancreatectomy was reported in anotherfive patients, two <strong>of</strong> who died postoperatively.EnucleationThe first reported enucleation <strong>of</strong> pancreatic mass was performed by Giuseppe Ruggi <strong>of</strong>Bologna on September 4, 1889. The patient was a 50 year female with physical findings <strong>of</strong> alarge, mobile mass in the upper abdomen associated with epigastric disdomfort, constipationand malaise. At operation, ascites as well as a large s<strong>of</strong>t tumor in proximity to the head <strong>of</strong>pancreas was fond. Histology showed an adenocarcinoma with adjacent glandular tissue.Billroth, Codivilla and HalstedtSeveral reports suggest that Theodor Billroth <strong>of</strong> Vienna undertook a presumed totalpancreatectomy in 1884 with good outcome (anectotal by Arthur William Mayo Robson in aspeech given to an international medical Congress in 1990). In June 5, 1885, Billroth alsoperformed excision <strong>of</strong> a large pancreatic cysta originating from the body <strong>of</strong> pancreas, almostcompletely replacing it. Along with resection <strong>of</strong> the atrophic pancreas body, Billroth resectedthe splenic vessels, which was not recognized until after the surgery. The transectedpancreas was not closed. This case represent the first reported true anatomic centralpancreatic resection.A landmark in pancreatic surgery was when Allesandro Codivilla <strong>of</strong> Imola, Italy, performedthe first pancreatoduodenectomy on Februari 9, 1898. Codivilla never published the case,but his successor Bartolo Del Monte did, which was brought to attention by Louis Sauve in1908. Codivilla operated on a 46 year old male who presented with 20 day history <strong>of</strong>epigastric distension and vomiting. On exploration he found a cancer involving stomach andpancreas and did distal gastrectomy, resection <strong>of</strong> portion <strong>of</strong> duodenum with head <strong>of</strong>pancreas and distal bile duct. The common bile duct and distal duodenal stump wereoversewn. Intestinal continuity was established by a Roux-en-Y gastrojejunostomy andcholecystojejunostomy over a Murphy’s buttons. The patient developed steatorrhea and died<strong>of</strong> cachexia 18 days after the operation.On February 14, 1898, William Stewart Halsted undertook the first resection <strong>of</strong> an ampullarytumor in a 60 year old female with a six month history <strong>of</strong> painless jaundice, gallbladderdistension and hepatomegaly. The operation included common bile duct exploration,transduodenal papillectomy with reanastomosis <strong>of</strong> pancreatic and bile duct and tubecholecystectomy. Three months later the patient developed jaundice on removal <strong>of</strong> tubecholecystostomy and cholecystoduodenostomy was done for terminal biliary stenosis.Biliary-enteric anastomosisThe concept <strong>of</strong> bilioenteric drainage was introduced in 1880 when Theodor Billroth’s formerstudent Alexander von Winiwarter performed a cholecystocolostomy which was later revisedto a cholecystojejunostomy. A successful cholecystojejunostomy in a patient with pancreatic

cancer was reported by Nestor Dimitrievic Monastyrski <strong>of</strong> St Petersburg, Russia, in 1987 anda cholecystoduodenostomy by Loui-Felix Terrier <strong>of</strong> Paris, France in 1889. In 1884, acholedochotomy was first attempted by Hermann Kummell <strong>of</strong> Hamburg, Germany, followedby a choldochoduodenostomy by Bernhard Riedel <strong>of</strong> Jena, Germany, in 1888 with fataloutcome in both cases. A successful choledochotomy was performed by New York surgeonRobert Abbe in 1889 and in 1891, Oskar Sprengel <strong>of</strong> Dresden, Germany, published the firstsuccessful choledochoduodenostomy. The first successful Roux-en-Y cholecystojejunostomywas performed by Ambrose Monpr<strong>of</strong>it <strong>of</strong> Angers, France, in 1904 a Roux-en-Ycholedochojejunostomy by Robert Dahl <strong>of</strong> Stockholm, Sweden, in 1908.Managing the pancreatic remnantThe first pancreatic head resection with transaction <strong>of</strong> the pancreatic duct was performed byDomenico Biondi <strong>of</strong> Cagliari, Italy, in 1894. He excised a fibroadenoma from the lower twothirds<strong>of</strong> the head <strong>of</strong> pancreas and reapproximated the duodenum and the pancreaticremnant. The postoperative course was complicated by an early biliary fistula and later by apancreatic fistula which eventually resolved.Pancreatic suturing was not published until 1905, Wien Carl Garre from Königsberg,Preussia, reporter a patient with completed tranaction <strong>of</strong> pancreas from blunt trauma, wherethe fully separated edges <strong>of</strong> the pancreatic halves were reapproximated successfully throughplacement <strong>of</strong> small silk sutures in the pancreatic capsule. The duct was not sutured and theresult was a pancreatic fistula which resolved in two months along with complete recovery,This technigue was applied to a midbody resection by John Finney <strong>of</strong> Baltimore, Maryland, in1909 as well as in the first successful partival pancreatoduodenectomy by Oskar Erhardt <strong>of</strong>Köningsberg in 1907. This was a 32 year old female who had undergone gastrojejunostomyrecently for what was thought to be an unresectable cancer <strong>of</strong> pylorus adherent to a secondmass in the head <strong>of</strong> pancreas. She came back with vomiting and was reexplored on August4, 1907. Oskar Ehrhardt resected the gastric antrum, pylorus, duodenal bulb, part <strong>of</strong> secondpart <strong>of</strong> duodenum and large parts <strong>of</strong> the head <strong>of</strong> pancreas within its capsule. A remnant <strong>of</strong>pancreas was left posterior to a partially transected pancreatic duct. The bile duct wasspared and the edges <strong>of</strong> the pancreatic capsule were reapproximated to cover the pancreaticduct. The postoperative course was complicated by a leak which was reasonably controlled.However, the patient died <strong>of</strong> recurrent disease after five months.In the same year Abel Desjardins <strong>of</strong> Paris published a technique <strong>of</strong> end-to-end double layerinvaginating pancreatojejunostomy smilar to today’s telescoping metod.Kausch and HirschelWalther Kausch applied the technique <strong>of</strong> the Kocher moneuver in pancreatic surgery and didhis first - and only - pancreatoduodenectomy in Berlin in June 15 in 1909 in a 49 year oldpatient with anorexia, weight loss, malnourishment, and jaundice. The operation consisted <strong>of</strong>a loop cholecystojejunostomy with a Braun anastomosis over a Murphy’s button and twomonths later a resection and a two-layer pancreatojejunal anastomosis. The patient had aleak which healed spontaneously, but the patient died nine months later <strong>of</strong> sepsis fromcholangitis.A successful one stage partival pancreaoduodenectomy was performed by Georg Hirschel <strong>of</strong>Heidelberg, Germany, in 1912 for ampullary carcinoma. The patient survived for one year butdied a year later from unknown cause.

Whipple and BraunschweigAllen Oldfather Whipple performed a pylorus-preserving partial pancreatoduoden-ectomy in1935. All pancreatoduodenectomies performed prior to 1937 were nonanatomic resectionsremoving only part <strong>of</strong> the head <strong>of</strong> pancreas and duodenum. On February 11, 1937,Alexander Braunschweig performed a two-stage pylorus-preserving pancreatoduodenectomyfor pancreatic carcinoma at the University <strong>of</strong> Chicago Hospital. This was the first trueanatomic resection with complete removal <strong>of</strong> the pancreatic head to the right <strong>of</strong> the superiormesenteric vein. On March 6, 1950 Allen Whipple operated at New York’s PresbytarianHospital on a patient thought to have carcinoma <strong>of</strong> the antrum <strong>of</strong> stomach. The stomach wasalready divided before it became apparent that the origon <strong>of</strong> the tumor was head <strong>of</strong>pancreas. That operation was most likely the first anatomic one-stage pancreatoduodenectomywith antrectomy and complete removal <strong>of</strong> the duodenum and marks thebeginning <strong>of</strong> modern pancreatic head resection.Rockey and PriestlyA true total pancreatectomy appears to have been first performed by Eugene Rockey <strong>of</strong>Portland, Oregon, on June 22, 1942, but the patient died 15 days later <strong>of</strong> bile peritonits.Three weeks later, on July 15, 1942, James Priestly <strong>of</strong> Rochester, Minnesota, performed atotal pancreatectomy on a 40 year old women who suffered from hypoglycemic episodes. Hecould not find the pancreatic tumor on exploration and therefore made the radical decision toperform a total pancreatectomy for what turned out to be a 1 cm insulinoma. The patientsurvived for 29 years before dying <strong>of</strong> cholangitis.Pancreatic duct drainage in chronic pancreatitis and pancreatic cancerWith the evolution <strong>of</strong> understanding <strong>of</strong> pathophysiology <strong>of</strong> chronic pancreatitis, Goethe Link<strong>of</strong> Indianaplois, Indiana, performed in March 1910 an exploration <strong>of</strong> the pancreatic duct,extracted a pancreatic duct stone and created an external distal tube pancreatostomy with agood long-term outcome. Short segment, loop pancreatojejunostomies stented by a T-tubewas performed by Richard Cattell for patients with pain from an unresectable pancreaticcancer in the 1940s.In 1951, William Longmire performed a caudal pancreatectomy with end-to-endpancreatojejunostomy later popularized by Merlin DuVal in 1954. In 1958, Charles Puestowand William Gillesby <strong>of</strong> Chicago, Illinois, modified this procedure to a caudal pancreatectomywith splenectomy, and extended longitudinal opening <strong>of</strong> the pancreatic duct and Roux-en-Yend-to-side or side-to-side pancreatojejunostomy. In 1960, Phillip Partington and RobertRochelle <strong>of</strong> Cleveland, Ohio, simplified the procedure by eliminating the caudalpancreatectomy and splenectomy. These pancreatic duct drainage procedure procedurespaved the way to the lateral pancreatojejunostomy with limited nonanatomic pancreatic headresection described by Charles Frey in 1987 and the duodenum-preserving partivalpancreatic head resection described by Hans Beger in 1980.Pancreatic transplantationEver since the first transplant in 1967 by Kelly and Lillihei, University <strong>of</strong> Minnesota has beenin forefront. The first pancreas islets autotransplant in the late seventies, successfulpancreas transplant series, livning donor pancreas transplant, living simultaneous kidneypancreas transplants open as well as laparoscopic are some <strong>of</strong> the more recentaccomplishments reported from this center.

Modern pancreatic historyHoward ReberDr. Howard Reber is a world-renowned pancreatologist in the area <strong>of</strong> basic pancreaticphysiology and the management<strong>of</strong> pancreatic diseases. As a 3rd year medical student, hebecame fascinated with both the physiology and function <strong>of</strong> the pancreas, as well as itsdiseases. During my surgical training at the University <strong>of</strong> Pennsylvania, he had the fortune tobe the recipient <strong>of</strong> a NationalInstitutes <strong>of</strong> Health Training Grant administered by the NationalInstitute <strong>of</strong> General Medical Sciences. Dr. Frank Brooks, who was then Chief <strong>of</strong> Gastroenterologyat the University <strong>of</strong> Pennsylvania, arranged a meeting with Dr. Henry Janowitz, agastroenterologist who had done pioneering work in the pancreas at Mt. Sinai Hospital inNew York, late in the summer <strong>of</strong> 1966. He started investigating the role <strong>of</strong> the pancreaticducts in the secretion <strong>of</strong> water and electrolytes by the gland together with Dr. David Dreiling.He then went to the Peter Bent Brigham Hospital in Boston. Over the years, he has devotedhis research efforts to several different problem areas. The first related to studies <strong>of</strong> basicphysiology and the processes <strong>of</strong> secretion, as exemplified by the micropuncture, and later onto both chronic pancreatitis and pancreatic cancer [102].John HowardIn 1942 John Howard as a sophomore student in the University <strong>of</strong> Pennsylvania School <strong>of</strong>Medicine, was studying pathology. A senior student, suggested the study <strong>of</strong> the anatomy <strong>of</strong>the pancreatic ampulla: “Is reflux <strong>of</strong> bile into the pancreatic ducts anatomically possible?” Of150 dissections a common channel’ was found in at least 50 percent (a confirmatory finding).In the early days, pancreatitis was considered by most clinicians to be a single disease. Ofcourse this isn’t true. Like pneumonia or gastroenteritis it consists <strong>of</strong> many diseases. In 1946John Howard an co-worker <strong>review</strong>ed the records <strong>of</strong> all 80 patients with acute pancreatitiswho had been admitted to the University <strong>of</strong> Pennsylvania Hospital in the previous 25 years(1922–1946 inclusive). The hospital mortality rate had been about 30 percent. The diagnosison each patient had been made at laparotomy or autopsy. Although not so classified, allwere idiopathic in that era. Fifty-three (two thirds) <strong>of</strong> the patients had had gallstones, butpancreatitis had not been attributed to the gallstones. Furthermore, <strong>of</strong> those patients havingundergone laparotomy, the majority had had a cholecystostomy regardless <strong>of</strong> the presenceor absence <strong>of</strong> gallstones. Later, Dr. George Jordan, Jr. and John Howard were youngsurgical colleagues at Baylor University in Houston. In systematically <strong>review</strong>ing thepancreatitis patients, the alcoholic patients at the Veterans Administration were found tohave quite a different disease from those nonalcoholic patients at the Charity Hospital. Acutepancreatitis was not a disease. It was clearly a reflection <strong>of</strong> multiple diseases, perhaps <strong>of</strong> ahundred or more! Each differed in its etiology, natural history and essential treatment [103].Katsusuke SatakePr<strong>of</strong>essor Dr Katsusuke Satake died on March 21, 2009, due to lung cancer. Dr Satake wasconsidered by many <strong>of</strong> us as an Ambassador for Pancreatic Research in Japan to theinternational community. He was a pioneering pancreatic investigator and surgeon and aninternational lecturer, writer, and editor. He searched within many Japanese forums foryoung investigators and colleagues to journey with him in his research. Dr Katsusuke Satakewas born in Osaka in 1935. He graduated from medical school at Osaka City University in1962, whereupon he immediately entered a 2-year internship at the US Air Force Hospital inTachikawa, Japan. Dr Satake continued his clinical training and research at the Department<strong>of</strong> Surgery, Osaka City University, and later became the Chief Resident <strong>of</strong> that department.In 1970, he decided to join Dr John M. Howard’s group as a Research Assistant in theDepartment <strong>of</strong> Surgery at Hahneman Medical College in Philadelphia, where he began his

esearch in pancreatology. Dr Satake’s initial research work on acute pancreatitis in dogswas published in Archives <strong>of</strong> Surgery and Annals <strong>of</strong> Surgery. Upon his return to Osaka CityUniversity in 1972, he continued his research in pancreatology by using rat and hamstermodels <strong>of</strong> pancreatic carcinogenesis as well as dog models <strong>of</strong> acute pancreatitis. Dr Satakewas promoted to Assistant Pr<strong>of</strong>essor in 1973, Lecturer in 1979, and subsequently toAssociate Pr<strong>of</strong>essor in 1989. During these highly productive periods <strong>of</strong> research inpancreatology and investigations on the pathophysiology and treatment <strong>of</strong> acute pancreatitis,carcinogenesis, chemoprevention, early detection, and effective treatment <strong>of</strong> pancreaticcancer, he used various technologies, including hormone assays, electron microscopy,hydrogen gas clearance, and tumor markers. In addition, Dr Satake used his vast knowledgeand leadership experience as a parttime faculty member at the Graduate School <strong>of</strong> Medicine,Kyoto University, from 2000 to 2006. He resigned from Osaka City University in 2006 andwas appointed Director <strong>of</strong> Otori Clinic, Sakai, Osaka, Japan [104].

PANCREATIC DEVELOPMENT, EMBRYOLOGY and ANATOMYRegenerative medicine, including cell-replacement strategies, may have an important role inthe treatment <strong>of</strong> type 1 and type 2 diabetes, both <strong>of</strong> which are associated with decreasedislet cell mass. To date, significant progress has been made in deriving insulin-secretingbeta-like cells from human ES (embryonic stem) cells. However, the cells are not fullydifferentiated, and there is a long way to go before they could be used as a replenishablesupply <strong>of</strong> insulin-secreting beta-cells for transplantation. For this reason, adult pancreaticstem cells are seen as an alternative source that could be expanded and differentiated exvivo, or induced to form new islets in situ. In one issue <strong>of</strong> the Biochemical Journal, Mato et al.used drug selection to purify a population <strong>of</strong> stellate cells from explant cultures <strong>of</strong> pancreasfrom lactating rats. The selected cells express some stem-cell markers and can be grown forover 2 years as a fibroblast-like monolayer. When plated on extracellular matrix, along with acocktail <strong>of</strong> growth factors that included insulin, transferrin, selenium and the GLP-1(glucagon-like peptide-1) analogue exendin-4, the cells differentiated into cells thatexpressed many <strong>of</strong> the phenotypic markers characteristic <strong>of</strong> a beta-cell, and exhibited aninsulin-secretory response, albeit weak, to glucose. The ability to purify this cell populationopens up the possibility <strong>of</strong> unravelling the mechanisms that control self-renewal anddifferentiation <strong>of</strong> pancreatic cells that share some <strong>of</strong> the properties <strong>of</strong> stem cells [105].Factors influencing developmentRegenerating gene IPancreatic regenerating gene I (reg I) has been implicated in cellular differentiation. Acinarcells can transdifferentiate into other pancreatic-derived cells, and it was postulated thatchanges in intracellular levels <strong>of</strong> reg I would affect the state <strong>of</strong> differentiation transfectedAR42J cells with a plasmid containing the entire coding sequence <strong>of</strong> reg I and isolatedclones with complementary DNA in sense (SS) or antisense (AS) orientation. It was foundthat in acinar cells, reg I overexpression is linked to acinar cell differentiation, whereasinhibition <strong>of</strong> reg I leads to beta cell and possibly ductal phenotype. Reg I expression in acinarcells is important in maintaining pancreatic cell lineage, and when decreased, cells candedifferentiate and move toward becoming other pancreatic cells [106].Transforming growth factor-beta (TGF-beta)Studies <strong>of</strong> the formation <strong>of</strong> pancreas and liver progenitors have focused on individualinductive signals and cellular responses. Here, it was investigated how bone morphogeneticprotein, transforming growth factor-beta (TGF-beta), and fibroblast growth factor signalingpathways converge on the earliest genes that elicit pancreas and liver induction in mouseembryos. The inductive network was found to be dynamic; it changed within hours. Differentsignals functioned in parallel to induce different early genes, and two permutations <strong>of</strong> signalsinduced liver progenitor domains, which revealed flexibility in cell programming. Also, thespecification <strong>of</strong> pancreas and liver progenitors was restricted by the TGF-beta pathway.These findings may enhance progenitor cell specification from stem cells for biomedicalpurposes and can help explain incomplete programming in stem cell differentiation protocols[107].Islet neogenesis-associated proteinEfforts to cure diabetes are now focused on restoring a physiologically-regulated population<strong>of</strong> insulin-producing cells to the patient. A number <strong>of</strong> animal models <strong>of</strong> beta cell regeneration

have been employed to study the mechanisms <strong>of</strong> the process. Islet neogenesis, theregeneration <strong>of</strong> pancreatic islets from pancreatic stem cells, is arguably the least fraught withbarriers to widespread use as a therapy for diabetes. These animal models have led to thedescription <strong>of</strong> the reg family <strong>of</strong> proteins that appear to be related to islet regeneration. Isletneogenesis-associated protein (INGAP) is an initiator <strong>of</strong> islet neogenesis in animal modelsand a peptide sequence from INGAP carries the biological activity. INGAP peptide has beenshown to stimulate an increase in beta cell mass in mice, rats, hamsters and dogs. INGAP isalso found in the pancreas in human pathological states involving islet neogenesis. Thepeptide has been tested in human clinical trials, with success being reported. The evidencepoints to INGAP as a major factor in stimulating islet neogenesis, and, therefore, may play asignificant therapeutic role in diabetes [108].ConnexinsDiabetes and the related metabolic syndrome are multisystem disorders that result fromimproper interactions between various cell types. Even though the underlying mechanismremains to be fully understood, it is most likely that both the long and the short distancerange cell interactions, which normally ensure the physiologic functioning <strong>of</strong> the pancreas,and its relationships with the insulin-targeted organs, are altered. One <strong>review</strong> focused on theshort-range type <strong>of</strong> interactions that depend on the contact between adjacent cells and,specifically, on the interactions that are dependent on connexins. The widespread distribution<strong>of</strong> these membrane proteins, their multiple modes <strong>of</strong> action, and their interactions withconditions/molecules associated to both the pathogenesis and the treatment <strong>of</strong> the 2 mainforms <strong>of</strong> diabetes and the metabolic syndrome, make connexins an essential part <strong>of</strong> thechain <strong>of</strong> events that leads to metabolic diseases [109].Diphtheria toxin gene A chain (DTA)Cell lineage analysis is critical in understanding the relationship between progenitors anddifferentiated cells as well as the mechanism underlying the process <strong>of</strong> differentiation. Inorder to study the zebrafish endocrine pancreas cell lineage, transgenic expression <strong>of</strong>diphtheria toxin gene A chain (DTA) under two cell type-specific promoters derived from theinsulin (ins) and somatostatin2 (sst2) genes was used to ablate the two types <strong>of</strong> endocrinecells: insulin-producing beta-cells and somatostatin-producing delta-cells, respectively. It wasfound that ablation <strong>of</strong> beta-cells resulted in a reduction <strong>of</strong> not only beta-cells but alsoglucagon-producing alpha-cells; in contrast, delta-cells were largely unaffected. Ablation <strong>of</strong>delta-cells led to reduction <strong>of</strong> all three types <strong>of</strong> endocrine cells: alpha-, beta-, and delta.Interestingly, alpha-cells were more pr<strong>of</strong>oundly affected in both beta- and delta-cell ablationsand were frequently reduced together with beta- and delta-cells. Thus, the currentobservations indicated differential interdependence <strong>of</strong> these three cell lineages. Thedevelopment <strong>of</strong> zebrafish alpha-cells, but not delta-cells, is dependent on beta-cells, whilethe development <strong>of</strong> both alpha- and beta-cells is dependent on delta-cells. In contrast, thedevelopment <strong>of</strong> delta-cells is independent <strong>of</strong> beta-cells [110].Cell-surface markersIt was developed a novel panel <strong>of</strong> cell-surface markers for the isolation and study <strong>of</strong> all majorcell types <strong>of</strong> the human pancreas. Hybridomas were selected after subtractive immunization<strong>of</strong> Balb/C mice with intact or dissociated human islets and assessed for cell-type specificityand cell-surface reactivity by immunohistochemistry and flow cytometry. Antibodies wereidentified by specific binding <strong>of</strong> surface antigens on islet (panendocrine or alpha-specific) andnonislet pancreatic cell subsets (exocrine and duct). These antibodies were used individuallyor in combination to isolate populations <strong>of</strong> alpha, beta, exocrine, or duct cells from primaryhuman pancreas by FACS and to characterize the detailed cell composition <strong>of</strong> human islet

preparations. They were also employed to show that human islet expansion culturesoriginated from nonendocrine cells and that insulin expression levels could be increased toup to 1 percent <strong>of</strong> normal islet cells by subpopulation sorting and overexpression <strong>of</strong> thetranscription factors Pdx-1 and ngn3, an improvement over previous results with this culturesystem. These methods permit the analysis and isolation <strong>of</strong> functionally distinct pancreaticcell populations with potential for cell therapy [111].OxygenBeyond its role as an electron acceptor in aerobic respiration, oxygen is also a key effector <strong>of</strong>many developmental events. The oxygen-sensing machinery and the very fabric <strong>of</strong> cellidentity and function have been shown to be deeply intertwined. Here it was taken a first lookat how oxygen might lie at the crossroads <strong>of</strong> at least two <strong>of</strong> the major molecular pathwaysthat shape pancreatic development. Based on recent evidence and a thorough <strong>review</strong> <strong>of</strong> the<strong>literature</strong>, it was presented a theoretical model whereby evolving oxygen tensions mightchoreograph to a large extent the sequence <strong>of</strong> molecular events resulting in the development<strong>of</strong> the organ. In particular, it was proposed that lower oxygenation prior to the expansion <strong>of</strong>the vasculature may favour HIF (hypoxia inducible factor)-mediated activation <strong>of</strong> Notch andrepression <strong>of</strong> Wnt/beta-catenin signalling, limiting endocrine cell differentiation. With thedevelopment <strong>of</strong> vasculature and improved oxygen delivery to the developing organ, HIFmediatedsupport for Notch signalling may decline while the beta-catenin-directed Wntsignalling is favoured, which would support endocrine cell differentiation and perhapsexocrine cell proliferation/differentiation [112].Thyrotropin-releasing hormoneThyrotropin-releasing hormone (TRH) is expressed in rodent and human adult pancreata andin mouse pancreas during embryonic development. However, expression <strong>of</strong> TRH receptors(TRHRs) in the pancreas is controversial. It was used quantitative reverse transcriptionpolymerasechain reaction to measure TRH and TRHR messenger RNA (mRNA). To studythe effects <strong>of</strong> TRHR expression in a pancreatic progenitor population, it was expressedTRHRs in human islet-derived precursor cells (hIPCs) by infection with adenoviral vectorAdCMVmTRHR. Thyrotropin-releasing hormone receptor signaling was measured as inositolphosphate production and intracellular calcium transients. Thyrotropin-releasing hormonereceptor expression was measured by [3H]methyl-TRH binding. Apoptosis was monitored byrelease <strong>of</strong> cytochrome c from mitochondria. It was shown that TRH mRNA is expressed inhuman fetal and adult pancreata, and that TRHR mRNA is expressed in fetal humanpancreas but not in adult human pancreas. Thyrotropin-releasing hormone receptorsexpressed in hIPCs were shown to signal normally. Most importantly, TRH treatment forseveral days stimulated apoptosis in hIPCs expressing approximately 400,000 TRHRs percell. These findings suggest a possible role for TRH/TRHR signaling in pancreatic precursorsto promote programmed cell death, a normal constituent <strong>of</strong> morphogenesis during embryonicdevelopment in humans [113].Pancreatic anatomy and malformationsEctopic pancreasTo describe the computed tomographic (CT) findings <strong>of</strong> ectopic pancreas and to identify thefeatures that differentiate it from other similarly manifesting gastric submucosal tumors suchas gastrointestinal stromal tumor (GIST) and leiomyoma, which are the most commongastrointestinal submucosal tumors a retrospective study investigated CT images <strong>of</strong>pathologically proved ectopic pancreases (n=14), GISTs (n=33), and leiomyomas (n=7) in

the stomach and duodenum. Analysis <strong>of</strong> the CT findings included evaluation <strong>of</strong> the location,contour, growth pattern, border, enhancement pattern, and enhancement grade <strong>of</strong> the tumor,as well as the presence <strong>of</strong> surface dimpling, prominent enhancement <strong>of</strong> overlying mucosa,and low intralesional attenuation. The attenuation <strong>of</strong> each lesion, the long diameter (LD), theshort diameter (SD), and the LD/SD ratio were measured. The typical location (prepyloricantrum and duodenum), endoluminal growth pattern, ill-defined border, prominentenhancement <strong>of</strong> overlying mucosa, and an LD/SD ratio <strong>of</strong> greater than 1.4 were found to besignificant for differentiating ectopic pancreas from other tumors. When at least two <strong>of</strong> thesefive criteria were used in combination, the sensitivity and specificity for diagnosing ectopicpancreas were 100 percent (14 <strong>of</strong> 14) and 83 percent (33 <strong>of</strong> 40), respectively. When four <strong>of</strong>these criteria were used, a sensitivity <strong>of</strong> 43 percent and a specificity <strong>of</strong> 100 percent wereachieved [114].Ectopic pancreatic tissue within a duodenal diverticulum has not been previously describedin the English-language <strong>literature</strong>. It was reported a case <strong>of</strong> a 52-year-old woman whopresented with a perforated duodenal diverticulum after upper endoscopy. Operativeresection and repair <strong>of</strong> the perforated diverticulum was performed, and, on microscopicexamination, ectopic pancreatic tissue was found within the diverticulum [115].Circumportal annulareThere have been 6 cases <strong>of</strong> circumportal pancreas reported, and 2 <strong>of</strong> them had the mainpancreatic duct in a retroportal dorsal portion. This extremely uncommon anomaly isasymptomatic and therefore incidentally discovered. For the surgeon, it is important todiscover this during pancreatic resection so the pancreatic duct can be closed and fistula isavoided. It was now describe a third case where a circumportal pancreas had its mainpancreatic duct passing under the portal vein. The duct was identified and ligated. A fistuladid not occur [116].Pancreas annulareAnnular pancreas is a rare embryonal abnormality. Its manifestation in adulthood is <strong>of</strong>tenpinpointed with a substantial delay, which is most <strong>of</strong>ten attributed to pancreatitis, biliarypathology or dyspepsia. It was presented a case <strong>of</strong> a 28-year-old woman who hadexacerbating symptoms <strong>of</strong> high bowel obstruction from 20th week <strong>of</strong> pregnancy, progressingafter premature delivery. Diagnostic work-up revealed partial annular pancreas compressingthe duodenum. Despite attempts <strong>of</strong> conservative treatment, her state deteriorated to such anextent that surgery was indicated and gastrojejunal bypass created. Her postoperativerecovery was uneventful. In cases in which symptoms <strong>of</strong> high bowel obstruction in pregnancypersist and prostration occurs, we suggest close monitoring and a more thorough diagnosticapproach. The question remains whether annular pancreas presents a cause <strong>of</strong> pathologicfindings, a c<strong>of</strong>actor, or a mere accidental diagnosis in the development <strong>of</strong> superposedpathologies [117].The purpose <strong>of</strong> one study was to <strong>review</strong> the CT, MRI, and ERCP findings <strong>of</strong> annularpancreas in adults. A search <strong>of</strong> the radiology and ERCP databases at one institution forcases <strong>of</strong> annular pancreas in adults yielded the records <strong>of</strong> 42 patients who underwent 29ERCP, 22 CT, and 13 MRI examinations. Nine <strong>of</strong> 24 (38 %) cases <strong>of</strong> annular pancreasdetected with CT or MRI did not have a radiologically complete ring <strong>of</strong> pancreatic tissuesurrounding the second part <strong>of</strong> the duodenum. Three <strong>of</strong> the nine patients (33 %) withradiologically incomplete annular pancreas and six <strong>of</strong> the 15 patients (40 %) with completeannular pancreas had gastric outlet obstruction. The presence <strong>of</strong> pancreatic tissueposterolateral to the second part <strong>of</strong> the duodenum had a high sensitivity (92 %) andspecificity (100 %) for the presence <strong>of</strong> annular pancreas. The rates <strong>of</strong> pancreas divisum (37%) and chronic pancreatitis (48 %) were high in this cohort. It was concluded that annular

pancreas can be diagnosed without the finding <strong>of</strong> a radiologically complete ring <strong>of</strong> pancreatictissue. A crocodile jaw configuration <strong>of</strong> pancreatic tissue is suggestive <strong>of</strong> the presence <strong>of</strong>annular pancreas [118].It was reported a rare case <strong>of</strong> a neonate with a duodenal stenosis due to the contemporarypresence <strong>of</strong> an annular pancreas and wind sock web [119].Polyspleni and short pancreasThe most common form <strong>of</strong> splenic anomaly with a concurrent short pancreas is polysplenia,which has been described in various studies in the radiological <strong>literature</strong>. However, splenicduplication has never been reported. It was now reported a case <strong>of</strong> splenic duplicationassociated with a short pancreas and pre-duodenal portal vein. This extremely rare case <strong>of</strong>splenic anomaly shows unique multidetector CT findings that are distinguishable from asplenic lobulation or cleft [120].Double common bile ductIt was presented a case <strong>of</strong> double common bile duct. Specifically, it was found a commonbile duct that was divided into two distinct ducts, one the main and the other the accessoryduct, during its course downwards. The two bile ducts had a parallel course emerging fromthe common bile duct after its formation and reuniting just above the head <strong>of</strong> the pancreas.Finally, they drained into the second portion <strong>of</strong> the duodenum at the site <strong>of</strong> major duodenalpapilla. This anomaly is <strong>of</strong> great importance because the duplication <strong>of</strong> the common bile ductcan lead to severe intraoperative injury to one <strong>of</strong> the two common bile ducts, which can bemistaken for the cystic duct and be ligated [121].Anomal pancreatic duct systemThe formation <strong>of</strong> the pancreatic duct system is the result <strong>of</strong> the fusion <strong>of</strong> 2 embryonic buds,the ventral and dorsal primordia. Frequently, this fusion process is localized in the pancreatichead; variations, however, may account for the structural diversity <strong>of</strong> the duct system.Pancreatic duct anomalies and diversity <strong>of</strong> body and tail are thought to be casuistic. Ninetynineconsecutive adult autopsies with reference to macroscopic anomalies in the distal part<strong>of</strong> the gland were evaluated. Pancreatograms were performed after large duodenal papillacannulation. Ducts parallel to gland axis with a diameter <strong>of</strong> at least one third <strong>of</strong> the mainpancreatic duct at the junction point and aberrant duct with different shapes or abnormalthird-degree ductuli architecture were noted. The study revealed a 10 percent frequency <strong>of</strong>main pancreatic duct diversity in the pancreatic corpus and tail. Eleven atypical ducts werevisible, 9 cranially and 2 caudally from the main pancreatic duct [122].Agenesia <strong>of</strong> the dorsal pancreatic neck, body and tailMorphogenesis <strong>of</strong> the pancreas is a complex process; nevertheless, congenital anomaliesare rare. At embryogenesis, the pancreas develops from the endoderm-lined dorsal andventral buds <strong>of</strong> the duodenum. The ventral bud gives rise to the lower head and uncinateprocess <strong>of</strong> the pancreas; whereas, the dorsal bud gives rise to the upper head, isthmus,body, and tail <strong>of</strong> the pancreas. Rarely, developmental failure <strong>of</strong> the dorsal pancreatic bud atembryogenesis results in the agenesis <strong>of</strong> the dorsal pancreas-neck, body, and tail. Evenrarer is the association <strong>of</strong> pancreatic tumors with agenesis <strong>of</strong> the dorsal pancreas. In additionto citing one case, it was provided a comprehensive <strong>review</strong> on agenesis <strong>of</strong> the dorsalpancreas and its association with pancreatic tumors [123].

Fatty pancreasTo investigate the clinical implications <strong>of</strong> lipid deposition in the pancreas (fatty pancreas) 293patients who had undergone abdominal computed tomography (CT) and sonography werestudied. Fatty pancreas was diagnosed by sonographic findings and subdivided into mild,moderate, and severe fatty pancreas groups comparing to the retroperitoneal fatechogenicity. Fatty pancreas was associated with higher levels for visceral fat, waistcircumference, aspartate aminotransferase (AST), alanine aminotransferase (ALT), totalcholesterol, triglyceride, high density lipoprotein, free fatty acid, gamma-GTP, insulin, and thehomeostasis model assessment <strong>of</strong> insulin resistance (HOMA-IR) than the control group (P

PANCREATIC PHYSIOLOGYSphincter <strong>of</strong> OddiThe most common functional disorder <strong>of</strong> the biliary tract and pancreas relates to the activity<strong>of</strong> the Sphincter <strong>of</strong> Oddi. The Sphincter <strong>of</strong> Oddi is a small smooth muscle sphincterstrategically placed at the junction <strong>of</strong> the bile duct, pancreatic duct, and duodenum. Thesphincter controls flow <strong>of</strong> bile and pancreatic juices into the duodenum and prevents reflux <strong>of</strong>duodenal content into the ducts. Disorder in its motility is called Sphincter <strong>of</strong> Oddidysfunction. Clinically this presents either with recurrent abdominal biliary type pain orepisodes <strong>of</strong> recurrent pancreatitis. Manometry may identify the motility abnormalities, themost clinically significant being an abnormally elevated basal pressure. The most effectivetreatment once an abnormal basal pressure is identified is division <strong>of</strong> the sphincter. This isassociated with good long-term results [126].Modulatory drugs <strong>of</strong> gastrointestinal (GI) motility are a possibility for use to relieve the mainclinical presentation <strong>of</strong> sphincter <strong>of</strong> Oddi (SO) dysfunctions which are not easily distinguishedfrom those occurring in high prevalence functional GI disorders. The aim <strong>of</strong> one study was toinvestigate the effects <strong>of</strong> GI motility modulators including pinaverium, domperidone,trimebutine, and tegaserod on the contractile activity <strong>of</strong> SO stimulated by carbachol in therabbit. The contraction responses precontracted by carbachol (0.1 µM) <strong>of</strong> in vitro rabbit SOrings were evaluated before and after the addition <strong>of</strong> a series concentration (10 -13 to 10 -3 M) <strong>of</strong>pinaverium, domperidone, trimebutine, and tegaserod. Pinaverium induced a concentrationdependentrelaxation <strong>of</strong> isolated SO rings precontracted with carbachol (0.1 µM). Tegaseroddid not significantly effect SO motility, but domperidone seemed to stimulate SOcontractions. At low doses (10 -13 to 10 -7 M), trimebutine stimulated SO contraction; however,high doses (10 -6 to 10 -3 M) <strong>of</strong> trimebutine inhibited SO motility. It was concluded thatpinaverium totally inhibits contractions induced by carbachol and tegaserod has no effect oncarbachol-induced contractions. Domperidone stimulates contractions induced by carbachol.Trimebutine could either stimulate or inhibit SO contractions depending on its dosage [127].FeedingThe complex control <strong>of</strong> food intake and energy metabolism in mammals relies on the ability<strong>of</strong> the brain to integrate multiple signals indicating the nutritional state and the energy level <strong>of</strong>the organism and to produce appropriate responses in terms <strong>of</strong> food intake, energyexpenditure, and metabolic activity. Central regulation <strong>of</strong> feeding is organized as a long-loopmechanism involving humoral signals and afferent neuronal pathways to the brain,processing in hypothalamic neuronal circuits, and descending commands using vagal andspinal neurons. Sensor mechanisms or receptors sensitive to glucose and fatty acidmetabolism, neuropeptide and cannabinoid receptors, as well as neurotransmitters andneuromodulators synthesized and secreted within the brain itself are all signals integrated inthe hypothalamus, which therefore functions as an integrator <strong>of</strong> signals from central andperipheral structures. Homeostatic feedback mechanisms involving afferent neuroendocrineinputs from peripheral organs, like adipose tissue, gut, stomach, endocrine pancreas,adrenal, muscle, and liver, to hypothalamic sites thus contribute to the maintenance <strong>of</strong>normal feeding behavior and energy balance. In addition to transcriptional events, peripheralhormones may also alter firing and/or connection (synaptology) <strong>of</strong> hypothalamic neuronalnetworks in order to modulate food intake. Moreover, intracellular energy sensing andsubsequent biochemical adaptations, including an increase in AMP-activated protein kinaseactivity, occur in hypothalamic neurons. Understanding the regulation <strong>of</strong> appetite is clearly amajor research effort but also seems promising for the development <strong>of</strong> novel therapeuticstrategies for obesity [128].

Studies <strong>of</strong> pancreatic duct secretionThe pancreatic ductal tree conveys enzymatic acinar products to the duodenum and secretesthe fluid and ionic components <strong>of</strong> pancreatic juice. The physiology <strong>of</strong> pancreatic duct cellshas been widely studied, but many questions are still unanswered concerning theirmechanisms <strong>of</strong> ionic transport. Differences in the transport mechanisms operating in theductal epithelium has been described both among different species and in the differentregions <strong>of</strong> the ductal tree. In a <strong>review</strong> it was summarized the methods developed to studypancreatic duct secretion both in vivo and in vitro, the different mechanisms <strong>of</strong> ionic transportthat have been reported to date in the basolateral and luminal membranes <strong>of</strong> pancreaticductal cells and the regulation <strong>of</strong> pancreatic duct secretion by nervous, endocrine andparacrine influences [129].CholecystokininCholecystokinin (CCK)-dependent exocrine pancreatic regulation seems to involve differentpathways in different species. The aims in one study were to explore the enteropancreaticreflex in the CCK-mediated regulation <strong>of</strong> the exocrine pancreas and to evaluate a possibleinvolvement <strong>of</strong> this reflex in the endocrine insulin release. In anesthetized pigs, CCK-33 inincreasing doses (4-130 pmol/kg per 10 min) was infused locally to the gastroduodenalartery, or systemically via the jugular vein. Also, a low CCK-33 dose (13 pmol/kg) wasinjected to the duodenum/antrum area before and after a bilateral truncal vagotomy.Cholecystokinin-33 in the physiological dose range 4 to 32 pmol/kg per 10 min increasedprotein and trypsin outputs after local infusion to the antral-duodenal area, whereas it had noeffect after systemic infusion. Cholecystokinin-33 in the pharmacological dose range 64 to130 pmol/kg per 10 min further increased the secretion after both local and systemicinfusions. Only CCK-33 infusions in the pharmacological dose range were able to elevate theplasma insulin levels. Vagotomy had no effect on CCK-33-mediated stimulation <strong>of</strong> theenzyme release, whereas it had a significant effect on the plasma insulin level [130].Pancreatic function in the elderlyAmong the various studies <strong>of</strong> pancreatic function in the elderly published so far, none havedealt with subjects over 90 years <strong>of</strong> age. The aim <strong>of</strong> one study was to examine pancreaticfunction in healthy individuals over 90 years old. Sixty-eight healthy noninstitutionalizedelderly persons, aged 91-104 years, with a mean age <strong>of</strong> 95 years, and 63 younger controlswere studied. Pancreatic function was studied by determining fecal elastase 1 concentration.In addition to this test, it was also measured serum amylase, pancreatic isoamylase andlipase in 53 <strong>of</strong> the 68 elderly subjects. All but 1 <strong>of</strong> the 68 elderly subjects had normal elastase1 values; the one who did not had a value slightly below normal. No significant differencewith controls was found. Serum pancreatic enzymes were normal in almost all <strong>of</strong> the 53elderly studied; 3 had a mild elevation only <strong>of</strong> amylase and 1 had a persistent elevation <strong>of</strong>amylase, pancreatic isoamylase and lipase. It was concluded that in subjects over 90 years<strong>of</strong> age, exocrine pancreatic function continues to be normal; if an impairment occurs, it ismild and not significant for digestion <strong>of</strong> food. In addition, serum pancreatic enzymes remainwithin normal limits in the vast majority <strong>of</strong> cases [131].Ethanol metabolismTo determine tissue-specific effects <strong>of</strong> alcohol on fatty acid synthesis and distribution asrelated to functional changes in triglyceride transport and membrane formation tissue fatty

acid pr<strong>of</strong>ile and de novo lipogenesis were determined in adult male Wistar rats after 5 weeks<strong>of</strong> ethanol feeding using deuterated water and gas chromatography/mass spectrometry. Liverand pancreas fatty acid pr<strong>of</strong>iles and new synthesis fractions were compared with those fromcontrol rats on an isocaloric diet. Fatty acid ratios in the liver indicated that there was a morethan 2-fold accumulation <strong>of</strong> stearate to that <strong>of</strong> palmitate, with an apparent decrease in oleatecontent. On the other hand, in the pancreas, there was a 17 percent decrease in thestearate-to-palmitate ratio, whereas the oleate-to-palmitate ratio was increased by 30percent. The fractions <strong>of</strong> deuterium-labeled palmitate and stearate were substantiallyreduced in the liver and pancreas <strong>of</strong> the alcohol-treated animals. Deuterium labeling <strong>of</strong> oleatewas reduced in the liver but not in the pancreas, consistent with the oleate/stearate ratios inthese tissues. It was concluded that long-term alcohol exposure results in opposite effects onthe desaturase activity in the liver and pancreas, limiting fatty acid transport in the liver butpromoting the exocrine function <strong>of</strong> the pancreas [132].IAPPThe red wine compound resveratrol can effectively inhibit the formation <strong>of</strong> amyloidpolypeptide, IAPP, amyloid that is found in type II diabetes. In vitro inhibition results do notdepend on the antioxidant activity <strong>of</strong> resveratrol. Further, the markedly enhanced cell survivalin the presence <strong>of</strong> resveratrol also indicates that the small oligomeric structures that areobserved during beta-sheet formation are not toxic and could be <strong>of</strong>f-pathway assemblyprodukts [133].Glucose metabolismFor type 2 diabetes mellitus treatments based on the incretin hormones provide a novelapproach to address some components <strong>of</strong> the complex pathophysiology <strong>of</strong> type 2 diabetes.The purpose <strong>of</strong> one <strong>review</strong> was to elucidate the science <strong>of</strong> the incretin hormones anddescribe the incretin effect and its regulatory role in beta-cell function, insulin secretion, andglucose metabolism. The key endogenous hormones <strong>of</strong> incretin system are glucosedependentinsulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a keyenzymatic regulator <strong>of</strong> these hormones is dipeptidyl peptidase-4, which rapidlyinactivates/degrades the incretin hormones. The roles <strong>of</strong> the incretin hormones in theregulation <strong>of</strong> glucose metabolism and other related physiologic processes such as gutmotility and food intake are disturbed in type 2 diabetes. These disturbances – defects in theincretin system – contribute to the pathophysiology <strong>of</strong> type 2 diabetes in manifold ways.Consequently, therapies designed to address impairments to the effects <strong>of</strong> the incretinhormones have the potential to improve glucose regulation and other abnormalities (e.g.weight gain, loss <strong>of</strong> beta-cell function) associated with type 2 diabetes [134].Progressive loss <strong>of</strong> beta-cell function is a pathophysiologic hallmark <strong>of</strong> type 2 diabetes.Recent science has elaborated on the role <strong>of</strong> the incretin hormones on beta-cell function andinsulin secretion, as well as the role that incretin-based pharmacotherapies may have onglycemic control and beta-cell function, possibly altering the progressive loss <strong>of</strong> beta-cellfunction and possibly reversing/halting disease progression. However, incretin-basedtherapies may also have benefits extending beyond glycemic control and insulin secretion. Inone <strong>review</strong> it was examined some <strong>of</strong> those "beyond-glycemic" benefits, includingpresentation <strong>of</strong> data on weight reduction, blood pressure lowering, beneficial changes in thelipid pr<strong>of</strong>ile, and improvements in myocardial and endothelial function [135].

Diabetic overviewTo provide an overview <strong>of</strong> the disease burden and current strategies in the treatment <strong>of</strong>patients with type 2 diabetes a Medline search <strong>of</strong> all relevant clinical and <strong>review</strong> articles wasdone. The prevalence <strong>of</strong> diabetes in the United States has reached epidemic proportionswith the total diagnosed and undiagnosed cases among people aged 20 years or olderestimated at 13 percent, and it continues to rise at an alarming rate. This upsurge has beenparalleled by an increase in rates <strong>of</strong> obesity. Type 2 diabetes accounts for up to 95 percent<strong>of</strong> diabetes cases and is <strong>of</strong>ten comorbid with hypertension and dyslipidemia. It wasconcluded that tight glycemic control is necessary for the management <strong>of</strong> type 2 diabetes,but progressive deterioration <strong>of</strong> beta-cell function can lead to a loss <strong>of</strong> glycemic control. Oralantidiabetes drugs and insulin are effective but do not always correct the associatedmetabolic and glucoregulatory dysfunctions, and hypoglycemia and weight gain are commonadverse effects <strong>of</strong> these agents. A clear need exists for aggressive therapeutic optionsparticularlyincretin-based agents-that can be combined with existing agents to preservebeta-cell function and halt the progression <strong>of</strong> type 2 diabetes [136].Incretin mimeticsAs a consequence <strong>of</strong> excess abdominal adiposity and genetic predisposition, type 2 diabetesis a progressive disease, <strong>of</strong>ten diagnosed after metabolic dysfunction has taken hold <strong>of</strong>multiple organ systems. Insulin deficiency, insulin resistance and impaired glucosehomeostasis resulting from beta-cell dysfunction characterize the disease. Current treatmentgoals are <strong>of</strong>ten unmet due to insufficient treatment modalities. Even when combined, thesetreatment modalities are frequently limited by safety, tolerability, weight gain, edema andgastrointestinal intolerance. Recently, new therapeutic classes have become available fortreatment. A <strong>review</strong> will examine the new therapeutic classes <strong>of</strong> incretin mimetics andenhancers in the treatment <strong>of</strong> type 2 diabetes [137].A PubMed search was conducted for the years 2000-2009, using as keywords the names <strong>of</strong>glucagon-like peptide-1 (GLP-1) receptor agonists (exenatide and liraglutide) and dipeptidylpeptidase-4 (DPP-4) inhibitors (sitagliptin, alogliptin, and saxagliptin). The author includedrandomized controlled trials <strong>of</strong> incretin therapies that were published in English and enrolled+100 participants. A total <strong>of</strong> 27 randomized controlled studies <strong>of</strong> incretin therapy wereidentified and included in the <strong>review</strong>. GLP-1 receptor agonists and DPP-4 inhibitors wereevaluated at different points in the diabetes treatment spectrum, i.e. added to diet andexercise alone (monotherapy) or added to oral antihyperglycemic regimens (combinationtherapy). In addition to decreasing glycemia in type 2 diabetes, incretin therapies mayimprove other important parameters, including beta-cell function, blood pressure, and lipidlevels, with a low risk for hypoglycemia. A comparison <strong>of</strong> the study data differentiates theclinical pr<strong>of</strong>iles <strong>of</strong> the GLP-1 receptor agonists, which are associated with weight loss, andDPP-4 inhibitors, which are weight neutral, as well as the individual agents within each class[138].Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that isalmost certain to worsen. Current therapies, which address glycemia and insulin resistance,have not adequately addressed the complications and treatment failures associated with thisdisease. New treatments based on the incretin hormones provide a novel approach toaddress some components <strong>of</strong> the complex pathophysiology <strong>of</strong> type 2 diabetes. The purpose<strong>of</strong> one <strong>review</strong> was to elucidate the science <strong>of</strong> the incretin hormones and describe the incretineffect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism.The key endogenous hormones <strong>of</strong> incretin system are glucose-dependent insulinotropicpolypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator <strong>of</strong> thesehormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin

hormones. The roles <strong>of</strong> the incretin hormones in the regulation <strong>of</strong> glucose metabolism andother related physiologic processes such as gut motility and food intake are disturbed in type2 diabetes. These disturbances – defects in the incretin system – contribute to thepathophysiology <strong>of</strong> type 2 diabetes in manifold ways. Consequently, therapies designed toaddress impairments to the effects <strong>of</strong> the incretin hormones have the potential to improveglucose regulation and other abnormalities (e.g. weight gain, loss <strong>of</strong> beta-cell function)associated with type 2 diabetes [139].Impaired insulin secretion plays a major role in the pathogenesis <strong>of</strong> type 2 diabetes mellitus,and progressive loss <strong>of</strong> beta-cell function is a pathophysiologic hallmark <strong>of</strong> type 2 diabetes.Recent science has elaborated on the role <strong>of</strong> the incretin hormones on beta-cell function andinsulin secretion, as well as the role that incretin-based pharmacotherapies may have onglycemic control and beta-cell function, possibly altering the progressive loss <strong>of</strong> beta-cellfunction and possibly reversing/halting disease progression. However, incretin-basedtherapies may also have benefits extending beyond glycemic control and insulin secretion. Inone <strong>review</strong> it wasd examine some <strong>of</strong> those "beyond-glycemic" benefits, includingpresentation <strong>of</strong> data on weight reduction, blood pressure lowering, beneficial changes in thelipid pr<strong>of</strong>ile, and improvements in myocardial and endothelial function [140].Stem cell therapyWith the already heightened demand placed on organ donation, stem cell therapy hasbecome a tantalizing idea to provide glucose-responsive insulin-producing cells to Type 1diabetic patients as an alternative to islet transplantation. Multiple groups have developedvaried approaches to create a population <strong>of</strong> cells with the appropriate characteristics. Bothadult and embryonic stem cells have received an enormous amount <strong>of</strong> attention as possiblesources <strong>of</strong> insulin-producing cells. Although adult stem cells lack the pluripotent nature <strong>of</strong>their embryonic counterparts, they appear to avoid the ethical debate that has centredaround the latter. This may limit the eventual application <strong>of</strong> embryonic stem cells, which havealready shown promise in early mouse models. One must also consider the potential <strong>of</strong> stemcells to form teratomas, a complication which would prove devastating in an immunologicallycompromised transplant recipient. One <strong>review</strong> looked at the progress to date in both theadult and embryonic stem cells fields as potential treatments for diabetes. It was alsoconsider some <strong>of</strong> the limitations <strong>of</strong> stem cell therapy and the potential complications that maydevelop with their use [141].

HISTOPATHOLOGYIn type 1 autoimmune diabetes there is a selective destruction <strong>of</strong> insulin-secreting beta cells.Around the time <strong>of</strong> clinical presentation, insulitis, a chronic inflammatory infiltrate <strong>of</strong> the isletsaffecting primarily insulin containing islets, is present in the majority <strong>of</strong> cases. Theinflammatory infiltrate consists primarily <strong>of</strong> T lymphocytes; CD8 cells outnumber CD4 cells,there are fewer B lymphocytes and macrophages are relatively scarce. beta cell death mayinvolve the Fas apoptotic pathway since they have been shown to express Fas, infiltrating Tlymphocytes express Fas-L and apoptotic beta cells have been described. Hyperexpression<strong>of</strong> class I MHC by all the endocrine cells in many insulin-containing islets is a well recognizedphenomenon, characteristic <strong>of</strong> the disease. It has been argued that this is an earlier eventthan insulitis within a given islet and appears to be due to secretion <strong>of</strong> interferon alpha bybeta cells within that islet. A recent study has found evidence <strong>of</strong> Coxsackie virus infection inbeta cells in three out <strong>of</strong> six pancreases <strong>of</strong> patients with recent-onset type 1 diabetes.Coxsackie viruses are known to induce interferon alpha secretion by beta cells and this couldinitiate the sequence <strong>of</strong> events that culminates in their autoimmune destruktion [142].Transplanting pancreatic isletsThe isolation <strong>of</strong> islets from the human pancreas critically depends on an efficient enzymeblend. Previous studies have solely focused on the presence <strong>of</strong> collagenase and neutralprotease/thermolysin. Despite improved characterization <strong>of</strong> these components, the lot-relatedvariability in efficacy still persists suggesting that additional so far disregarded enzymes arerequired for efficient islet cleavage. Varying activities <strong>of</strong> a tryptic-like enzyme were nowidentified within collagenase NB1 lots, which were selected according to a matched ratiobetween tryptic-like and collagenase activity (TLA-ratio). Rat and human pancreata wereprocessed with current standard procedures. Increasing the TLA-ratio from 1.3 to 10 percentreduced pancreas dissociation time in rats by 50 percent without affecting islet yield, viability,or posttransplant function in diabetic nude mice. Enhancing the TLA-ratio from 1.3 to 12.6percent for human pancreas processing resulted in a significant reduction <strong>of</strong> recirculationtime and increased incrementally human islet yield without affecting purity, in vitro function orrecovery after culture. Optimized pancreas digestion correlated with a higher percentage <strong>of</strong>islet preparations fulfilling quality criteria for clinical transplantation. It was concluded thatTLA is an effective component that should be included in moderate amounts in enzymeblends for human islet isolation to optimize the efficiency and minimize the lot-relatedvariability [143].Previously, it was found that human islets experimentally transplanted beneath the kidneycapsule have lower vascular density than native islets. One study aimed to investigatewhether human islets experimentally transplanted into the liver are also poorly revascularizedin the same manner as islets at the renal subcapsular site. Human islets were transplanted tonude mice. The vascular density in the intraportally transplanted human islets was found tobe similarly low as in human islets transplanted beneath the kidney capsule. The intrahepatichuman islets were coated with numerous vessels, but few vessels could be seen within theislets. Human islets transplanted intraportally into the liver become poorly revascularized.This could contribute to the loss <strong>of</strong> function in human islets transplanted into the liver overtime [144].

ACUTE PANCREATITISAcute pancreatitis is an inflammatory disease characterized by steady, acute abdominal pain<strong>of</strong> varying severity, <strong>of</strong>ten radiating from the epigastrium to the back. Its presentation rangesfrom a self-limiting mild disorder to a more severe and fulminant disease. Excessive acinarcell injury leads to a condition called systemic inflammatory response syndrome (SIRS).Protracted SIRS is responsible for most <strong>of</strong> the life-threatening complications associated withacute pancreatitis. Drugs such as resveratrol and rosiglitazone are being investigated aspotential candidates for the treatment <strong>of</strong> acute pancreatitis [145].Despite nearly a century <strong>of</strong> inquiry into the mysteries <strong>of</strong> the cataclysmic cascade <strong>of</strong>pancreatic enzyme activation, the key initiating factors and the subsequent mechanisms <strong>of</strong>glandular damage as well as the varied pathophysiological consequences <strong>of</strong> acutepancreatic inflammation are still poorly understood. The principal factor that leads topancreatic injury is believed to be pathological activation <strong>of</strong> intracellular digestive enzymes,possibly as a result <strong>of</strong> colocalization <strong>of</strong> pancreatic zymogens with lysosomal enzymes toproduce active trypsin. Disruption <strong>of</strong> the pancreatic acinar cell membrane is also postulatedas a key initiating event in the pathogenesis <strong>of</strong> acute pancreatitis. Recent work hashighlighted the role <strong>of</strong> disruption <strong>of</strong> protective mechanisms such as specific trypsin inhibitors(e.g. serine protease inhibitor Kazal type 1), compartmentalization <strong>of</strong> enzymes, and lowintracellular Ca 2+ concentrations, which prevent pathologic activation <strong>of</strong> trypsinogen. Inaddition, the downstream enzymatic, inflammatory, and cell death pathways and theconsequent activation <strong>of</strong> the systemic inflammatory response syndrome in severe acutepancreatitis have received considerable attention, especially with regard to theextrapancreatic facets <strong>of</strong> the disease. However, contemporary understanding <strong>of</strong> thepathogenesis is mostly derived from animal models and at the present time, the degree towhich these models reflect human disease remains limited [146].Overall resultsTo determine overall mortality and timing <strong>of</strong> death in patients with severe acute pancreatitisand factors affecting mortality a retrospective, observational study <strong>of</strong> 110 patients admitted toa general intensive care unit (ICU) from 2003 to 2006 was performed. The overall mortalityrate was 54 percent (59/110); 25 percent (n=15) <strong>of</strong> deaths were early (< 14 days after ICUadmission). There were no significant differences in age, sex, or surgical/medical treatmentbetween survivors and nonsurvivors. Median Acute Physiology and Chronic HealthEvaluation (APACHE) II score was significantly higher among nonsurvivors than survivors,and the duration <strong>of</strong> hospitalization before ICU admission was significantly longer (4 vs 1 day).Among the 59 patients who died, those in the early-mortality group were admitted to the ICUsignificantly earlier than those in the late-mortality group (3 vs 6.5 days) [147].MortalityMortality in acute pancreatitis has 2 peaks. The first peak is caused by systemicinflammatory response syndrome (SIRS), which takes place in the first week <strong>of</strong> the disease.Sepsis is responsible for a second peak. It begins 1 to 3 weeks after the onset <strong>of</strong> acutepancreatitis and is caused by pancreatic superinfection. Sepsis as a result <strong>of</strong> infectedpancreatic necrosis is the most serious complication in late phase <strong>of</strong> severe acutepancreatitis (SAP) and contributes to the high mortality rate <strong>of</strong> this disease. This complicationis thought to be a result <strong>of</strong> the bacterial translocation from the gastrointestinal tract. Thedamage <strong>of</strong> the microvessels and the subsequent onset <strong>of</strong> systemic cascade reactions playsalso an important role during acute pancreatitis. Recent experimental data suggest also therole <strong>of</strong> nervous system in etiopathogenesis <strong>of</strong> acute pancreatitis. It may be assumed that the

diagnostic and treatment strategy can not improve without a thorough knowledge <strong>of</strong> thephysiology and patophysiology <strong>of</strong> acute pancreatitis [148].Epidemiology and demographyAn increased incidenceThe pathophysiology and treatment <strong>of</strong> acute pancreatitis has been intensely studied duringthe last century and our aim is to <strong>review</strong> recent evidence and achievements in the diagnosisand treatment as pancreatitis is a growing problem in Europe, posing significant medical,surgical and financial sequelae. The mean age <strong>of</strong> the first attack is in the 6th decade whichcan be explained by an increasing incidence <strong>of</strong> gallstone pancreatitis among white womenover the age <strong>of</strong> 60 years. The incidence <strong>of</strong> acute pancreatitis has been reported to bemarkedly increasing. The explanation <strong>of</strong> this increased incidence could be explained by theroutine testing <strong>of</strong> pancreatic enzymes in patients presenting with abdominal pain atemergency departments, and in over-diagnosis in cases <strong>of</strong> non-specific increases inenzymes due to other causes. Another explanation is an increase in the incidence <strong>of</strong>gallstone disease and obesity in the population [022].Risk factors in the USKnowledge <strong>of</strong> the number <strong>of</strong> deaths caused by risk factors is needed for health policy andpriority setting. The aim <strong>of</strong> one study was to estimate the mortality effects <strong>of</strong> the following 12modifiable dietary, lifestyle, and metabolic risk factors in the United States (US) usingconsistent and comparable methods: high blood glucose, low-density lipoprotein (LDL)cholesterol, and blood pressure; overweight-obesity; high dietary trans fatty acids and salt;low dietary polyunsaturated fatty acids, omega-3 fatty acids (seafood), and fruits andvegetables; physical inactivity; alcohol use; and tobacco smoking. It was used data on riskfactor exposures in the US population from nationally representative health surveys anddisease-specific mortality statistics from the National Center for Health Statistics. In 2005,tobacco smoking and high blood pressure were responsible for an estimated 467,000 (95 %confidence interval 436,000 to 500,000) and 395,000 (372,000 to 414,000) deaths,respectively, accounting for about one in five or six deaths in US adults. Overweight-obesity(216,000; 188,000 to 237,000) and physical inactivity (191,000; 164,000 to 222,000) wereeach responsible for nearly 1 in 10 deaths. High dietary salt (102,000; 97,000 to 107,000),low dietary omega-3 fatty acids (84,000; 72,000 to 96,000), and high dietary trans fatty acids(82,000; 63,000 to 97,000) were the dietary risks with the largest mortality effects. Although26,000 (23,000 to 40,000) deaths from ischemic heart disease, ischemic stroke, anddiabetes were averted by current alcohol use, they were outweighed by 90,000 (88,000 to94,000) deaths from other cardiovascular diseases, cancers, liver cirrhosis, pancreatitis,alcohol use disorders, road traffic and other injuries, and violence [149].GermanySeveral European studies have reported an increase in acute pancreatitis. Therefore, it wasdecided to investigate whether acute pancreatitis in one area <strong>of</strong> Germany also displayschanges in frequency, etiology, and severity over time. The study included 608 patients witha first attack <strong>of</strong> acute pancreatitis, all from Lüneburg County, northern Germany, admitted toone municipal hospital between 1987 and 2006. The age-standardized rate (world) per100,000 inhabitants/year was 16.0 for men and 10.2 for women. Division <strong>of</strong> the study periodinto four 5-year segments revealed no increase or decrease in the frequency <strong>of</strong> acutepancreatitis nor did the etiology change. The severity <strong>of</strong> disease, however, decreased overthe course <strong>of</strong> time, as shown by lower Ranson scores, a lower proportion <strong>of</strong> cases with

necrosis or a severe course, and lower lethality. Other measures <strong>of</strong> severity remainedunchanged. The decrease in severity was particularly marked in patients with alcohol-relatedpancreatitis who are apparently seeking hospital treatment earlier than used to be the case.It was concluded that in contrast to other European countries (Denmark, United Kingdom,The Netherlands, and Sweden), this study showed no change over time in the frequency oretiology <strong>of</strong> acute pancreatitis. There were, however, signs <strong>of</strong> a decrease in disease severity,and this aspect merits further investigation [150].IndiaA prospective analysis <strong>of</strong> the epidemiology and outcome <strong>of</strong> patients admitted with acutepancreatitis to a tertiary health care centre in Goa, India, was carried out during the timeperiod <strong>of</strong> 2003 to 2005. The patients studied were those who were admitted to the GoaMedical College with a diagnosis <strong>of</strong> acute pancreatitis based on a serum amylase <strong>of</strong> greaterthan 180 Somogyii units with appropriate clinical and radiographic evidence. The selectioncriteria were fulfilled by 282 patients. Acute pancreatitis accounted for 2.3 percent <strong>of</strong> alladmissions and 4.9 percent <strong>of</strong> all deaths in the department <strong>of</strong> surgery. The disease was seento affect males more commonly (96 %), alcohol, being the predominant (92 %) aetiologicalfactor. The median age for occurrence <strong>of</strong> the disease was 40 years. Severe acutepancreatitis was encountered in 33 percent <strong>of</strong> cases with a mortality rate <strong>of</strong> 12 percent.Mortality was higher in patients older than 50 years. The widespread availability and use <strong>of</strong>locally made cheaper varieties <strong>of</strong> alcohol in the geographical location explains the trendtowards alcoholic pancreatitis and younger age groups being affected by the disease [151].Etiologic factors and factors <strong>of</strong> importance for development <strong>of</strong> pancreatitisCytokinesTNFTo determine whether increases in soluble tumor necrosis factor receptors (sTNFRs) areassociated with the levels <strong>of</strong> cytokines and proteinases in patients undergoing major surgery.Eleven patients who underwent esophagectomy for squamous cell carcinoma <strong>of</strong> the thoracicesophagus were studied. The circulating blood concentrations <strong>of</strong> interleukin-6 (IL-6), IL-8,sTNF-R55, sTNF-R75, elastase/al-proteinase inhibitor complex (elastase) and matrixmetalloproteinase-9 (MMP-9) were measured by ELISA or EIA before surgery, just aftersurgery, and on postoperative days (POD) 1 and 3. The levels <strong>of</strong> serum IL-6, plasma IL-8,plasma elastase and plasma MMP-9 increased significantly after surgery, peaking just aftersurgery or on POD 1 and then declining. In contrast, the serum levels <strong>of</strong> sTNFRs increasedapproximately 2-fold just after surgery compared with the preoperative values and thenremained elevated. The IL-6 level correlated with the levels <strong>of</strong> sTNF-R55 and sTNF-R75after surgery. These results suggest that increases <strong>of</strong> IL-6, serine proteinases and MMPsmay be involved in the upregulation <strong>of</strong> sTNFRs in patients undergoing major surgery [152].Interleukin 17The evaluation <strong>of</strong> the interleukin 17 capacity as precociously predictive marker <strong>of</strong> the severeforms <strong>of</strong> acute pancreatitis was done in a prospective and diagnosis study that took placeduring 2006-2008 on a sample <strong>of</strong> 83 subjects hospitalized with acute pancreatitis. Amongthese, 48 have submitted forms mild disease and formed batch A. Subjects with severeacute pancreatitis formed batch B (n=16), to whom it was applied peritoneal lavage extendedby laparoscopic method and batch C (n=19), who have used conventional methods <strong>of</strong>treatment, had their serum concentrations <strong>of</strong> interleukin 17 determined in the first and tenthdays <strong>of</strong> admission for the subjects <strong>of</strong> A and C lots and in the first, third and tenth day at thensubjects <strong>of</strong> B lot. Interleukin 17 has proved a sensitivity <strong>of</strong> 97 percent and a specificity <strong>of</strong> 94

percent in early identification forms <strong>of</strong> severe acute pancreatitis, with a correlation coefficient<strong>of</strong> 0.81. The correlation was good even in combination with organic disfunction (0.66) and therisk <strong>of</strong> death (0.54). The predictive capacity <strong>of</strong> sepsis has been reduced (0.44). Thedynamics <strong>of</strong> this cytokines show a significant decrease in concentrations forms mild disease(batch A) and in severe forms treated with peritoneal extended lavage (lot B). In conversely,the subjects treated by conventional methods (lot C) the decrease was not significantbetween the first and tenth days <strong>of</strong> admission. A similar dynamic has been recorded aftershort peritoneal lavage, lasting three days. At large in, the concentrations <strong>of</strong> interleukin 17evolved in parallel with those <strong>of</strong> interleukin 6 [153].Zinc and copperThe aims <strong>of</strong> one study were to measure the concentrations <strong>of</strong> zinc (Zn), copper (Cu), andmetallothionein and the Cu/Zn superoxide dismutase activity as elements engaged in anessential manner in the prooxidative and antioxidative balance <strong>of</strong> organism and todemonstrate the degree to which metallothionein and Cu/Zn superoxide dismutase areinvolved in the inflammatory processes occurring in the pancreas. The concentration <strong>of</strong>metallothionein was measured by immunoenzymatic method. Serum Cu/Zn superoxidedismutase activity was determined using a commercial test. The measurements <strong>of</strong> Zn andCu concentrations in serum were assessed with the use <strong>of</strong> flame atomic absorptionspectrometry. Lowered serum Zn concentration and higher Cu level were observed in theserum <strong>of</strong> patients with chronic exacerbated pancreatitis and chronic pancreatitis. Thesignificant increase <strong>of</strong> metallothionein concentration and Cu/Zn superoxide dismutase activitywas observed in the blood <strong>of</strong> patients with chronic exacerbated pancreatitis and chronicpancreatitis. In slices <strong>of</strong> the pancreas during pancreatitis, it was observed inimmunohistochemical reaction the variable involvement <strong>of</strong> Cu/Zn superoxide dismutase andmetallothionein. The results presented in these studies indicate an essential and variableinvolvement <strong>of</strong> antioxidants such Cu/Zn superoxide dismutase and metallothionein anddisordered Cu and Zn homeostasis depending on the progression <strong>of</strong> inflammatory processesin patients with pancreatitis [154].Prop<strong>of</strong>olThe use <strong>of</strong> prop<strong>of</strong>ol is controversial in patients with a history <strong>of</strong> acute pancreatitis or thosetaking drugs, including certain chemotherapeutic drugs that are associated with pancreatitis.To investigate this issue, it was <strong>review</strong>ed the medical records <strong>of</strong> all children who werediagnosed with pancreatitis while receiving chemotherapy for acute leukemia during a 5-yearperiod. A temporal relationship between prop<strong>of</strong>ol use and development <strong>of</strong> acute pancreatitiscould not be established. Prop<strong>of</strong>ol can thus be considered for general anesthesia in childrenwho are receiving chemotherapeutic drugs that are themselves associated with acutepancreatitis or those who have a history <strong>of</strong> chemotherapy-induced pancreatitis [155].Genetic polymorphismSystemic inflammatory reaction in acute pancreatitis is associated with activation <strong>of</strong> thecoagulation system. The prothrombotic component <strong>of</strong> the coagulation system, which maypromote microvascular thrombosis and vital organ injury, is strengthened by genetic factorssuch as polymorphism <strong>of</strong> plasminogen activator inhibitor type 1 (PAI-1) and factor V Leiden(FVL) mutation. It was now studied the occurrence <strong>of</strong> FVL and PAI-1 4G/5G polymorphismsin patients with acute pancreatitis This case control association study included 397 patientswith acute pancreatitis and 310 controls. Severe acute pancreatitis was determinedaccording to the Atlanta Classification. Genotyping was performed by matrix-assisted laserdesorption/ionization-time-<strong>of</strong>-flight mass spectrometry-assisted genotyping method. Factor VLeiden was identified in 5 (3.3 %) <strong>of</strong> 152 cases <strong>of</strong> severe acute pancreatitis and in 8 (3.3 %)

<strong>of</strong> 245 cases <strong>of</strong> mild acute pancreatitis. The prothrombotic PAI-1 4G allele frequency was0.49 for patients with severe acute pancreatitis and 0.57 for patients with mild acutepancreatitis, which was a significant difference. Patients with septic infectious complications(n=47) and patients with organ failure (n=55) had genotype distribution not different fromthose with mild, uncomplicated disease (n=245). The results do not support the hypothesisthat prothrombotic polymorphisms such as FVL mutation and PAI-1 4G/5G are associatedwith acute pancreatitis severity [156].Oxidative stressAcute pancreatitis is fatal when severe and oxidative stress is postulated to play an importantrole in its pathophysiology and the development <strong>of</strong> complications. Patients presenting to agastroenterology ward with early acute pancreatitis, i.e. within 72 hours <strong>of</strong> onset <strong>of</strong> pain,were included in the study. Also samples from 50 healthy controls were obtained forcomparison. Oxidative stress was estimated by levels <strong>of</strong> blood superoxide dismutase (SOD)and lipid peroxidation (thiobarbituric acid reactive substances; TBARS) and antioxidantstatus (AOS) by the ferric reducing ability <strong>of</strong> plasma (FRAP) and vitamin C at days 1, 3, and7 <strong>of</strong> admission. Oxidative stress was significantly higher in cases as compared with controlson all days and showed a gradual decrease from day 1 to 7. TBARS showed a higher fall inmild acute pancreatitis and better clinical outcome. Regarding the AOS, FRAP wassignificantly lower in cases and decreased significantly from day 1 to 3. Thus, high oxidativestress was observed during early phase <strong>of</strong> acute pancreatitis and a gradually improvingantioxidant status was associated with a better clinical outcome in patients with acutepancreatitis [157].HemoconcentrationIt was examined the relationship between early hemoconcentration and in-hospital mortalityin an observational cohort study <strong>of</strong> patients with acute pancreatitis. Data was collected from177 US hospitals from 2004 to 2005. Early hemoconcentration was defined as hemoglobin >14.6 mg/dl (hematocrit ~44 %) at any point during the first 24 hours <strong>of</strong> initial hospitalization.For transferred cases, it was linked clinical data from the first hospitalization to outcomesfrom the second hospitalization. It was then examined the impact <strong>of</strong> hospital transfer statuson the prognostic utility <strong>of</strong> hemoconcentration. It was identified 388 (2.2 %) cases asinterhospital transfers. Of these, it was successfully linked 198 (51 %) to their initialhospitalization. Early hemoconcentration was associated with increased mortality amongtransferred cases (odds ratio 7.4, 95 % confidence interval 1.6 to 35.4). However, no suchrelationship existed among non-transferred cases (odds artio 0.9, 95 % confidence interval0.7 to 1.2). Differences in outcome between transferred versus nontransferred cases werenot explained by extent <strong>of</strong> comorbid illness or initial disease severity (either APACHE II ororgan failure). It was concluded that early hemoconcentration predicted increased risk <strong>of</strong>mortality only among transferred cases despite similar levels <strong>of</strong> initial disease severity [158].Caboxypeptidase BThe concentration <strong>of</strong> carboxypeptidase B activation peptide (CAPAP) is proposed to be apredictor <strong>of</strong> severe acute pancreatitis. The activated protein C (APC)-protein C inhibitor (PCI;APC-PCI) complex in plasma could be useful in detecting the hypercoagulative condition insevere acute pancreatitis. In a prospective study, mild (n = 50) and severe (n = 9) cases <strong>of</strong>acute pancreatitis were compared with respect to levels <strong>of</strong> CAPAP and APC-PCI, and sortedin time intervals from onset <strong>of</strong> symptoms to sampling. The peak values <strong>of</strong> the C-reactiveprotein (CRP) within the 1st week were also compared. CRP detected the severe cases witha sensitivity <strong>of</strong> 0.89 and a specificity <strong>of</strong> 0.74 (cut-<strong>of</strong>f level 200 mg/l). In the interval 0-72 h,CAPAP could predict the severity <strong>of</strong> the disease in serum and urine (sensitivity 0.52/0.29,

specificity 0.73/0.93, cut-<strong>of</strong>f 2 nM/60 nM). The level <strong>of</strong> APC-PCI in plasma could predict thesevere condition in the interval 0-24 h after the onset <strong>of</strong> symptoms (sensitivity 0.6, specificity0.66, cut-<strong>of</strong>f level 0.54 µg/l). It was concluded that <strong>of</strong>f the parameters explored, CRP is stillthe best biochemical marker to distinguish between severe and mild acute pancreatitis.CAPAP could be useful in combination with other tests, but the APC-PCI complex'sdiagnostic time interval is too short to be used in the clinical routine [159].ObesityObesity markedly increases the risk <strong>of</strong> severe acute pancreatitis (SAP), possibly through theaction <strong>of</strong> adipokines. It was tested the hypothesis that serum adiponectin, the primary antiinflammatoryadipokine, is associated with functional polymorphisms in the adiponectin gene(ADIPOQ) and inversely associated with SAP. Severe AP was defined as the presence <strong>of</strong>remote organ failure. ADIPOQ polymorphisms rs2241766T>G and rs1501299G>T wereevaluated by DNA sequencing. Serum samples were assayed using a Luminex assay. Onehundred thirty-three patients with acute pancreatitis and 94 healthy controls wereascertained. Adiponectin levels were measured in 60 patients with early serum samples (27patients with mild AP and 33 patients with SAP). Adiponectin levels from days 1 to 3 wereinversely correlated with body mass index (BMI) and were significantly lower for patients withSAP than those with mild acute pancreatis. Neither ADIPOQ polymorphism affectedsusceptibility to or severity <strong>of</strong> acute pancreatitis. A receiver operating characteristics curveusing adiponectin levels as the severity predictor provided an area under the curve <strong>of</strong> 0.75.Serum adiponectin levels in patients with acute pancreatitis are inversely correlated with BMIand organ dysfunction [160].DyslipedemiaAdmissions with acute pancreatitis were prospectively evaluated. A comparison <strong>of</strong> thedemographic pr<strong>of</strong>ile, etiology, disease severity scores, complications and deaths was madein relationship to the lipid pr<strong>of</strong>iles. From 2001 to 2005, there were 230 admissions. Thepancreatitis was associated with alcohol (63 %), gallstones (18 %), idiopathic (9 %) andisolated dyslipidaemia (10 %). Dyslipidaemia was significantly different between the twopredominant race groups: Indian 51 percent and African 18 percent. Seventy-eight (34 %)had associated dyslipidemia and 152 (66 %) were normolipaemic at admission. The averagebody mass index was significantly higher in the dyslipidemic group (27 ± 6) than in thenormolipemic group (24.5 ± 6.20). The mortality rate was similar between the dyslipidemicand normolipemic patients (10 and 8 %, respectively) and unrelated to race. The 9 deaths inthe dyslipidaemic group occurred in those with persistent hypertriglyceridaemia irrespective<strong>of</strong> its level. It was concluded that adverse outcomes in those with dyslipidaemia werepredominantly associated with hypertriglyceridaemia [161].Dominant dorsal duct syndromeAcute recurrent pancreatitis in children can be caused by anomalies <strong>of</strong> fusion <strong>of</strong> pancreaticducts such as the dominant dorsal duct syndrome wherein a dominant dorsal pancreatic ductis associated with stenosis <strong>of</strong> the minor papilla. Clinical presentations and management <strong>of</strong>two patients are discussed. An infant presented with severe acute pancreatitis withpseudocyst formation due to an underlying ductal disruption. Surgical treatment was <strong>of</strong>feredon account <strong>of</strong> failure <strong>of</strong> medical therapy and endoscopic stenting. A dominant dorsal ductwith minor papilla stenosis was encountered. Sphincteroplasty <strong>of</strong> the minor papilla and lateralpancreaticojejunostomy were performed with good result. A 14-year-old boy with a type onecholedochal cyst was troubled by recurrent acute pancreatitis. At operation, a dilated dorsalpancreatic duct opening into a stenosed minor papilla was found in addition to thecholedochal cyst. Choledochal cyst excision, choledochoduodenostomy, and sphinctero-

plasty <strong>of</strong> the minor papilla stenosis were performed. Dominant dorsal duct syndrome is a rarecause <strong>of</strong> acute pancreatitis in children. A high index <strong>of</strong> suspicion is necessary to establish aprecise diagnosis. Sphincteroplasty <strong>of</strong> the minor papilla may affect adequate pancreaticdrainage and prevent recurrent pancreatitis [162].Classification and prediction <strong>of</strong> severityThe prediction <strong>of</strong> severe acute pancreatitis should be achieved by careful ongoing clinicalassessment coupled with the use <strong>of</strong> a multiple factor scoring system and imaging studies.Over the past 30 years several scoring systems have been developed to predict the severity<strong>of</strong> acute pancreatitis. However, there are no complete scoring index with high sensitivity andspecificity till now. The interest in new biological markers and predictive models foridentifying severe acute pancreatitis testifies to the continued clinical importance <strong>of</strong> earlyseverity prediction. Among them, IL-6, IL-10, procalcitonin, and trypsinogen activationpeptide are most likely to be used in clinical practice as predictors <strong>of</strong> severity. Even ifcontrast-enhanced CT has been considered the gold standard for diagnosing pancreaticnecrosis, early scanning for the prediction <strong>of</strong> severity is limited because the full extent <strong>of</strong>pancreatic necrosis may not develop within the first 48 hour <strong>of</strong> presentation [163].Scoring systemsIn acute pancreatitis early identification <strong>of</strong> high-risk patients can be difficult. For this reason, aplethora <strong>of</strong> different prognostic variables and scoring systems have been assessed to see ifthey can reliably predict the severity <strong>of</strong> pancreatitis and/or subsequent mortality. All studiesthat focused on acute pancreatitis, including retrospective series and prospective trials, wereretrieved and analysed for factors that could influence mortality. Articles that analysed factorsinfluencing the severity <strong>of</strong> the disease or the manifestation <strong>of</strong> disease-related complicationswere excluded. Fifty-eight articles meeting the inclusion criteria were identified. Among thevarious factors investigated, APACHE II seemed to have the highest positive predictive value(69 %). However, most prognostic variables and scores showed high negative predictivevalues but suboptimal values for positive predictive power. It was concluded that despite theproliferation <strong>of</strong> scoring systems for grading acute pancreatitis, none are ideal for theprediction <strong>of</strong> mortality. With the exception <strong>of</strong> the APACHE II, the other scores and indexes donot have a high degree <strong>of</strong> sensitivity, specificity and predictive values [164].The distinction between mild and severe forms <strong>of</strong> acute pancreatitis within 24-48 hours <strong>of</strong>hospital admission is very important for the treatment <strong>of</strong> these patients. The usage <strong>of</strong>multifactorial scoring systems holds a lot <strong>of</strong> promise, reaching reliability in the diseaseseverity estimation <strong>of</strong> approximately 70-80 percent. The main purpose <strong>of</strong> one prospectivestudy was to assess the correlation <strong>of</strong> the Acute Physiology and Chronic Health Evaluation II(APACHE II) and the Bernard Organ Failure Score (BOFS) scoring systems in estimation <strong>of</strong>disease severity and outcome prediction. Sixty patients with acute pancreatitis participated inthe study, all <strong>of</strong> them scored with the APACHE II and BOFS scores. The results were usedfor integration <strong>of</strong> laboratory and clinical parameters. In the study, it was found a highlysignificant correlation between the APACHE II and BOFS scores from the disease onset untilthe end <strong>of</strong> treatment.There was a highly significant correlation between these two scores andthe serum C-reactive protein concentration level. The concept <strong>of</strong> the BOFS score has moreadvantages than the APACHE II score in the patients with severe forms <strong>of</strong> acute pancreatitiswith organ dysfunction [165].

Single factorsRenal rim gradeMultifactor scoring systems, such as the Acute Physiology and Chronic Health Evaluation(APACHE) II, are useful for predicting the severity <strong>of</strong> acute pancreatitis; however, they arerather complicated. The aim <strong>of</strong> one study was to introduce renal rim grade (RRG) as aseverity assessment measure for acute pancreatitis. One hundred twenty-two eligible acutepancreatitis patients who underwent abdominal computed tomography (CT) on admissionwere evaluated for RRG (grades 1-3). The end points were the severity <strong>of</strong> illness andhospital mortality. Furthermore, RRG was compared with the Balthazar score, the CTseverity index, the Ranson score, and the APACHE II score, using a receiver operatingcharacteristic analysis. The exacerbation rates into severe disease were 3 percent (grade 1),48 percent (grade 2), and 89 percent (grade 3). The mortality rates were 3 percent (grade 1),8 percent (grade 2), and 31 percent (grade 3). The area under the receiver operatingcharacteristic curves to predict the severe disease and mortality using the RRG system wascomparable with other scoring systems. It was concluded that renal rim grade is useful forthe evaluation <strong>of</strong> the severity <strong>of</strong> AP [166].Organ failureOrgan failure (OF) is a main cause <strong>of</strong> death in severe acute pancreatitis (SAP). One studyhad the primary aim to evaluate the morbidity and mortality <strong>of</strong> patients admitted with SAPwith no OF (NOF), single OF (SOF), and multiple (>2) OF (MOF). Medical records <strong>of</strong> 207consecutive patients admitted with SAP to the Mayo Clinic between 1992 and 2001 were<strong>review</strong>ed. OF was defined according to the Atlanta classification and patients werecategorized in the three groups: NOF, SOF, and MOF. Primary outcomes were in-hospitalmortality, duration <strong>of</strong> hospitalization, need for the intensive care unit (ICU), and the meanlength <strong>of</strong> stay in the ICU. Organ failure occurred in 108 patients (52 %). Gastrointestinalbleeding occurred in 18 percent, respiratory failure in 36 percent, hypotension in 28 percent,and renal failure in 26 percent. Compared to patients with MOF, patients with NOF hadsignificantly shorter hospitalizations (28 vs 55 days), less need for ICU care (50 % vs 90 %),shorter time in the ICU (5 vs 34 days), and decreased in-hospital mortality (2 % vs 46 %).Odds ratios evaluating the risk <strong>of</strong> in-hospital mortality for subjects with any organ failure was28 (7-186), 10 (2-69) for patients with SOF, and 64 (15-464) for patients with MOF. It wasconcluded that patients with SAP and NOF have prolonged hospitalizations but low mortality.The Atlanta classification should be revised to include a patient group defined as "moderatelysevere acute pancreatitis" that identifies those patients currently classified as SAP withoutorgan failure [167].AlbuminSeveral studies indicated that the mortality rate <strong>of</strong> patients with acute pancreatitis is currentlyapproximately 3.8 to 7.0 percent, in severe acute pancreatitis (SAP), it varies from 7 to 42percent. In previous studies, several biological markers and clinical events had been used topredict the mortality. However, few studies have addressed the role <strong>of</strong> factors asindependent predictors that can early predict fatal outcome in hospitalized medical patients.The primary aim <strong>of</strong> one study was therefore to analyze the conventional clinical data andparameters within 24 hours after admission <strong>of</strong> 338 patients with SAP, particularly the effect <strong>of</strong>C-reactive protein (CRP), albumin (ALB), and total cholesterol (TC). The mean age <strong>of</strong> the338 patients with SAP was 54 years. The overall inhospital mortality rate was 8.3 percent(28/338). The mean time from hospital admission to death was 29 days (range, 9-47 days).Multivariate analysis indicated that the inhospital mortality increased significantly more than7-fold higher in patients with severe hypoalbuminemia (ALB < 30 g/L). The CRP levelsexceeding 170 mg/L were significantly associated with a 7-fold inhospital death. A serumtotal colesterol level between 4.37 to 5.23 mmol/L had significant protective effect. Totalcholesterol levels exceeding 5.23 mmol/L were risk factors to predict inhospital mortality with

no significant difference. The strongest prognostic factor was serum ALB. Subanalysisindicated that CRP was negatively linearly associated with TC. This analysis also identifiedthat the odds ratio <strong>of</strong> hypoalbuminemia for mortality was much higher than that <strong>of</strong> high CRPlevels. The ability <strong>of</strong> elevated serum TC level to predict survival in SAP seems unintuitivebecause the primary cause <strong>of</strong> acute pancreatitis is hypercholesteremia, which is a strong riskfactor to SAP. Moderately elevated TC levels can increase resistance to inflammatoryreaction and reduce the severity <strong>of</strong> SAP and the rate <strong>of</strong> mortality [168].AdiponectinObesity markedly increases the risk <strong>of</strong> severe acute pancreatitis, possibly through the action<strong>of</strong> adipokines. It was tested the hypothesis that serum adiponectin, the primary antiinflammatoryadipokine, is associated with functional polymorphisms in the adiponectin gene(ADIPOQ) and inversely associated with severe acute pancreatitis, defined as the presence<strong>of</strong> remote organ failure. ADIPOQ polymorphisms rs2241766T>G and rs1501299G>T wereevaluated by DNA sequencing. One hundred thirty-three patients with acute pancreatitis and94 healthy controls were ascertained. Adiponectin levels were measured in 60 patients withearly serum samples (27 patients with mild AP and 33 patients with SAP). Adiponectin levelsfrom days 1 to 3 were inversely correlated with body mass index (BMI) and were significantlylower for patients with SAP than those with mild AP. Neither ADIPOQ polymorphism affectedsusceptibility to or severity <strong>of</strong> acute pancreatitis. A receiver operating characteristics curveusing adiponectin levels as the severity predictor provided an area under the curve <strong>of</strong> 0.75.Serum adiponectin levels in patients with acute pancreatitis are inversely correlated with BMIand organ dysfunction. Further studies are needed to determine whether adiponectin is amarker <strong>of</strong> low BMI or if it provides significant protection from SAP [169].Soluble form <strong>of</strong> the receptor for advanced glycation end products (sRAGE)To study in patients with acute pancreatitis the plasma soluble form <strong>of</strong> the receptor foradvanced glycation end products (sRAGE) and high-mobility group box chromosomal protein1 (HMGB1) levels, followed-up for 12 days after hospitalization, in relation to the occurrence<strong>of</strong> organ failure and mortality. It was studied 38 patients with severe acute pancreatitis andorgan failure (grade 2) and a control group (127 patients) consisting <strong>of</strong> 38 patients withsevere acute pancreatitis without organ failure (grade 1) and 89 patients with mild acutepancreatitis (grade 0). Plasma samples for determination <strong>of</strong> HMGB1 and sRAGE levels werecollected on admission and on days 1 and 2, days 3 and 4, and days 7 and 12 afteradmission. The median <strong>of</strong> the highest sRAGE levels was higher in grade 2 patients than ingrade 0 plus grade 1 patients. Among the patients with detectable HMGB1, the median <strong>of</strong> thehighest HMGB1 levels was 117 ng/mL in grade 2 patients and 87 ng/mL in grade 0 plusgrade 1 patients. It was thus demonstrated that sRAGE level, but not HMGB1 level, issignificantly higher in acute pancreatitis patients who develop organ failure than in acutepancreatitis patients without organ failure who recover [170].High- versus low-volume hospitalsAcute pancreatitisAlthough limited initially to operative procedures, studies evaluating the relationship betweenhospital volume and outcome have been extended to include medical conditions such asmyocardial infarction and critical care. In an analysis <strong>of</strong> the Nationwide Inpatient Sample, astudy evaluated the impact <strong>of</strong> treatment in a high volume center on in-hospital mortality,length <strong>of</strong> stay, and hospital charges in acute pancreatitis. High-volume centers were definedas the top one third <strong>of</strong> hospitals by the number <strong>of</strong> acute pancreatitis admissions in eachsurvey year. The main finding was that adjusted mortality, length <strong>of</strong> stay, and hospitalcharges were reduced when high-volume centers were compared with low-volume centers.

An inherent difficulty in comparing outcomes across hospitals is the difference in baselineclinical severity <strong>of</strong> diseases. High-volume centers typically serve as referral hospitals and arelikely to treat a more severely ill patient population. As a result, high-volume centers thataccept outside hospital transfers may report worse overall outcomes compared with lowvolumecenters. The use <strong>of</strong> propensity scores to create a matched cohort <strong>of</strong> patients hasemerged as an important method for risk adjustment in outcomes research. A characteristicfeature <strong>of</strong> a propensity-matched cohort study is that patients are matched according toexposure, in contrast to a traditional case-control study wherein patients are matchedaccording to outcome. After risk adjustment, treatment in a high-volume center was thenassociated with reduced mortality, length <strong>of</strong> stay, and charges. There are several potentialexplanations for the impact <strong>of</strong> hospital volume on outcomes in acute pancreatitis. In the pastdecade, numerous developments have emerged in management <strong>of</strong> acute pancreatitis,including aggressive fluid resuscitation, enteral nutritional support, and use <strong>of</strong> innovativeendoscopic, radiologic, and operative techniques for specific complications. Themanagement <strong>of</strong> complicated cases <strong>of</strong> acute pancreatitis requires not only the availability <strong>of</strong>numerous specialty services (critical care, gastroenterology, surgery, and interventionalradiology), but also the experience to coordinate such multidisciplinary care. The task athand is to identify which practices contribute to the success <strong>of</strong> high-volume centers as wellas to determine which patients may benefit from treatment in a high-volume center. Theimpact <strong>of</strong> hospital volume on outcomes in acute pancreatitis requires further evaluationbefore policy decisions can be considered [171].CholecystectomyIt was explored whether admission volumes for cholecystectomy and pancreatitis wereassociated with receiving cholecystectomy after hospitalization for acute biliary pancreatitis(ABP). It was identified admissions for ABP in the Nationwide Inpatient Sample between1998 and 2003. It was used multivariate analysis to assess the association betweenlikelihood <strong>of</strong> cholecystectomy and hospital volumes <strong>of</strong> cholecystectomy, pancreatitis, andendoscopic retrograde cholangiopancreatography (ERCP). The overall rate <strong>of</strong>cholecystectomy for ABP was 50 percent. After adjustment for confounders, the likelihood <strong>of</strong>cholecystectomy increased with every quartile <strong>of</strong> cholecystectomy volume relative to thebottom quartile (adjusted odds ratios <strong>of</strong> 4.36, 7.92, and 12.51 for quartiles 2, 3, and 4,respectively). Pancreatitis volume was inversely correlated with likelihood <strong>of</strong> cholecystectomy(adjusted odds ratios <strong>of</strong> 0.72, 0.62, and 0.48 for quartiles 2, 3, and 4, respectively, vs bottomquartile). Admissions to hospitals in the top quartile for ERCP volume (>35 ERCPs/year) had15 percent lower odds <strong>of</strong> cholecystectomy than the lowest quartile. Patients from rural areasand with lower income were disproportionately admitted to hospitals with lowercholecystectomy volumes. It was concluded US hospitals are not achieving targets forcholecystectomy after acute biliary pancreatitis as set by national and internationalguidelines. Centers with smaller cholecystectomy volumes are the least adherent torecommendations for cholecystectomy possibly because <strong>of</strong> hospital-level resource limitations[172].Diagnostics in acute pancreatitisSymptomsIt was reported the coexistence <strong>of</strong> Cullen's and Grey Turner's signs in acute pancreatitis[173].

Urinary trypsinogen-2There is not any quantitative diagnostic test for acute pancreatitis. In the present study it wasinvestigated the value <strong>of</strong> the qualitative urinary trypsinogen-2 measurement in the diagnosis<strong>of</strong> acute pancreatitis by an immuno-chromatographic dipstick test. A prospective,randomized, clinical trial was planned on 99 patients (53 male, 46 female; male/female :1.11; age range: 16-83; mean age: 37.4). Patients were divided into two groups: 50 caseswere referred to our emergency surgical unit due to abdominal pain and diagnosed withacute pancreatitis by abdominal computerized tomography (CT) (group 1); 49 cases werereferred to the emergency surgical unit due to abdominal pain and whose abdominal CTs didnot show any sign <strong>of</strong> acute pancreatitis (group 2). Qualitative urinary trypsinogen-2measurement, abdominal CT and blood amylase values were obtained in all cases. In group1, urinary trypsinogen-2 measurement was found positive in 28 cases out <strong>of</strong> 50 casesdiagnosed with acute pancreatitis (56 % sensitivity). In group 2, results were found positive in3 out <strong>of</strong> 49 patients with abdominal pain, who lacked an acute pancreatitis diagnosis (91 %specificity). Severe intra-abdominal inflammation was present in three cases <strong>of</strong> group 2where we obtained false positive results which may stimulate the pancreatic exocrinesekretion [174].Dip-slide diagnosisIn acute pancreatitis, rapid diagnosis and early treatment are <strong>of</strong> importance for clinicaloutcome. Urinary trypsinogen-2 has been suggested as a promising diagnostic marker;however, studies using the urinary trypsinogen-2 dipstick test (UTDT) have provided varyingresults. The study was set to evaluate the use <strong>of</strong> the UTDT in apparent first attack <strong>of</strong> acutepancreatitis in daily clinics. Acute pancreatitis was defined as more than a 3-fold increase inplasma amylase levels. It was included 75 patients admitted with acute pancreatitis. Thirtyfourpatients with acute abdominal pain <strong>of</strong> causes other than acute pancreatitis served as acontrol group. In 58 <strong>of</strong> 75 patients, the UTDT result was positive, giving a sensitivity <strong>of</strong> 77percent (95 % confidence interval 66 % to 86 %). In severe cases, the sensitivity improved to87 percent (95 % confidence interval 69 % to 96 %). In 33 <strong>of</strong> 34 controls, the test result wasnegative, giving a specificity <strong>of</strong> 97 percent (95 % confidence interval 84 % to 100 %). It wasconcluded that UTDT had a low sensitivity but high specificity. These results do not supportthe UTDT to replace standard plasma amylase for the diagnosis <strong>of</strong> apparent first attack <strong>of</strong>acute pancreatitis [175].HyperamylasemiaIt was reported a case <strong>of</strong> suspected acute pancreatitis after bilateral total knee arthroplasty.Airway management including jaw thrust maneuvers was performed. Postoperatively, thepatient complained <strong>of</strong> nausea with vomiting. Further examination revealed high serumamylase levels, and an abdominal CT scan revealed confined inflammation near the head <strong>of</strong>the pancreas. The amylase isozyme patterns identified the salivary-type amylase. Agastroduodenoscopy procedure performed on the 21st postoperative day revealed aduodenal ulcer. It was speculated that the primary cause <strong>of</strong> hyperamylasemia wasaccumulation <strong>of</strong> amylase in the parotid glands and the CT findings showed the inflammation<strong>of</strong> the pancreas itself or extrapancreatic exudates resulting from duodenal ulcer [176].Hyperamylasemia is <strong>of</strong>ten reported in patients with acute liver failure (ALF). Direct toxiceffects <strong>of</strong> acetaminophen on the pancreas have been postulated, but the occurrence <strong>of</strong>hyperamylasemia in other etiologies raises the question <strong>of</strong> whether multiorgan failure is part<strong>of</strong> the pathogenesis <strong>of</strong> in this setting. Patients enrolled in the Acute Liver Failure Study Groupregistry with an admission amylase value available were included. For the purpose <strong>of</strong> thisanalysis, hyperamylasemia was defined as > 3x upper limits <strong>of</strong> normal. Patients were

classified as having acetaminophen (APAP)- or non-APAP-induced ALF, and by amylasegroup: normal (345). In total, 622eligible patients were identified in the database, including 287 (46 %) with APAP-inducedALF; 76 (12 %) patients met the criteria for hyperamylasemia. Among patients withhyperamylasemia, 7 (9 %) had documented clinical pancreatitis. The incidence <strong>of</strong>hyperamylasemia was similar among APAP (13 %) and non-APAP (12 %) patients. Althoughhyperamylasemia was associated with renal failure and greater Model for End-stage LiverDisease scores for both groups, hyperamylasemia was not an independent predictor <strong>of</strong>mortality in multivariate analysis. It was concluded that although not an independent predictor<strong>of</strong> mortality, hyperamylasemia in ALF was present in all etiologies and was associated withdiminished overall survival. Hyperamylasemia appeared to be related to renal dysfunction inboth groups and multiorgan failure in non-APAP ALF [177].AsymptomaticFrom 2005 to 2008, 63 subjects with asymptomatic pancreatic hyperenzymemia werestudied by MRCP. In addition, amylase, pancreatic isoamylase, and lipase were determinedfor 5 consecutive days. In most subjects (91 %), MRCP showed a normal pancreas. In theremaining 6 subjects (10 %), the following alterations were found: pancreas divisum in 2,small intrapancreatic cyst in 2, anatomic variant <strong>of</strong> the Wirsung in 1, and mild dilatation <strong>of</strong> 3secondary ducts in 1. In these 6 subjects, hyperenzymemia was highly variable from day today, with frequent normalizations, as was also true for the 30 subjects with no MRCPalterations in whom diurnal enzyme determinations were made. It was concluded that most<strong>of</strong> the subjects with asymptomatic pancreatic hyperenzymemia did not have pancreaticlesions detectable by MRCP. In the few subjects in whom a lesion was found, the greatvariability and the frequent transient normalization <strong>of</strong> serum enzyme levels tend to exclude arelation between the lesion and the hyperenzymemia [178].In critical ill patientsElevations in the levels <strong>of</strong> pancreatic enzymes are observed in up to 80 percent <strong>of</strong> intensivecare patients. Most <strong>of</strong> these patients do not develop clinically relevant pancreatitis. However,elevations in enzyme levels do represent pancreatic damage with a risk <strong>of</strong> complications.Different factors have been discussed, which may contribute to pancreatic damage incritically ill patients. These include splanchnic hypoperfusion during shock or major surgery,bacterial translocation, elevated triglyceride levels, development <strong>of</strong> biliary sluge, and biliarypancreatitis, as well as several drugs. Imaging procedures and inflammatory markers help toidentify relevant disease. Several therapeutic options have been discussed recently with afocus on early enteral nutrition. Thus, pancreatic damage is frequently observed in critically illpatients, but in most <strong>of</strong> these patients, this is without major clinical consequences. However,some patients develop relevant pancreatitis, which contributes to morbidity and mortality[179].After prop<strong>of</strong>olVarious case reports have indicated a possible relationship between prop<strong>of</strong>ol andpancreatitis. However, it is not clear whether this relationship (if any) is dose-related oridiosyncratic. Therefore, a prospective study was conducted to evaluate the effect <strong>of</strong> differentdoses <strong>of</strong> prop<strong>of</strong>ol on postoperative pancreatic enzymes and serum triglyceride levels. Onehundred and fifty patients, aged 18 to 60 years, belonging to ASA physical status I and II,undergoing non-abdominal surgery were divided into three groups. Anaesthesia was inducedwith prop<strong>of</strong>ol 2 to 2.5 mg/kg in all groups. It was maintained with is<strong>of</strong>lurane in group I,prop<strong>of</strong>ol infusion < 5 mg/kg/h in group II and prop<strong>of</strong>ol infusion > 5 mg/kg/h in group III. Allthree groups also received nitrous oxide in oxygen for maintenance <strong>of</strong> anaesthesia. Serumamylase, lipase and triglyceride were estimated before prop<strong>of</strong>ol administration and at 24 and72 hours postoperatively. The mean values <strong>of</strong> serum amylase, lipase and triglycerideremained within the normal range in the three groups. These values did not differ significantlyin between the groups even despite the significantly different doses <strong>of</strong> prop<strong>of</strong>ol in the three

groups. None <strong>of</strong> the patients in the three groups developed any feature suggestive <strong>of</strong> acutepancreatitis in the postoperative period. These findings indicate that prop<strong>of</strong>ol administrationat recommended doses does not produce dose-related increases in pancreatic enzyme andtriglyceride levels in ASA physical status I and II patients [180].In smokersThe newest conducted investigations showed the significant role <strong>of</strong> tobacco smoking ininducing pathological changes in pancreas. Additionally exposure to heavy metals presentson polluted environment influences on function this organ. However, the mechanism <strong>of</strong>development <strong>of</strong> these changes has not been fully recognised. The aim <strong>of</strong> this study is toprove the influence <strong>of</strong> tobacco smoking on total amylase and termolabile amylase activity inserum <strong>of</strong> smoking and nonsmoking healthy persons and workers at cooper foundry inLegnica occupationally exposed to heavy metals: cadmium, arsenic, lead. Blood has beencollected from 28 healthy persons and 60 founders. The enzyme total activity has beendetermined using the colorimetric method with substrate 1,2-odilauryl-rac-glycero-3-glutaricacid-(6-methylresorufin) ester. The thermolability activity has been determined using thethermolability test. It has been noted significant higher total amylase and thermolabileamylase activity in serum <strong>of</strong> smoking healthy persons and <strong>of</strong> non-smoking and smokingfounders comparison with non-smoking healthy persons. It hasn't been found significantdifferences in total and thermolabile amylase activity in smoking founders and non-smokingfounders. The fact that there are significant differences in serum amylase activity in serum <strong>of</strong>smoking and nonsmoking founders in comparison with nonsmoking healthy persons prove asignificant influence <strong>of</strong> exposure to heavy metals on exocrine function <strong>of</strong> pancreas [181].HyperlipedemiaThe association <strong>of</strong> pregnancy, hypertriglyceridemia, and acute pancreatitis is wellestablished even though gestational hyperlipidemic pancreatitis is an uncommon but seriousdisorder. In women having type I, IV, or V hyperlipoproteinemia (HLP), the superimposition <strong>of</strong>the physiologic hyperlipidemia <strong>of</strong> pregnancy may lead to acute pancreatitis. Type III HLP isan inborn error <strong>of</strong> metabolism characterized by defective apo E, which is a ligand for thereceptor-mediated uptake <strong>of</strong> chylomicron and VLDL remnants by the liver. More than 90percent <strong>of</strong> type III HLP subjects are homozygous carriers <strong>of</strong> apo E2 (Arg158 -> Cys), whichdisplays less than 1 percent binding affinity for the cell surface lipoprotein receptors.However, less than 10 percent <strong>of</strong> apo E2/E2 homozygous subjects have hyperlipidemia.These observations indicate that other genetic environmental factors or concomitantdiseases are necessary for expression <strong>of</strong> the hyperlipidemia in apo E2/E2 subjects. A casedescribed was the first case <strong>of</strong> apo E2/E2 homozygous familial type III HLP-relatedgestational hyperlipidemic pancreatitis. A 39-year-old gravida 3-para woman without knownmedical history except hyperlipidemia for 3 years and regular medication until 6 monthsbefore preparation <strong>of</strong> gestation was referred to our hospital for acute pancreatitis at 14 weeks<strong>of</strong> gestation. On arrival, the lipid pr<strong>of</strong>iles showed hypercholesterolemia (807 mg/dL) andhypertriglyceridemia (3596 mg/dL). During her stay in the hospital, she received totalparenteral nutrition for 14 days and resumed oral intake with low-fat diet smoothly. She wasdischarged at 18 weeks <strong>of</strong> gestation and continued with the low-fat diet with fish oilsupplement (4 g/d) according to the dietitian's instruction. She gave birth to a healthy maleinfant at 39 weeks <strong>of</strong> gestation, and her triglyceride level fell below 1000 mg/dL after delivery.Fish oil is well known to decrease VLDL secretion from the liver and thus lower theproduction <strong>of</strong> intermediate-density lipoproteins and low-density lipoprotein. A dose <strong>of</strong> 3 to 4 gn-3 fatty acids per day decreases serum triglyceride levels by around 30-50 percent inhypertriglyceridemic patients. Thus, fish oil supplement could be an effective therapy forprevention <strong>of</strong> gestational hyperlipidemic pancreatitis [182].In a patient with diabetic ketoacidosis complicated by severe elevation <strong>of</strong> plasma triglyceride

concentrations, treatment with low-level intravenous unfractionated heparin led to promptreduction in plasma triglyceride concentration and may have prevented the development <strong>of</strong>hypertriglyceridemia-associated acute pancreatitis. One article <strong>review</strong>ed the rationale for thistreatment and surveys prior publications using heparin in this and similar settings [183].d-DimerStudies on the clinical value <strong>of</strong> parameters <strong>of</strong> hemostasis in predicting pancreatitisassociatedcomplications are still scarce. The aim <strong>of</strong> one prospective study was to identifythe useful hemostatic markers for accurate determination <strong>of</strong> the subsequent development <strong>of</strong>organ failure during the very early course <strong>of</strong> acute pancreatitis. In 91 consecutive primarilyadmitted patients with acute pancreatitis, prothrombin time, activated partial thromboplastintime, fibrinogen, antithrombin III, protein C, plasminogen activator inhibitor 1, d-dimer, andplasminogen were measured in plasma within the first 24 hours <strong>of</strong> admission and 24 hoursthereafter. Two study groups comprising 24 patients with organ failure and 67 patientswithout organ failure were compared. Levels <strong>of</strong> prothrombin time, fibrinogen, and d-dimer onadmission were significantly different between the organ failure and non-organ failuregroups, and all these parameters plus antithrombin III were significantly different 24 hourslater. d-Dimer in predicting the development <strong>of</strong> organ failure had a sensitivity, specificity, andpositive and negative predictive values <strong>of</strong> 90, 89, 75, and 96 percent, respectively [184].CTA prospective study aimed at evaluating dynamic computed tomography (CT) as aprognostic indicator <strong>of</strong> local complications in patients with pancreatic necrosis. It wasanalyzed the relationship between the anatomic pattern <strong>of</strong> pancreatic necrosis at dynamicCT (pancreatic necrosis, peripancreatic necrosis, and transparenchymal necrosis) and thedevelopment <strong>of</strong> local complications (infected pancreatic necrosis and pseudocyst). Onehundred thirty-eight patients were included in the study. Nine patients were excluded, and 86required surgery. Average time from the onset <strong>of</strong> symptoms to dynamic CT was 8.3 days.Multivariate analysis identified prognostic factors for local complications:- extent <strong>of</strong> pancreatic necrosis (odds ratio, 7)- presence <strong>of</strong> peripancreatic necrosis (odds ratio 37)- transparenchymal necrosis with upstream viable (enhancing) pancreas (odds ratio36)- no peripancreatic necrosis (odds ratio 0.016)It was concluded that dynamic CT prognostic factors useful to predict local complications inpatients with pancreatic necrosis were the extent <strong>of</strong> pancreatic necrosis, presence <strong>of</strong>peripancreatic necrosis, and the finding <strong>of</strong> transparenchymal necrosis with upstream viable(enhancing) pancreas [185].MRDiffusion-weighted imaging (DWI) is a new magnetic resonance imaging (MRI) techniquethat evaluates the random motion <strong>of</strong> water molecules in biological tissues. The clinical utility<strong>of</strong> DWI has been established for acute stroke and brain tumors. Recent technicaladvancements in MRI have enabled DWI for the body and several studies have revealed theefficacy <strong>of</strong> DWI for detecting various diseases. One study documented the efficacy <strong>of</strong> DWIfor the evaluation <strong>of</strong> acute pancreatitis. MRI was performed with sequences including T1-weighted, T2-weighted, diffusion-weighted imaging, MR cholangiopancreatography (MRCP)and computed tomography (CT) examinations on 11 patients with mild acute pancreatitis.MRI examinations were performed using 1.5-T imager. Two experienced radiologists

evaluated the presence or absence <strong>of</strong> acute pancreatitis, complications and the cause <strong>of</strong>acute pancreatitis on the MRI and CT images. There were no differences between the DWIand the CT images regarding their abilities to detect acute pancreatitis. However, DWI coulddetect acute pancreatitis more clearly than CT without enhancing material. The DWI findingswere consistent with the clinical findings, the results <strong>of</strong> chemical analyses and the CTfindings. Furthermore, DWI could detect pancreatic cancer causing acute pancreatitis andMR cholangiopancreatography (MRCP) could detect choledocholithiasis and pancreasdivisum causing acute pancreatitis [186].To determine the diagnostic value <strong>of</strong> magnetic resonance (MR) grading focusing on elevatedsignal on T1-weighted images in the prediction <strong>of</strong> severity and prognosis <strong>of</strong> acutepancreatitis as compared with the Balthazar computed tomography (CT) grading 31 patientswith acute pancreatitis who underwent CT and MR imaging including fat-suppressed T1-weighted images within a 48-hour interval were included in a study. The severity <strong>of</strong>pancreatitis was evaluated by two observers using the Balthazar CT grading system and anMR grading system that is focused on an elevated signal on T1-weighted images. The MRgrading was correlated with the CT grading, and each MR or CT grade was compared withpatient outcome parameters, including the duration <strong>of</strong> hospitalization, local and systemiccomplications, and clinical outcome grading. There was a significant correlation between CTand MR gradings for pancreatic or peripancreatic inflammation. However, for all <strong>of</strong> theoutcome parameters and outcome grading, a stronger correlation was seen with the MRgrading than with the CT grading. No significant correlation was found between CT gradingand infected necrosis. It was concluded that magnetic resonance imaging including fatsuppressedT1-weighted images is more accurate to predict the severity and prognosis <strong>of</strong>acute pancreatitis in comparison with CT [187].Economical aspectsBoth endoscopic retrograde cholangiopancreatography (ERCP) and endoscopicultrasonography (EUS) are commonly performed in the evaluation <strong>of</strong> idiopathic pancreatitis.However, comparative trials <strong>of</strong> these modalities are lacking, and thus the ideal endoscopicdiagnostic strategy to evaluate idiopathic pancreatitis remains unknown. A decision analysismodel <strong>of</strong> patients with 2 attacks <strong>of</strong> idiopathic pancreatitis with gallbladder in situ wasconstructed using TreeAge s<strong>of</strong>tware. It was analyzed cost and overall diagnostic ability <strong>of</strong> 3strategies, namely, EUS, ERCP with manometry and bile aspiration, and laparoscopiccholecystectomy. Using the base case analysis, initial EUS was the preferred initial modalityfor the diagnosis. The expected cost for initial EUS was USD 4469 compared with USD 4615for ERCP and USD 6268 for laparoscopic cholecystectomy. For cholecystectomy to be thepreferred strategy, the total cost would need to be less than USD 1314, well below anyrealistic cost estimate. If the prevalence <strong>of</strong> microlithiasis/sludge was greater than 80 percent,then cholecystectomy would be preferred, whereas ERCP would be preferred with aprevalence <strong>of</strong> less than 41 percent. This cost minimization study identifies EUS as the leastcostly initial test for the diagnostic evaluation <strong>of</strong> patients with idiopathic pancreatitis withgallbladder in situ [188].Differential diagnosisEctopic pregnancy may lead to massive haemorrhage, infertility or death. Prompt diagnosisand treatment are crucial to save patients who would otherwise die. Serum amylase andlipase measurements are known biochemical markers <strong>of</strong> pancreatic inflammation and arecognized finding that may help diagnose acute pancreatitis. It was now reported that amisdiagnosed ruptured ectopic pregnancy in the event <strong>of</strong> elevated activities <strong>of</strong> pancreaticenzymes may lead to delayed diagnosis <strong>of</strong> haemorrhage to peritoneum, resulting in

hemodynamic instability [189].Acute pancreatitis in childrenEpidemiologyStudies show an increased incidence <strong>of</strong> adult acute pancreatitis in recent decades. Aretrospective <strong>review</strong> <strong>of</strong> computerized databases at the Children's Hospital <strong>of</strong> Pittsburgh from1993 to 2004 was performed. The incidence <strong>of</strong> acute pancreatitis was compared with ordersfor amylase and lipase testings and with the catchment population. Over the study period,there were a total <strong>of</strong> 1021 discharge diagnoses <strong>of</strong> acute pancreatitis (731 first diagnoses).The diagnosis <strong>of</strong> acute pancreatitis increased from a low <strong>of</strong> 28 total cases (21 firstdiagnoses) in 1993 to a high <strong>of</strong> 141 total cases (109 first diagnoses) in 2004. The catchmentpopulation decreased from 882,000 to 826,500. The estimated incidences <strong>of</strong> first acutepancreatitis admission were 2.4 to 13.2 per 100,000 children. Linear regression analysissuggests that increased testing for amylase and lipase could account for 94 percent <strong>of</strong> thechange in all acute pancreatitis admissions. It was concluded that the increased incidence <strong>of</strong>AP at the Children's Hospital <strong>of</strong> Pittsburgh from 1993 to 2004 may have been primarily drivenby increased testing for the disease [190].Acute pancreatitis in pediatric acute lymphoblastic leukemiaAcute pancreatitis is a complication in children with acute lymphoblastic leukemia (ALL)receiving chemotherapy and has <strong>of</strong>ten been reported associated with L-asparaginase (L-asp)therapy. To determine the incidence, risk factors, clinical data, outcome, and mortality <strong>of</strong>acute pancreatitis in children with ALL a retrospective cohort study was conducted by<strong>review</strong>ing the data <strong>of</strong> total 192 pediatric ALL patients from one hospital from 2000 to 2006 toassess incidence, clinical data, outcome, and mortality <strong>of</strong> AP. Then, a nested case-controlstudy was conducted to identify potential risk factors for AP by recruiting all patients withacute pancreatitis as cases (n=16), and randomly selected patients without acute pancreatitisto serve as controls up to approximately four controls per case with the total <strong>of</strong> 68 controls.The total incidence <strong>of</strong> acute pancreatitis in children with ALL and L-asp-associated acutepancreatitis was 8.3 percent and 7.3 percent, respectively. In patients with L-asp-associateddisease, pancreatitis developed after the median 6 doses (range: 1 to 20 doses) <strong>of</strong> L-asptherapy and the median interval from the last dose <strong>of</strong> L-asp to the onset <strong>of</strong> acute pancreatitiswas 4 days (range: 1 to 13 days). The mortality rate <strong>of</strong> the pancreatitis group wassignificantly higher than the patients without acute pancreatitis (44 % vs 19 %). Mortality wasassociated with concurrent systemic infection and complications <strong>of</strong> underlying diseases.Multivariate analysis identified using a high-risk chemotherapy regimen was the only riskfactor for acute pancreatitis [191].Specific injuriesPulmonary injuryOne <strong>of</strong> the most common complications <strong>of</strong> acute pancreatitis is acute lung injury, duringwhich intercellular adhesion molecule-1 (ICAM-1) plays an important role by participating inleukocyte adhesion and activation as well as by inducing the "cascade effect" <strong>of</strong> inflammatorymediators, pulmonary microcirculation dysfunction and even acute respiratory distresssyndrome, multiple organ failure or death. Although it is generally believed that themodulatory mechanism <strong>of</strong> ICAM-1 during this process is associated with the activation <strong>of</strong>nuclear transcription factor kappa B which is mediated by IL-1, IL-6, IL-18 and oxygen free

adical, etc, further studies are still required to clarify it. Since the upregulation <strong>of</strong> ICAM-1expression in the lung during acute lung injury is one <strong>of</strong> main pathogeneses, the earlydetection <strong>of</strong> the ICAM-1 expression level may contribute to the prevention and treatment <strong>of</strong>acute lung injury. Moreover, reducing pulmonary ICAM-1 expression levels through treatmentwith anti-ICAM-1 monoclonal antibody (aICAM-1) and antagonists <strong>of</strong> the neurokinin 1receptor, etc, should have a positive effect on protecting the lungs during acute pancreatitis.One <strong>review</strong> aimed to further clarify the relationship between ICAM-1 and acute pancreatitiscomplicated by acute lung injury, and therefore provides a theoretical basis for theformulation <strong>of</strong> corresponding therapeutic measures in clinical practice for acute pancreatitis[192].OsteonecrosisThere was a case report on multifocal osteonecrosis caused by traumatic pancreatitis in achild [193].Abdominal aortic aneurysm following acute pancreatitisVascular lesions may complicate the course <strong>of</strong> acute pancreatitis. The activated pancreaticenzymes, particularly elastase, might cause lysis <strong>of</strong> the elastic component <strong>of</strong> the arterial wallthus leading to aneurysmal changes. It was reported on a case <strong>of</strong> aneurysm <strong>of</strong> the infrarenalaorta following complicated acute pancreatitis and treated by endovascular technique [194].Colonic obstruction in acute pancreatitisSeveral forms <strong>of</strong> colonic complications are rarely observed during the clinical course <strong>of</strong> acutepancreatitis, and potentially fatal in some cases. Colonic lesions associated with acutepancreatitis can be divided into several groups from a pathogenic point <strong>of</strong> view. Possiblepathogenesis includes: 1) spread <strong>of</strong> pancreatic enzymes through the retroperitoneum tomesocolon, causing pericolitis, 2) external inflammatory compression by mesocolic masssecondary to necrosis <strong>of</strong> fatty tissue, and 3) hypotension due to shock, and thrombosis <strong>of</strong>mesenteric arteries. These might lead to colonic infarction, fistula formation, perforation, andobstruction during follow-up. It was reported two cases <strong>of</strong> colonic obstruction following acutepancreatitis with possible different mechanisms and <strong>review</strong> Korean cases. One patientdeveloped colonic obstruction due to severe necrotizing pancreatitis, possibly as a result <strong>of</strong>pericolitis, and the other developed stenosis as a result <strong>of</strong> ischemic colitis induced by acutepancreatitis [195].Pancreatitis in anorexia nervosaAnorexia nervosa, a syndrome most commonly affecting young women, is characterized byweight less than 85 percent <strong>of</strong> weight that is considered normal for that person’s age andheight, distorted body image, and fear <strong>of</strong> becoming obese. It was presented a case <strong>of</strong> a 33-year-old woman with a 9-year history <strong>of</strong> anorexia nervosa. Her body mass index was 11.5kg/m 2 <strong>of</strong> the time admission. Initial aminotransferase level was severely elevated, but it wasnormalized solely with improved nutrition and weight gain. Five and sixteen days after theadmission urinary tract infection and elevation <strong>of</strong> pancreatic enzymes occurred. They weresuccessfully treated with antibiotics and nutritional support. Fifty seven days after theadmission, she discharged [196].

Subgroups <strong>of</strong> acute forms <strong>of</strong> pancreatitisGallstone-induced pancreatitisGuidelines for treatmentAll patients that presented with gallstone pancreatitis over a 4-year period to a Scottishhospital were audited retrospectively. Data were collated for radiological diagnosis within 48hours, ERCP within 72 hours, CT at 6-10 days, and use <strong>of</strong> high-dependency or intensivetherapy units in severe gallstone pancreatitis, and definitive treatment <strong>of</strong> gallstonepancreatitis within 2 weeks as recommended in national guidelines. Forty-six patients hadsevere gallstone pancreatitis and 54 patients mild pancreatitis. Etiology was establishedwithin 48 hours in 92 patients. Six (13 %) out <strong>of</strong> the patients with severe gallstonepancreatitis were managed in a high dependency unit. Fifteen (33 %) patients with severegallstone pancreatitis underwent CT within 6-10 days <strong>of</strong> admission. Four (9 %) <strong>of</strong> the 46patients with severe gallstone pancreatitis had urgent ERCP (less than 72 hours). Overall22/100 patients unsuitable for surgery underwent endoscopic sphincterotomy as definitivetreatment. Seventy-eight patients had surgery, with 40 (51 %) <strong>of</strong> these patients undergoingan index admission cholecystectomy, and 38 (49 %) patients were discharged for intervalcholecystectomy. Overall 81 patients with gallstone pancreatitis had definitive therapy duringthe index to same admission (cholecystectomy or sphincterotomy). Two (5 %) patients werereadmitted whilst awaiting interval cholecystectomy: one with acute cholecystitis and onewith acute pancreatitis. There were no mortalities in this cohort. The study highlighteddifficulties in implementation <strong>of</strong> national guidelines, as the use <strong>of</strong> critical care, timing <strong>of</strong> ERCPand CT, and definitive treatment prior to discharge did not concur with national targets forgallstone pancreatitis [197].Impact on prognosis <strong>of</strong> ERCP + ESTDanish guidelines recommend that patients with presumed severe gallstone-induced acutepancreatitis should receive endoscopic retrograde cholangiopancreatography (ERCP) within72 hours. The results <strong>of</strong> a newly performed meta-analysis show that acute ERCP in patientswith gallstone-induced acute pancreatitis does not reduce the risk <strong>of</strong> complications, andERCP is therefore not to be used routinely in gallstone-induced acute pancreatitis patients.The possible benefits <strong>of</strong> replacing ERCP with either endoscopic ultrasonography or magneticresonance cholangiopancreatograhy have yet to be demonstrated [198].Early versus late cholecystectomyIn patients with biliary acute pancreatitis, cholecystectomy is mandatory to prevent furtherbiliary events, but timing <strong>of</strong> cholecystectomy remains a subject <strong>of</strong> ongoing debate. Theobjective <strong>of</strong> the present, retrospective study was to compare the outcomes <strong>of</strong> early (within 2weeks after onset <strong>of</strong> disease) versus delayed cholecystectomy in patients with biliary acutepancreatitis. Between 2000 and 2005, 112 patients underwent cholecystectomy because <strong>of</strong>biliary pancreatitis. Thirteen patients were excluded from analysis because <strong>of</strong> necrotizingpancreatitis on the initial computed tomography. Thirty-two were operated within 14 days(group A) and 67 after a longer time period (group B). The primary end point <strong>of</strong> the study wasthe rate <strong>of</strong> biliary complications before cholecystectomy. There were no differences regardingconversion rates to open surgery (6 % vs 3 %), local (3 % vs 4 %), or systemic complications(0 % vs 3 %), and mean postoperative stay (4.7 vs 5.7 days). Nevertheless, a greater rate <strong>of</strong>recurrent biliary pancreatitis was found in the group undergoing cholecystectomy later (0 %vs 13 %). It was concluded that the timing <strong>of</strong> cholecystectomy seems to have no clinicallyrelevant effect on local or systemic complications, but delaying cholecystectomy isassociated with an increase <strong>of</strong> biliary complications in patients with non-necrotizing biliaryacute pancreatitis [199].

Precut at sphincterotomyPrecut is performed when biliary access at endoscopic retrograde cholangiopancreatography(ERCP) fails. Precut may have adjunctive risks, but some authors have suggested that theattempts to cannulate the papilla that precede precutting cause complications. It wastherefore evaluated the role <strong>of</strong> the timing <strong>of</strong> precut in determining the development <strong>of</strong>complications and with respect to the other factors involved. During ERCP, after 10 min <strong>of</strong>attempts to cannulate, patients were randomized to an early-precut group (n=77) undergoingprecut immediately or a late-access group (n=74) in which cannulation was attempted for 10further minutes before the endoscopist was free to perform precut or to persist incannulation. Occurrence <strong>of</strong> complications and the associated risk factors were recorded. Thetwo groups were similar for general characteristics. The number <strong>of</strong> attempts to cannulate, thenumber <strong>of</strong> pancreas injections, and the incidence <strong>of</strong> acinarization were higher in the lateaccessgroup. The cannulation rate was 94 percent. The incidence <strong>of</strong> overall complicationswas similar, but the pancreatitis rate was higher in the late-access group (14.9 vs 2.6 %).Amylase levels increased by 399 + 879 in the early-precut group and 834 + 1478 in the lateaccessgroup, which was a significant difference. Nondilated bile duct and pancreaticinjection were related to the development <strong>of</strong> pancreatitis, whereas the performance <strong>of</strong> precutwas related to other complications. The authors concluded that early precut is associatedwith lower pancreatitis rate, suggesting that pancreatitis develops as a consequence <strong>of</strong> theattempts to cannulate the papilla and pancreatic injection, and not pre-cutting [200].ERCP in severe biliary pancreatitisPrevious studies have included only a relatively small number <strong>of</strong> patients with predictedsevere acute biliary pancreatitis in most studies. It was now again investigated the clinicaleffects <strong>of</strong> early ERCP in these patients in a prospective, observational multicenter study in 8university medical centers and 7 major teaching hospitals. One hundred fifty-three patientswith predicted severe acute biliary pancreatitis without cholangitis were enrolled in arandomized multicenter trial on probiotic prophylaxis in acute pancreatitis and wereprospectively followed. Conservative treatment or ERCP within 72 hours after symptomonset (at discretion <strong>of</strong> the treating physician) were compared for complications and mortality.Patients without and with cholestasis (bilirubin: >2.3 mg/dL and/or dilated common bile duct)were analyzed separately. Of the 153 patients, 81 (53 %) underwent ERCP and 72 (47 %)conservative treatment. Groups were highly comparable at baseline. Seventy-eight patients(51 %) had cholestasis. In patients with cholestasis, ERCP (52/78 patients: 67 %), ascompared with conservative treatment, was associated with significantly fewer complications(25 % vs 54 %). This included significantly fewer patients with >30 percent pancreaticnecrosis (8 % vs 31 %). Mortality was nonsignificantly lower after ERCP (6 % vs 15 %). Inpatients without cholestasis, ERCP (29/75 patients: 39 %) was not associated with reducedcomplications (45 % vs 41 %) or mortality (14 % vs 17 %). It was concluded that early ERCPis associated with fewer complications in predicted severe acute biliary pancreatitis ifcholestasis is present [201].Value <strong>of</strong> EUSWhen conventional ERCP methods fail because <strong>of</strong> periampullary or ductal obstruction, EUSguidedcholangiopancreatography (EUS-CP) may aid in pancreaticobiliary access.Consecutive patients undergoing EUS-CP were prospectively identified. These patients hadundergone failed attempt(s) at therapeutic ERCP. Technical success was decompression <strong>of</strong>the duct <strong>of</strong> interest. Clinical success was resolution <strong>of</strong> jaundice or at least a 50 percentreduction in pain or narcotics, as applicable. Between 2003 and 2007, EUS-CP wasattempted in 20 patients (11 men, 9 women age 58 years). Indications included jaundice(n=8), biliary stones (n=3), chronic pancreatitis (n=6), acute pancreatitis (n=2), and papillarystenosis (n=1). Reasons for failed ERCP included periampullary mass (n=8), intradiverticularpapillae (n=4), and pancreatic duct stricture (n=7) or stone (n=1). Technical success wasachieved in 18 <strong>of</strong> 20 patients (90 %). Biliary decompression was obtained in 11 <strong>of</strong> 12 patients(92 %) (7 transpapillary and 4 transenteric-transcholedochal). Pancreatic decompression

was obtained in 7 <strong>of</strong> 8 patients (88 %) (3 transpapillary, 4 transgastric). On follow-up, clinicalimprovement was noted in 15 <strong>of</strong> 20 patients (70 %). For treatment <strong>of</strong> pain associated withchronic pancreatitis, pain scores decreased. Complications (in 2 <strong>of</strong> 20) included perforation(n=1) and respiratory failure (n=1). It was concluded that a single-operator EUS-guidedcholangiopancreatography provided decompression <strong>of</strong> obstructed ducts and may beperformed after a failed attempt at conventional ERCP during the same endoscopic session[202].Correlation between laboratory values and remaining common bile duct stoneAn important question to be answered in all cases <strong>of</strong> acute biliary pancreatitis is whether ornot a calculous biliary obstruction is still present. Answering this question conditionssubsequent management, include the need for endoscopic retrograde cholangiopancreatography(ERCP). The aim <strong>of</strong> one study was to determine the relationship between persistentcommon bile duct stone (CBDS) and laboratory values, and dilation <strong>of</strong> bile duct in order t<strong>of</strong>ind possible significant associations in patients with acute biliary pancreatitis (ABP). It wasretrospectively, statistical evaluated a group <strong>of</strong> 76 patients with ABP who had received earlyERCP. The prevalence <strong>of</strong> choledocholithiasis in patients > 70 years old was 54 percent, inpatients < 70 years old it was 37 percent. Following cholecystectomy, CBDS was present in82 percent <strong>of</strong> patients. The probability <strong>of</strong> CBDS occurrence in patients > 70 years old withbile duct dilation was 81 percent; in the absence <strong>of</strong> bile duct dilation CBDS was not present.The probability <strong>of</strong> CBDS occurrence in patients 70 years old with bile duct dilation was 58percent, in the absence <strong>of</strong> bile duct dilation CBDS was present in 15 percent, which was asignificant difference. In patients with bile duct dilation predictive factors were as follows:bilirubin, after excluding patients with acute cholecystitis and cholangitis; alanineaminotransferase in patients 70 years old; gamma-glutamyl transferase in patients > 70years old. It was concluded that ERCP is indicated in patients with acute biliary pancreatitis ifbiliary obstruction is present and the presence <strong>of</strong> a ductal stone is suspected. From theresults it is clear that the predictive parameter for choledocholithiasis is the dilation <strong>of</strong> the bileduct and previous cholecystectomy [203].Mild biliary pancreatitisGallstones represent the most common cause <strong>of</strong> acute pancreatitis in Sweden.Epidemiological data concerning timing <strong>of</strong> cholecystectomy and sphincterotomy in patientswith first attack <strong>of</strong> mild acute biliary pancreatitis (MABP) are scarce. Our aim was to analysereadmissions for biliary disease, cholecystectomy within one year, and mortality within 90days <strong>of</strong> index admission for MABP. Hospital discharge and death certificate data were linkedfor patients with first attack acute pancreatitis in Sweden 1988-2003. Mortality was calculatedas case fatality rate (CFR) and standardized mortality ratio (SMR). MABP was defined asacute pancreatitis <strong>of</strong> biliary aetiology without mortality during an index stay <strong>of</strong> 10 days orshorter. Patients were analysed according to four different treatment policies:Cholecystectomy during index stay (group 1), no cholecystectomy during index stay butwithin 30 days <strong>of</strong> index admission (group 2), sphincterotomy but not cholecystectomy within30 days <strong>of</strong> index admission (group 3), and neither cholecystectomy nor sphincterotomywithin 30 days <strong>of</strong> index admission (group 4). Of 11636 patients with acute biliary pancreatitis,8631 patients (74 %) met the criteria for MABP. After exclusion <strong>of</strong> those withcholecystectomy or sphincterotomy during the year before index admission (n=212), 8419patients with MABP remained for analysis. Patients in group 1 and 2 were significantlyyounger than patients in group 3 and 4. Length <strong>of</strong> index stay differed significantly betweenthe groups, from 4 (3-6) days, (representing median, 25 and 75 percentiles) in group 2 to 7(5-8) days in groups 1. In group 1, 4.9 percent <strong>of</strong> patients were readmitted at least once forbiliary disease within one year after index admission, compared to 100 percent in group 2, 63percent in group 3, and 76mpercent in group 4. One year after index admission, 31 percent<strong>of</strong> patients in group 3 and 48 percent <strong>of</strong> patients in group 4 had undergone cholecystectomy.SMR did not differ between the four groups. It was concluded that cholecystectomy duringindex stay slightly prolongs this stay, but drastically reduces readmissions for biliary

indications [204].Hypercalcemia-induced pancreatitisHypercalcemia due to hyperparathyroidism is a rare etiology for acute pancreatitis, oscillatingbetween 1.5 and 7 percent in the different series. Although the cause-effect relationship andthe pathophysiology <strong>of</strong> the condition are not clear, it seems that the association among themis not incidental, and serum calcium could be a major risk factor, so that pancreatitis wouldcome to occur during severe hypercalcemia attacks. Mutations in different genes have beenproposed as well to justify why only some patients with primary hyperparathyroidism andhypercalcemia develop acute pancreatitis. References to cases like these ones are rare inthe <strong>literature</strong>. It was reported two patients with acute pancreatitis associated withhyperparathyroidism and hypercalcemia, one <strong>of</strong> them with a fatal outcome [205].Hypercalcemia is an important etiology to consider in the evaluation <strong>of</strong> acute pancreatitis.Not only is it a treatable cause, but understanding the basis for this etiology may provide newinsight into the common biochemical mechanisms involved in the pathogenesis <strong>of</strong>pancreatitis. It was reported a case <strong>of</strong> an 11-year-old girl with hypercalcemia due to primaryhyperparathyroidism who developed recurrent pancreatitis [206].Alcohol-induced pancreatitisThe aim <strong>of</strong> one study was to investigate the association between lifetime consumption <strong>of</strong>alcoholic beverages and cancer risk. Data were collected in a population-based case-controlstudy, conducted in Montreal in the mid-1980s, designed to assess the associations betweenhundreds <strong>of</strong> non-occupational and occupational exposures and multiple cancer sites in men.It was presented results for 13 cancer sites 83 patients with pancreas cancer in comparisonto population controls (n=507). Odds ratios (OR) were estimated for the associationsbetween lifetime consumption <strong>of</strong> total alcoholic beverages, beer, wine, and/or spirits,altogether and separately, and each cancer site, while carefully adjusting for smoking andother covariates using polytomous logistic regression. For several cancers (oesophagus,stomach, colon, liver, pancreas, lung, prostate) there was evidence <strong>of</strong> increased risk amongalcohol consumers compared with abstainers and occasional drinkers. For most sites, it wasbeer and to a lesser extent spirits consumption that drove the excess risks. The resultssupport the hypothesis that moderate and high alcohol intake levels over the lifetime mightincrease cancer risk at several sites [207].During 2006 to 2007, 78 patients with acute pancreatitis were prospectively searched for theetiology by:- Performing liver chemistry tests and transabdominal ultrasonography (US) forgallstone in every case- Measuring serum triglyceride and calcium in every case- Investigating definite drugs use or other identified etiology- Asking about the amount <strong>of</strong> alcohol ingestion (amount > 80 g/day for > 5 years wasrequired for alcoholic AP- Performing CT scan (if age > 40 years) and EUS if no etiology was identified.Of the 78 patients, the etiologies were alcohol in 32 (41 %), gallstones in 29 (37 %),miscellaneous in 13 (1 7%) and idiopathic acute pancreatitis in 4 patients (5 %). Among the45 patients <strong>of</strong> the study period (58 %) who consumed alcohol more than the definedthreshold for alcoholic acute pancreatitis, 13 (29 %) were found to have other explainablecauses <strong>of</strong> pancreatitis, i.e gallstones in 10, hypertriglyceridemia in 2 and AIDScholangiopathy in 1 patient. The authors concluded that alcohol was probably over-

diagnosed as a leading etiology <strong>of</strong> pancreatitis in the past. One-fourth <strong>of</strong> AP patients whowere heavy drinkers had other explainable etiologies <strong>of</strong> acute pancreatitis [208].In the long term, half <strong>of</strong> patients with their first alcohol-associated acute pancreatitis developacute recurrence, alcohol consumption being the main risk factor. None <strong>of</strong> the recent nationalor international guidelines for treatment include recommendations aimed to decreaserecurrences, possibly because <strong>of</strong> a lack <strong>of</strong> studies. One study investigated whether acuterecurrences can be reduced. One hundred and twenty patients admitted to a universityhospital for their first alcohol-associated acute pancreatitis were randomized either torepeated intervention (n=59) or initial intervention only (n=61). The patients in the two groupsdid not differ. A registered nurse performed an intervention in both groups before discharge,after which it was repeated in the study group at 6-month intervals at the gastrointestinaloutpatient clinic. Acute recurrences during the next 2 years were monitored. There were 9recurrent pancreatitis episodes in 5 patients in the repeated-intervention group comparedwith 20 episodes in 13 patients in the control group, which was a signifikant difference. Therecurrence rates were similar during the first 6 months (4 vs 5 episodes), after which therepeated-intervention group had significantly fewer recurrences than the control group (5 vs15 episodes). It was concluded that the repeated visits at 6-month intervals at thegastrointestinal outpatient clinic, consisting <strong>of</strong> an intervention against alcohol consumption,appear to be better than the single standardized intervention alone during hospitalization inreducing the development <strong>of</strong> recurrent acute pancreatitis during a 2-year period [209].Acute alcoholic pancreatitis (AAP) recurs in up to half <strong>of</strong> the patients, continuous alcoholconsumption being an important risk factor. Changes in pancreatic function and morphologyafter acute pancreatitis have been characterized previously, but their association with laterrecurrences has not been adequately studied. In a prospective follow-up study, thepancreatic function <strong>of</strong> 54 patients (47 males and 7 females) with a median age <strong>of</strong> 49 years(range 25-71) and morphology (35 patients) were evaluated. Pancreatic morphology wasevaluated by secretin-stimulated magnetic resonance pancreatography (SMRP). Patientswere evaluated early (baseline) and at 2 years after the first episode <strong>of</strong> AAP. In order toevaluate later recurrences, the patients were followed for a median <strong>of</strong> 47 (range 28-66)months. Of the 46 patients without previous diabetes, 17 patients (37 %) developed impairedglucose metabolism during the 2 years following the first AAP. The prevalence <strong>of</strong> exocrinedysfunction decreased from 39 percent at baseline to 9 percent at 2 years. Of the patientswith severe pancreatitis (n=13, 24 %), 31 percent had elevated glycosylated haemoglobinlevels compared to 7 percent in patients with mild pancreatitis (odds ratio 5.5, 95 %confidence interval 1.04 to 29.0]. Twenty percent (7/35) <strong>of</strong> the patients had changesconsistent with chronic pancreatitis on baseline SMRP, which persisted in all cases. Of the29 percent <strong>of</strong> patients with acute changes on baseline SMRP, the acute changes resolved in50 percent and chronic pancreatitis was detected in the remaining 50 percent at 2 years.Development <strong>of</strong> chronic changes did not depend on continued alcohol consumption, as itwas also found in three patients practising complete abstinence following their first attack <strong>of</strong>AAP. The presence <strong>of</strong> a chronic pseudocyst at 2 years predicted pancreatitis whencompared to patients lacking pseudocyst formation: 4 (80 %) versus 5 (17 %) (odds ratio 2095 % confidence interval 1.83 to 219). It was concluded taht the severity <strong>of</strong> the first episode<strong>of</strong> AAP was associated with deteriorated diabetes control, but not with pancreatic exocrinedysfunction at 2 years. The number <strong>of</strong> patients with chronic changes on SMRP increasedindependently <strong>of</strong> alcohol consumption. Chronic pseudocyst formation seen on SMRP 2 yearsafter AAP was significantly associated with recurrence <strong>of</strong> pancreatitis [210].Post-ERCP-pancreatitisProphylactic effect <strong>of</strong> allupurinolTo assess the efficacy <strong>of</strong> allopurinol to prevent hyperamylasemia and pancreatitis after

endoscopic retrograde cholangiopancreatography 170 patients were enrolled andrandomized to two groups: a study group (n=85) who received 300 mg <strong>of</strong> oral allopurinol at15 h and 3 h before endoscopic retrograde cholangiopancreatography (ERCP) and a controlgroup (n=85) receiving an oral placebo at the same times. Main Outcome Measurementsincluded serum amylase levels and the number severity <strong>of</strong> the episodes <strong>of</strong> pancreatitis.Serum amylase levels were classified as normal (< 150 IU/L) or hyperamylasemia (> 151IU/L). Episodes <strong>of</strong> pancreatitis were classified following Ranson's criteria and CT severityindex. Distribution <strong>of</strong> benign pathology was similar between groups. Hyperamylasemia wasmore common in the control group. Mild pancreatitis developed in two patients from the studygroup (2.3 %) and eight (9.4 %) from control group, which was a significant difference; sevenepisodes were observed in high-risk patients <strong>of</strong> the control group (25 %) and one in theallopurinol group (3 %). Significant risk factors for post-procedure pancreatitis were precutsphincterotomy, pancreatic duct manipulation, and multiple procedures. There were nodeaths or side effects. It was concluded that allopurinol before ERCP decreased theincidences <strong>of</strong> hyperamylasemia and pancreatitis in patients submitted to high-risk procedures[211].Sprayed epinephrine as prophylaxisEpinephrine sprayed on the papilla may reduce papillary edema and thus prevent acutepancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). The aim <strong>of</strong> onestudy was to determine the efficacy <strong>of</strong> this technique for prevention <strong>of</strong> post- ERCPpancreatitis. It was randomized the patients to have 10 ml <strong>of</strong> either 0.02 percent epinephrine(epinephrine group) or saline (control group) sprayed on the papilla after diagnostic ERCPand prospectively analyzed the occurrence <strong>of</strong> post-ERCP pancreatitis between the groups.There was no significant difference between the groups with regard to visualization <strong>of</strong> the bileduct and/or the main and accessory pancreatic ducts, presence <strong>of</strong> pancreatic acinarization,number <strong>of</strong> injections into the pancreatic duct, total volume <strong>of</strong> contrast used, and procedureduration. Overall, post-ERCP pancreatitis occurred in 4 <strong>of</strong> the 370 patients (1 %). Theincidence <strong>of</strong> pancreatitis tended to be higher in the control group (4/185) than in theepinephrine group (0/185), but this was not a statistically significant difference. Furtherstudies on the efficacy <strong>of</strong> this technique in patients at high risk for pancreatitis, and on othervolumes and/or concentrations <strong>of</strong> epinephrine, are warranted [212].Interleukin-10 as prophylaxisPancreatitis is the most common major complication <strong>of</strong> endoscopic retrogradecholangiopancreatography (ERCP). Inflammatory cytokines are released during acutepancreatitis. Interleukin-10 (IL-10) is a potent inhibitor <strong>of</strong> cytokines and has been shown toattenuate pancreatitis in animal models and pilot human studies. One study aimed todetermine whether prophylactic IL-10 administration reduces the frequency or severity <strong>of</strong>post-ERCP pancreatitis in high-risk patients. A randomized, multicenter, double-blind,placebo-controlled study was conducted. Patients received IL-10 at a dose <strong>of</strong> either 8 or 20microg/kg or placebo as a single intravenous injection 15 to 30 minutes before ERCP.Standardized criteria were used to diagnose and grade the severity <strong>of</strong> postprocedurepancreatitis. A total <strong>of</strong> 305 <strong>of</strong> the planned total enrollment <strong>of</strong> 948 patients were randomized.There was a 15, 22, and 14 percent incidence <strong>of</strong> post-ERCP pancreatitis in the IL-10 (8microg/kg), IL-10 (20 microg/kg), and placebo treatment groups, respectively. Due toapparent lack <strong>of</strong> efficacy, the study was terminated at an interim analysis [213].Antibiotics as prophylaxisIt was determined the prophylactic effect <strong>of</strong> antibiotics on post-endoscopic retrogradecholangiopancreatography (ERCP) cholangitis or sepsis reduction in randomized controlledtrials. Databases including MEDLINE, EMBASE, Cochrane Library, and Science CitationIndex updated to June 2007 were searched. Main outcome measure was post-ERCPcholangitis or sepsis. Seven trials were identified, and a total <strong>of</strong> 1389 patients were included;post-ERCP cholangitis occurred in 5.8 percent <strong>of</strong> controls (41/705) versus 3.4 percent <strong>of</strong>

treated patients (23/684), without statistical significance (relative risk [RR], 0.58; 95 %confidence interval [CI], 0.22 tgo 1.55). Subsequent sensitivity analysis on trials mainlytargeted at patients with suspicious biliary obstruction showed that the incidences <strong>of</strong> post-ERCP cholangitis were 2.8 percent (12/425) and 5.4 percent (24/441) in the antibiotics andcontrol groups, respectively, and this sensitivity analysis did not support antibiotics'preventive effect (RR, 0.33; 95 % CI, 0.03 to 3.32). Another sensitivity analysis exclusivelyincluding trials with intravenous route <strong>of</strong> antibiotics administration also failed to confirm theprophylactic effect <strong>of</strong> antibiotics (RR, 0.53; 95 % CI, 0.18 to 1.60). It was concluded thatantibiotics cannot significantly prevent ERCP-induced cholangitis in unselected patients andshould not be routinely recommended [214].To determine the prophylactic effect <strong>of</strong> antibiotics on post-endoscopic retrogradecholangiopancreatography (ERCP) cholangitis or sepsis reduction in randomized controlledtrials a search was done in databases including MEDLINE, EMBASE, Cochrane Library, andScience Citation Index updated to June 2007. Main outcome measure was post-ERCPcholangitis or sepsis. Seven trials were identified, and a total <strong>of</strong> 1389 patients were included;post-ERCP cholangitis occurred in 5.8 percent <strong>of</strong> controls (41/705) versus 3.4 percent <strong>of</strong>treated patients (23/684), without statistical significance. Subsequent sensitivity analysis ontrials mainly targeted at patients with suspicious biliary obstruction showed that theincidences <strong>of</strong> post-ERCP cholangitis were 2.8 percent (12/425) and 5.4 percent (24/441) inthe antibiotics and control groups, respectively, and this sensitivity analysis did not supportantibiotics' preventive effect. Another sensitivity analysis exclusively including trials withintravenous route <strong>of</strong> antibiotics administration also failed to confirm the prophylactic effect <strong>of</strong>antibiotics [215].TAP for monitoring post-ERCP-pancreatitisTrypsinogen activation peptide (TAP) is a small peptide <strong>of</strong> 7 to 10 amino acids capable <strong>of</strong>activating trypsinogen into trypsin, and it reflects the amount <strong>of</strong> activated trypsinogen. SerumTAP concentrations determined before and 6 hours after ERCP did not differ probablybecause the half-life <strong>of</strong> TAP is approximately 8 minutes, and this time interval is too long todetect its alteration. Therefore, the primary end point <strong>of</strong> the study was to evaluate the hourlyTAP concentration elevation after ERCP. All consecutive patients who underwentinterventional ERCP from 2005 to 2007 were studied. Post-ERCP acute pancreatitis wasdefined as the appearance <strong>of</strong> typical abdominal pain associated with an increase in serumamylase activity greater than 3 times the upper reference limit. Elevation <strong>of</strong> serum TAPconcentration was estimated in 30 percent <strong>of</strong> patients who developed postprocedural acutepancreatitis. It was enrolled 75 patients (38 men and 37 women). The reasons for which theyunderwent operative ERCP were cholangitis or jaundice in 63 patients (84 %), the need toinsert a biliary stent in 4 (5 %), persistent pain or jaundice in 6 patients (8 %) with recurrentpancreatitis, and the need to insert a pancreatic stent in 2 (3 %). The mean endoscopicprocedure lasted for 45 minutes (range, 15-95 minutes). There was difficult cannulation in 29patients (39 %); Wirsung injection in 40 (53 %); mechanic lithotripsy in 2 (3 %); biliarysphincterotomy in 44 (59 %); major papilla pancreatic sphincterotomy in 6 (8 %); minorpapilla sphincterotomy in 2 (3 %); and insertion <strong>of</strong> endoscopic biliary drainage in 23 (31 %),<strong>of</strong> pancreatic drainage in 6 (8 %), <strong>of</strong> a biliary stent in 17 (23 %), and <strong>of</strong> a pancreatic stent in 3(4 %). Sixty-one patients (81 %) received intravenous gabexate mersilat as a prophylactictreatment to prevent postprocedural ERCP. Postprocedural abdominal pain was recorded at1 hour in 35 patients (47 %), 2 hours in 34 (45 %), 3 hours in 14 (19 %), 4 hours in 8 (11 %),and 6 hours in another 8 (11 %); 6 patients (8 %) had pain for more than 6 hours.Postprocedural acute pancreatitis developed in 13 patients (17 %), and it was in all <strong>of</strong> themclinically mild. The frequency <strong>of</strong> patients with acute pancreatitis who had pain after 2 hours(11/13; 85 %) was significantly higher when compared with patients without acutepancreatitis (23/62; 37 %). Postprocedural acute pancreatitis developed in 20 % (12/61) <strong>of</strong>patients who received gabexate and 7 percent (1/14) <strong>of</strong> those who did not, which was a notsignificant difference. In the 65 patients who completed the study, at basal examination

(before ERCP), serum TAP was detectable in all patients. One- and 2-hour post-ERCPserum TAP concentrations remained elevated, whereas these concentrations significantlydeclined at 4 hours. Urine TAP showed the same behavior as serum TAP; detectable urineconcentrations were present in 6 (9 %) <strong>of</strong> the 65 patients before ERCP and after 2 hours,whereas at 4 and 6 hours, all patients had no detectable urinary TAP concentrations. Meanserum trypsinogen concentrations were slightly below the upper reference limit (57 ng/mL)before ERCP examination, and then they were significantly increased thereafter. BeforeERCP, there were no significant differences in the serum and urinary levels <strong>of</strong> the enzymesstudied among the different final diagnoses. Serum and urine TAP levels and serumtrypsinogen concentration showed no significant differences between patients whodeveloped acute pancreatitis after ERCP and those who did not in any <strong>of</strong> the time intervalsstudied. The same behaviour was present between patients who were treatedprophylactically with gabexate and those who did not receive the drug. Regarding theprimary end point, all patients had detectable concentrations <strong>of</strong> serum and urine TAP beforeERCP, and no differences in basal TAP values were observed among patients with lithiasis<strong>of</strong> the common bile duct, those with benign stenosis <strong>of</strong> the common bile duct, those withchronic pancreatitis, and those with common bile duct pancreatic neoplasms. The serumconcentrations <strong>of</strong> TAP remained elevated for the subsequent observation period (at 1 and 2hours) and then progressively declined at 3, 4, and 6 hours. This observation confirms dataon the low sensitivity <strong>of</strong> serum TAP in diagnosing acute pancreatitis because TAP is rapidlyeliminated from the circulation. Urine TAP gave the same results [216].Ischemic pancreatitisAcute pancreatitis due to pancreatic ischemia is a rare condition. In a case report it wasdescribed a 57-year-old male who developed an acute necrotizing pancreatitis after runninga marathon and visiting a sauna the same evening, with an inadequate fluid and foodconsumption during both events. Pancreatic ischemia imposed by mechanical and physicalstress and dehydration can induce the development <strong>of</strong> acute pancreatitis. Separately, thesefactors are rare causes <strong>of</strong> ischemic acute pancreatitis. But when combined, as in thisparticular case, the risk <strong>of</strong> an acute necrotizing pancreatitis cannot be neglected [217].Drug-induced pancreatitisIt was reported a case <strong>of</strong> a 35-year-old patient with acute pancreatitis after administration <strong>of</strong>ceftriaxone. She was given ceftriaxone (2g/day) for 9 days because <strong>of</strong> diverticulitis <strong>of</strong> thecolon but was admitted to our hospital again because <strong>of</strong> epigastralgia 12 days after the firstadministration <strong>of</strong> ceftriaxone. Laboratory examination showed markedly elevated serumamylase, and CT scan demonstrated findings consistent with acute pancreatitis, in additionto sludge in the common bile duct and gall bladder, which was not identified before theadministration <strong>of</strong> ceftriaxone. One may be aware <strong>of</strong> the fact that administration <strong>of</strong> ceftriaxonesometimes results in the formation <strong>of</strong> biliary sludge and can cause severe adverse eventssuch as cholecystitis and pancreatitis, not only in children, but also in adult patients [218].Infective pancreatitisAscarisAscaris lumbricoides infestations are endemic in tropical countries. Ascaris lumbricoides canoccasionally cause biliary obstruction and result in obstructive jaundice or pancreatitis. It waspresent a 34-year-old Bangladeshi woman with biliary ascariasis, resulting in recurrentpancreatitis. Her diagnosis was made with endoscopic retrograde cholangiopancreatographyperformed during an acute attack <strong>of</strong> pain [219].

BrucellosisBrucellosis is an acute, subacute or chronical disease, from the zoonosis group, caused byvarious types <strong>of</strong> bacteria belonging to genus Brucellae. It is transmitted to humans fromdomestic animals: goats, sheep, cattle, pigs and dogs. The course <strong>of</strong> the disease may eitherbe asymptomatic, or produce a variety <strong>of</strong> clinical manifestations, ranging from light ones toextremely severe clinical forms. The aim <strong>of</strong> one study was to follow the clinical features <strong>of</strong>brucella infection in the hospital-treated patients, as well as its course and outcome. Theinvestigation included 15 patients, treated for brucella infection during the last two years(2004 and 2005). All patients were adults, their age ranged from 18 to 71, 50 on average.The epidemiological questionnaire was positive in all patients, confirming contacts with theailing animals, or consumption <strong>of</strong> cheese made from milk <strong>of</strong> diseased animals. They allexhibited the classic symptoms: increased body temperature and shiver, fever, sweating,malaise and headache, the so called flu like state. The serum agglutination test was positivein respect to brucellosis, the titre ranged from 1:80 to 1:1280. Eight patients sufferedexcessive back pain, accompanied with impeded walk. In half <strong>of</strong> them magnetic resonanceimaging confirmed the spondylodiscitis diagnosis. Three patients had clinical features <strong>of</strong>knee arthritis, two had bronchopneumonia, one pancreatitis, and one developed the signs <strong>of</strong>an acute kidney insufficiency. The outcome was favourable in all patients. They recuperatedor healed completely. In one patient a relapse occurred, leading to the chronic course <strong>of</strong> theillness. Although predominantly Mediterranean Brucellosis is a worldwide spread disease[220].LeptospirosisEven though leptospiral infection is not uncommon, it can have different rare presentations.Acute pancreatitis is one such rare gastrointestinal manifestation <strong>of</strong> acute pancreatitis. Apartfrom the typical clinical features; elevated serum lipase or elastase-1, along with radiologicalevidence and positive leptospiral serology confirms this rare association [221].Attempts to non-surgical treatmentEnteral nutritionAlthough the benefits <strong>of</strong> enteral nutrition in acute pancreatitis are well established, theoptimal composition <strong>of</strong> enteral feeding is largely unknown. The aim <strong>of</strong> one study was tocompare the tolerance and safety <strong>of</strong> enteral nutrition formulations in patients with acutepancreatitis. Electronic databases (Scopus, MEDLINE, Cochrane Controlled Clinical TrialsRegister) and the proceedings <strong>of</strong> major pancreatology conferences were searched. Twentyrandomized controlled trials, including 1070 patients, met the inclusion criteria. None <strong>of</strong> thefollowing was associated with a significant difference in feeding intolerance: the use <strong>of</strong>(semi)elemental versus polymeric formulation (relative risk 0.62; 95 percent confidenceinterval 0.10 to 3.97); supplementation <strong>of</strong> enteral nutrition with probiotics (relative risk 0.69;95 percent confidence interval 0.43 to 1.09); or immunonutrition (relative risk 1.60; 95percent confidence interval 0.31 to 8.29). The risk <strong>of</strong> infectious complications and death didnot differ significantly in any <strong>of</strong> the comparisons. It was concluded that the use <strong>of</strong> polymeric,compared with (semi)elemental, formulation does not lead to a significantly higher risk <strong>of</strong>feeding intolerance, infectious complications or death in patients with acute pancreatitis.Neither the supplementation <strong>of</strong> enteral nutrition with probiotics nor the use <strong>of</strong> immunonutritionsignificantly improves the clinical outcomes [222].Plasmapheresis <strong>of</strong> triglyceridesIt was presented case report shows hypertriglycerydemia treatment problem in 26-year-oldwoman with 2 episodes <strong>of</strong> acute pancreatitis history. Very high serum triglycerides

concentration and clinical symptoms suggested chylomicronemia syndrome with urgent needfor treatment. After a course <strong>of</strong> several subsequent therapeutic plasmapheresis triglyceridessignificantly decreased. Safety and effectiveness <strong>of</strong> this method was confirmed [223].Intravenous protease inhibitorsSevere acute pancreatitis is poor prognosis. Continuous regional arterial infusion <strong>of</strong> proteaseinhibitors and antibiotics were developed in Japan. It was evaluated whether arterial infusionboth celiac artery and superior mesenteric artery for this disease would reduce mortality.Seventeen patients were treated arterial infusion <strong>of</strong> protease inhibitor and antibiotics via bothceliac artery and superior mesenteric artery. Changes <strong>of</strong> Acute Physiology and ChronicHealth Evaluation II score and mortality were evaluated. Arterial infusion via two routesreduced the mortality rate and improved Acute Physiology and Chronic Health Evaluation IIscore. The overall mortality rate was 12 percent. The mortality rate in patients in those thatwere treated within 3 days after the onset was significantly lower than that in patients inwhom were treated without 3 days after the onset. Arterial infusion via superior mesentericartery might prevent both bacterial translocation and non-occlusive mesenteric ischemia.Continuous arterial infusion both celiac artery and superior mesenteric artery might beeffective for reducing mortality and preventing the development <strong>of</strong> pancreatitis, especiallywhen initiated within 3 days after the onset [224].Dialysis as a treatment for acute pancreatitisThe aim <strong>of</strong> one study was to study the therapeutic effects and the mechanism <strong>of</strong> combination<strong>of</strong> hem<strong>of</strong>iltration (HF) and peritoneal dialysis (PD) in the treatment <strong>of</strong> severe acutepancreatitis (SAP). Fifty-one cases <strong>of</strong> severe acute pancreatitis were randomly divided intothe HF+PD group (treated group, 36 patients) and the non-HF+PD group (control group, 15patients). Both groups were treated by the same traditional methods. The relief time <strong>of</strong>abdominal pain and abdominal distension, computed tomographic scores, acute physiologyand chronic health enquiry II scores, length <strong>of</strong> stay, cost <strong>of</strong> hospitalization, operability, andrecovery rate <strong>of</strong> the 2 groups were compared. The concentration <strong>of</strong> tumor necrosis factoralpha,IL-6, and IL-8 in serum and ascites volumes was determined before and aftertreatment. The mean time <strong>of</strong> abdominal pain relief, amelioration <strong>of</strong> abdominal distension,decrease <strong>of</strong> computed tomographic scores, acute physiology and chronic health enquiry IIscores, the mean length <strong>of</strong> stay, and cost <strong>of</strong> hospitalization <strong>of</strong> the treated group weresignificantly shorter or less than those <strong>of</strong> the control group. The aforementioned inflammatorycytokines, detected at the end <strong>of</strong> 1 day and 2 days after HF+PD treatment, were decreasedsignificantly compared with those observed in pretherapy and the control group. It wasconcluded that inflammatory cytokines, which overproduced in SAP, can be eliminatedeffectively from the blood and the ascites by HF+PD treatment [225].Peritoneal lavageThe evaluation <strong>of</strong> precocious and prolonged lavage and drainage by laparoscopic approachin the treatment <strong>of</strong> severe acute pancreatitis was studied 2006-2008 on a sample consisting<strong>of</strong> 35 subjects with the severe acute pancreatitis that was divided into two lots. One lot wasformed by 16 patients whom were applied the method mentioned ahead and in the B lot, 19patients, treated by conventional and known methods <strong>of</strong> treatment. The method proposed,completed about laparoscopic approach in a third day <strong>of</strong> admission, consists, after settinglesional balance, in lavage <strong>of</strong> peritoneal space and mounting two tubes drainage, onesubhepatic space and the other in Douglas space. Peritoneal lavage discontinuous withphysiological serum was done during 7 days. For an accurate assessment may weredetermined serum and peritoneal concentrations <strong>of</strong> interleukin 6. The duration <strong>of</strong> organicdysfunction was 8 days for A lot subjects and 18 days for B lot subjects. The mortality at A lot

was 13 percent (n=2) and at lot B 37 percent (n=7). The tardive mortality by sepsis was nullat subjects with lavage and was 16 percent (n=3) at subjects without lavage. The precociousmortality was 13 percent (n=2) in the A lot and 21 percent (n=4) in the lot B. The averagehospitalization was 26 days in subjects with peritoneal lavage and 36 days in those treatedconservatively, the difference is statistically significant. The method has proved notgenerating <strong>of</strong> morbidity and supplementary mortality. Study <strong>of</strong> the variation <strong>of</strong> serum andperitoneal concentrations <strong>of</strong> interleukin 6 shows the modulator effect <strong>of</strong> the peritoneal lavageearly and prolonged <strong>of</strong> the inflammatory response and <strong>of</strong>fers an argument <strong>of</strong> the inefficiency<strong>of</strong> short peritoneal lavage [226].ProbioticsA cohort study <strong>of</strong> 731 patients with a primary episode <strong>of</strong> acute pancreatitis in 2004-2007,including 296 patients involved in a randomized controlled trial to investigate the value <strong>of</strong>probiotic treatment in severe pancreatitis, was evaluated regarding time <strong>of</strong> onset <strong>of</strong>bacteraemia, pneumonia, infected pancreatic necrosis, persistent organ failure and deathwere recorded. The initial infection in 173 patients was diagnosed a median <strong>of</strong> 8 (interquartilerange 3-20) days after admission (infected necrosis, median day 26;bacteraemia/pneumonia, median day 7). Eighty percent <strong>of</strong> 61 patients who died had aninfection. In 154 patients with pancreatic parenchymal necrosis, bacteraemia wassignificantly associated with increased risk <strong>of</strong> infected necrosis (65 vs 38 %). In 98 patientswith infected necrosis, bacteraemia was associated with higher mortality (40 vs 16 %). Inmultivariable analysis, persistent organ failure (odds ratio 18.0), bacteraemia (odds ratio 3.4)and age (odds ratio 1.1) were associated with death. It was concluded that infections occurearly in acute pancreatitis, and have a significant impact on mortality, especially bacteraemia[227].To determine the relation between intestinal barrier dysfunction, bacterial translocation, andclinical outcome in patients with predicted severe acute pancreatitis and the influence <strong>of</strong>probiotics on these processes a randomized, placebo-controlled, multicenter trial on probioticprophylaxis (Ecologic 641) in patients with predicted severe acute pancreatitis wasperformed (PROPATRIA). Excretion <strong>of</strong> intestinal fatty acid binding protein (IFABP, aparameter for enterocyte damage), recovery <strong>of</strong> polyethylene glycols (PEGs, a parameter forintestinal permeability), and excretion <strong>of</strong> nitric oxide (NOx, a parameter for bacterialtranslocation) were assessed in urine <strong>of</strong> 141 patients collected 24 to 48 h after start <strong>of</strong>probiotic or placebo treatment and 7 days thereafter. IFABP concentrations in the first 72hours were significantly higher in patients who developed bacteremia, infected necrosis, andorgan failure. PEG recovery was significantly higher in patients who developed bacteremia(PEG 4000), organ failure (PEG 4000), or died (PEG 4000). Probiotic prophylaxis wassignificantly associated with an increase in IFABP (median 362 vs 199 pg/mL), mostevidently in patients with organ failure, and did not influence intestinal permeability. Overall,probiotics decreased NOx but, in patients with organ failure, increased NOx. It wasconcluded that bacteremia, infected necrosis, organ failure, and mortality were all associatedwith intestinal barrier dysfunction early in the course <strong>of</strong> acute pancreatitis. Overall,prophylaxis with this specific combination <strong>of</strong> probiotic strains reduced bacterial translocation,but was associated with increased bacterial translocation and enterocyte damage in patientswith organ failure [228].It has been proposed that probiotics can favorably influence the course <strong>of</strong> critically ill patientswith acute pancreatitis. To address this question, a limited systematic <strong>review</strong> was undertaken(MEDLINE search for articles published in English) to identify randomized, controlled trialsthat compared a group <strong>of</strong> critically ill patients taking probiotics with a group that did not. Tensuch trials, mostly with high risks <strong>of</strong> methodologic bias, were identified. When the data werecombined, the probiotics did not appear to influence mortality or duration <strong>of</strong> hospitalization.

However, the recipients <strong>of</strong> the probiotics had fewer infectious episodes (absolute riskdifferente -21 %). This effect was seen particularly in trials employing one combination <strong>of</strong>probiotic agents (Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillusparacasei, Lactobacillus plantarum). Unfortunately, this effect may be overly optimistic, asmethodologic shortcomings could have introduced biases into the trials. Three trials <strong>of</strong>patients with severe acute pancreatitis were not included in this primary analysis because notall <strong>of</strong> the patients were in the intensive care unit. The largest <strong>of</strong> these, and the one with thelowest risk <strong>of</strong> bias, demonstrated that probiotics increased mortality, in part because <strong>of</strong> theprecipitation <strong>of</strong> ischemic bowel disease (in patients who were also receiving postpyloricenteral nutrition infusions). Probiotics also appeared to reduce the incidence <strong>of</strong> antibioticassociateddiarrhea in hospitalized patients, although these trials did not specifically focusonly on those who were critically ill. In summary, it is not clear that probiotics are beneficial(and they may even be harmful) in the critically ill patient group [229].AntibioticsThe aim <strong>of</strong> one study was to analyze the evidence-based use <strong>of</strong> antibiotic therapy in thetreatment <strong>of</strong> acute pancreatitis and to identify factors influencing the introduction <strong>of</strong> antibiotictherapy in the setting <strong>of</strong> transitional country clinical hospital. A retrospective study wasconducted from hospital records <strong>of</strong> patients treated for acute pancreatitis during 2005. Datacollected from patients' histories were compared with indications for antibiotic treatment andantibiotics with demonstrated therapeutic efficacy in acute pancreatitis which were obtainedfrom published <strong>literature</strong>. Antibiotic therapy was used in 68 percent <strong>of</strong> patients with acutepancreatitis. Combination <strong>of</strong> amoxicillin plus clavulanic acid was most frequentlyadministered, either as monotherapy or in combination with metronidazole and/or gentamicin(37 %), followed by cefuroxime (33 %) and cefoperazone (27 %). The choice <strong>of</strong> antibioticwas appropriate in 36 perent <strong>of</strong> study patients; however in 30 percent <strong>of</strong> patients who wereadministered antibiotics had no indication for this therapy; and 47 percent <strong>of</strong> patients whohad indications for receiving antibiotic therapy didn't receive it. In the groups <strong>of</strong> patientstreated with antibiotics, the cost <strong>of</strong> treatment was significantly higher compared to groups <strong>of</strong>patients who were not treated with antibiotics. In addition to antibiotic therapy, the cost <strong>of</strong>treatment was significantly influenced by the length <strong>of</strong> hospital stay and treatment atintensive care unit. The use <strong>of</strong> antibiotics in the setting <strong>of</strong> transitional country universityhospital in patients with acute pancreatitis is not evidence-based. Decision on theintroduction <strong>of</strong> antibiotic therapy is not based on objective parameters <strong>of</strong> disease severity orevidence <strong>of</strong> therapeutic efficacy <strong>of</strong> particular antibiotics. The cost <strong>of</strong> treatment is significantlyincreased by the use <strong>of</strong> antibiotic therapy [230].NecrosectomyTraditional open surgical necrosectomy for treatment <strong>of</strong> infected pancreatic necrosis isassociated with high morbidity and mortality, leading to a shift toward minimally invasiveendoscopic, radiologic, and laparoscopic approaches. Percutaneous drainage is useful as atemporizing method to control sepsis and as an adjunctive treatment to surgical intervention.It is limited because <strong>of</strong> the requirement for frequent catheter care and the need for repeatedprocedures. Endoscopic transgastric or transduodenal therapies with endoscopicdebridement/necrosectomy have recently been described and are highly successful incarefully selected patients. It avoids the need for open necrosectomy and can be used inpoor operative candidates. Laparoscopic necrosectomy is also promising for treatment <strong>of</strong>pancreatic necrosis. However, the need for inducing a pneumoperitoneum and the potentialrisk <strong>of</strong> infection limit its usefulness in patients with critical illness. Retroperitoneal access witha nephroscope is used to directly approach the necrosis with complete removal <strong>of</strong> asequestrum. Retroperitoneal drainage using the delay-until-liquefaction strategy also appears

to be successful to treat pancreatic necrosis. The anatomic location <strong>of</strong> the necrosis, clinicalcomorbidities, and operator experience determine the best approach for a particular patient.Tertiary care centers with sufficient expertise are increasingly using minimally invasiveprocedures to manage pancreatic necrosis [231].Minimal invasive methodsInfection <strong>of</strong> pancreatic necrosis is a life-threatening complication during the course <strong>of</strong> acutepancreatitis. In critically ill patients, surgical or extended endoscopic interventions areassociated with high morbidity and mortality. Minimally invasive procedures on the otherhand are <strong>of</strong>ten insufficient in patients suffering from large necrotic areas containing solid orpurulent material. It was presented a strategy combining percutaneous and transgastricdrainage with continuous high-volume lavage for treatment <strong>of</strong> extended necroses and liquidcollections in a series <strong>of</strong> patients with severe acute pancreatitis. Seven consecutive patientswith severe acute pancreatitis and large confluent infected pancreatic necrosis were enrolled.In all cases, the first therapeutic procedure was placement <strong>of</strong> a CT-guided drainage catheterinto the fluid collection surrounding peripancreatic necrosis. Thereafter, a secondendosonographically guided drainage was inserted via the gastric or the duodenal wall. Aftercommunication between the separate drains had been proven, an external to internaldirected high-volume lavage with a daily volume <strong>of</strong> 500 ml up to 2,000 ml was started. In allpatients, pancreatic necrosis/liquid collections could be resolved completely by the presentedregime. No patient died in the course <strong>of</strong> the study. After initiation <strong>of</strong> the directed high-volumelavage, there was a significant clinical improvement in all patients. Double drainage wasperformed for a median <strong>of</strong> 101 days, high-volume lavage for a median <strong>of</strong> 41 days. Severalendoscopic interventions for stent replacement were required (median 8). Complicationssuch as bleeding or perforation could be managed endoscopically, and no subsequentsurgical therapy was necessary. All patients could be dismissed from the hospital after amedian duration <strong>of</strong> 78 days. This approach <strong>of</strong> combined percutaneous or endoscopicdrainage with high-volume lavage shows promising results in critically ill patients withextended infected pancreatic necrosis and high risk <strong>of</strong> surgical intervention. Neither surgicalnor endoscopic necrosectomy was necessary in any <strong>of</strong> our patients [232].Minimally invasive necrosectomy is an umbrella term encapsulating the retroperitoneal,endoscopic and laparoscopic approaches which all share the common goal <strong>of</strong> avoidance <strong>of</strong>the physiological insult <strong>of</strong> the traditional “open” laparotomy approach to necrosectomy.However, there is no randomised trial evidence comparing these techniques meaning thatcurrent evidence is unclear in terms <strong>of</strong> which approach to select in any particular setting.Patients with pancreatic necrosis represent individuals at high risk for adverse outcome andshould be managed by a multidisciplinary team in a specialist unit. At a minimum, thereshould be input from surgical, radiological, and gastroenterological experts. Procedures mustnot be selected simply on the expertise <strong>of</strong> a single discipline. Specialist care should reflectevidence from the open necrosectomy era that is likely to translate to minimally invasiveinterventions. In contemporary pancreatic surgical practice, magnetic resonance (MR)scanning provides additional diagnostic information (in addition to computed tomography andendoscopic ultrasonography) in the critical later stages <strong>of</strong> pancreatic sepsis and in particularin relation to the fluid/solid components <strong>of</strong> necrosis. Although it could be argued that MR isnot widely available and that CT remains the gold-standard test, an equally validcounterargument is that complex, novel approaches to pancreatic necrosis should not beadopted in units that are not comprehensively equipped. With staging information to hand, abroad categorization can be made into individuals with predominantly solid necrosis andthose with fluid-predominant collection. In the former category, collections tracking to the leftparacolic gutter and retroperitoneum are in the category wherein good outcomes have beenreported from image-guided placement <strong>of</strong> guidewires, the Seldinger technique for placement<strong>of</strong> drains followed by retroperitoneal necrosectomy. The retroperitoneal approach seems far

less safe for predominantly cephalic collections because <strong>of</strong> the proximity <strong>of</strong> theportal/superior mesenteric venous confluence. In the setting <strong>of</strong> retrogastric collections whichare “fluid predominant” (including the type <strong>of</strong> collection recently termed “walled <strong>of</strong>f pancreaticnecrosis”) there is equipoise between laparoscopic and endoscopic approaches. Currentevidence in relation to timing <strong>of</strong> surgery, use <strong>of</strong> fine-needle aspiration and detailed imagingby magnetic resonance scanning is incorporated into a modern treatment algorithm. Withthese constraints in place, there may be some advantages inherent to each approach: theendoscopic approach with a side-viewing duodenoscope allows opportunities for radiologicaldelineation <strong>of</strong> the relationship between the fluid collection and the main pancreatic duct andalso for assessment <strong>of</strong> the integrity <strong>of</strong> the main duct; laparoscopic debridement allows thelesser sac to be examined under direct vision and the use <strong>of</strong> high-flow irrigation withpiecemeal necrosectomy. Combinations <strong>of</strong> these approaches – “laparo-endoscopic”approaches – have also been reported. Radiologically guided percutaneous drainage is alsoa recognised option: simple or passive external drainage can be used in the setting <strong>of</strong>salvage for a critically ill patient whilst more active percutaneous drainage with tract dilatationand irrigation can be used as a means <strong>of</strong> achieving necrosectomy. Open necrosectomy stillretains a place in this hierarchy <strong>of</strong> care: patients with a clinical suspicious <strong>of</strong> ischaemicintestine or colonic complications <strong>of</strong> pancreatitis are invariably treated by urgent openlaparotomy. Further, patients with multi-loculated intra-peritoneal collections together withlesser sac or retroperitoneal sepsis may be best addressed by open surgery. It is thusconcluded that the era <strong>of</strong> minimally invasive necrosectomy has arrived. In the absence <strong>of</strong>randomised trial evidence, the keys to contemporary management <strong>of</strong> pancreatic necrosis aregood multidisciplinary care, adequate high-quality imaging and careful consideration <strong>of</strong> allavailable treatment options including traditional open approaches [233].While sterile pancreatic necrosis should be managed conservatively, infected pancreaticnecrosis requires debridement and drainage supplemented by antibiotic therapy. Surgicalnecrosectomy is the traditional approach, but less invasive techniques (retroperitoneal orlaparoscopic necrosectomy, computed tomography-guided percutaneous catheter drainage)may be equally effective [234].Intraparenchymal pancreatic airEmphysematous pancreatitis is characterized by the presence <strong>of</strong> intraparenchymalpancreatic air in the setting <strong>of</strong> necrotizing pancreatitis. Mortality and morbidity rates approachapproximately 40 percent and 100 percent, respectively. Traditionally, emphysematouspancreatitis was an indication for surgical intervention. The purpose <strong>of</strong> one <strong>review</strong> was todiscuss the experience with nonoperative management <strong>of</strong> emphysematous pancreatitis.Between 2005 and 2007, 5 patients with emphysematous pancreatitis were admitted. The 5male patients ranged in age from 50 to 77 years. Four required at least 1 week in theintensive care unit. All 5 cases <strong>of</strong> emphysematous pancreatitis went on to be treatedsuccessfully with nonoperative management. Furthermore, after a minimum <strong>of</strong> 1-year followup,they remain out <strong>of</strong> hospital and continue to do well. The data suggest thatemphysematous pancreatitis may be a favorable subtype <strong>of</strong> severe pancreatitis. In wellselectedpatients, nonoperative management with aggressive antibiotic treatment andnutritional support may suffice [235].Intrahepatic fluid collectionsPeripancreatic fluid collection suggests the anatomical-clinical scenario <strong>of</strong> necrotizing acutepancreatitis. However, intrahepatic fluid collection is a rare occurrence with fewer than 30cases being reported in the medical <strong>literature</strong>. It was described 2 cases <strong>of</strong> intrahepatic fluidcollection in 2 patients with acute biliary pancreatitis and discussed the therapeuticpossibilities. The patients were successfully treated with percutaneous US/CT guided

drainage. It was concluded that intrahepatic fluid collection in the course <strong>of</strong> acute biliarypancreatitis is a rare occurrence. The therapeutic approach is the same as that for pancreaticand peripancreatic fluid collections. In case <strong>of</strong> infection, the patient undergoes percutaneousUS/CT guided drainage [236].Endoscopic treatmentNecrosectomy is the gold standard treatment for infected pancreatic necrosis (IPN). Apercutaneous and endoscopic approach has been accepted in selected cases. Endoscopicdrainage (ED) <strong>of</strong> IPN can be performed by using transpapillary or transmural procedures, ora combination <strong>of</strong> both with or without endoscopic ultrasound. The aim <strong>of</strong> one study was todetermine the indications, complications, success rate, and the importance <strong>of</strong> assessment <strong>of</strong>main pancreatic duct integrity by endoscopic retrograde pancreatography (ERP) in patientswith IPN. Records <strong>of</strong> all patients who underwent endoscopic necrosectomy from 2002 toDecmber 2007 were <strong>review</strong>ed. A total <strong>of</strong> 56 patients were included. ED was performed usingdaily transmural and transpapillary drainage. A diagnostic pancreatogram (ERP) to searchfor communications between the pancreatic duct and the collection were performed in allcases and in cases where communication existed. A pre-cut needle knife was used topuncture the cyst wall, aspirate the content and then enter at the cyst cavity (contrast wasinjected to ensure opacification <strong>of</strong> the cyst and subsequent drainage). Sphincterotomycatheter or balloons were used to enlarge and ensure a wide cystoenterostomy. All patientswere followed with computerized tomography scans or ultrasound to ensure clinicalresolution. Mean follow-up was 21 months.49/56 patients could be successfully treated. EDwas successful in 49 patients (87 %) and in 3 (13 %) it failed. Mean follow-up was 21months. During this period, there were 2 (11 %) pseudocyst recurrences and only 1 (5 %)recurrence <strong>of</strong> new episodes <strong>of</strong> pancreatic necrosis, and all were managed clinically and/orendoscopically. No mortality was related to the procedure [237].It was described a case <strong>of</strong> successful endoscopic management <strong>of</strong> two pancreatic abscessesin a critically ill patient. CT scan showed two large abscesses. The first was bulging to theposterior wall <strong>of</strong> the stomach and another at the tail <strong>of</strong> the pancreas. An endoscopicretrograde cholangiopancreatography was performed. The pancreatic duct communicatedwith the abscess at the tail <strong>of</strong> the pancreas. The drainage <strong>of</strong> this abscess was donetranspapillarily. Endoscopic cystogastrostomy was performed to treat the pancreatic abscessthat bulged to the posterior gastric wall. A double nasocystic tube was placed for continuouslavage <strong>of</strong> the abscess. Pseudomonas aeruginosa was cultured and antibiotics wereadministered according to sensitivity tests. The clinical status returned gradually to normal. Afollow-up CT scan 4 months later showed complete resolution <strong>of</strong> abscesses. It wasconcluded that endoscopic drainge <strong>of</strong> pancreatic abscesses may be the therapy <strong>of</strong> choice insuch patients mainly because it does not prevent the chance <strong>of</strong> subsequent surgicalintervention if needed [238].Radiologic interventionsIt has previously been reported that organ failure and mortality in necrotizing pancreatitis(NP) are not different between patients with infected and sterile necrosis. However,management <strong>of</strong> this disease has evolved to include image-guided percutaneous catheterdrainage (PCD) to improve morbidity and mortality. A total <strong>of</strong> 689 consecutive patientstreated for acute pancreatitis between 2001 and 2005, <strong>of</strong> whom 64 (9 %) had pancreaticnecrosis documented on contrast-enhanced computed tomography was studied. In the 64patients with documented necrotizing pancreatitis, overall mortality was 16 percent. Thirty-sixpatients (56 %) had organ failure according to the Atlanta classification. Compared withpatients with sterile necrosis, those with infected necrosis did not have an increasedprevalence <strong>of</strong> organ failure or increased need for intubation, pressors, or dialysis but had an

increased mortality. Mortality in patients treated conservatively was 1 <strong>of</strong> 29 (3 %); in thosewith PCD alone, 6 <strong>of</strong> 11 (55 %); in those with percutaneous catheter drainage and surgery, 2<strong>of</strong> 17 (12 %); and in those with surgery alone, 1 <strong>of</strong> 7 (14 %). All patients treated with PCDalone had organ failure, whereas 10 (59%) <strong>of</strong> those with PCD and surgery had organ failure.It was concluded that the use <strong>of</strong> percutaneous catheter drainage did not improve themortality <strong>of</strong> necrotizing pancreatitisamong patients with organ failure [239].Quality <strong>of</strong> life after acute pancreatitisTo explore the quality <strong>of</strong> life in patients treated medically during the acute phase <strong>of</strong>pancreatitis as well as at 2 and 12 months after discharge from the hospital. Forty patientswere studied. The etiology <strong>of</strong> the pancreatitis was biliary causes in 31 patients and nonbiliarycauses in 9; mild disease was present in 29 patients and severe disease in 11. Thirtypatients completed the two surveys at 2 and 12 months after hospital discharge. The SF-12and EORTC QLQ-C30 questionnaires were used for the purpose <strong>of</strong> the study. The twophysical and mental component summaries <strong>of</strong> SF-12, all the domains <strong>of</strong> EORTC QLQ-C30(except for physical functioning and cognitive functioning) and some symptom scales <strong>of</strong>EORTC QLQ-C30 (fatigue, nausea/vomiting, pain, and constipation) were significantlyimpaired during the acute phase <strong>of</strong> pancreatitis. There was a significant improvement in theSF-12 physical component summary, and global health, role functioning, social functioning,nausea/vomiting, pain, dyspnea, and financial difficulties (EORTC QLQ-C30) at 2 monthsafter discharge as compared to the basal evaluation. Similar results were found after 12months except for the mental component score at 12-month evaluation, which wassignificantly impaired in acute pancreatitis patients in comparison to the norms. The physicalfunctioning <strong>of</strong> the EORTC QLQ-C30 at basal evaluation was significantly impaired in patientswith severe pancreatitis in comparison to patients with mild pancreatitis. It was concludedthat two different patterns can be recognized in the quality <strong>of</strong> life <strong>of</strong> patients with acutepancreatitis: physical impairment is immediately present followed by mental impairmentwhich appears progressively in the follow-up period [240].ExperimentalThe aim <strong>of</strong> one study was to study the effects <strong>of</strong> resveratrol on severe acute pancreatitis(SAP)-induced brain injury. Ninety-six male Sprague-Dawley rats were randomly divided into4 equal groups: sham operation, SAP, resveratrol-treated, and dexamethasone-treated.Each group was evaluated at 3, 6, and 12 hours. Myelin basic protein and zonula occludens1 levels <strong>of</strong> the resveratrol group were lower than the SAP group at all time points. Thetreated group had significantly improved pathologic brain, increase in Bcl-2 expression, anddecrease in Bax and caspases-3 expressions compared with the SAP group. The authorsconcluded that degradation <strong>of</strong> zonula occludens 1 is involved in the pathophysiology <strong>of</strong> braininjury in SAP; myelin basic protein can be used as a marker <strong>of</strong> brain injury in SAP. Theprotective effect <strong>of</strong> resveratrol might be associated with the up-regulation <strong>of</strong> Bcl-2 and downregulation<strong>of</strong> Bax and caspase-3 [241].It was previously observed decreased histopathological severity <strong>of</strong> acute necrotizingpancreatitis by parenteral nutrition with n-3 fatty acids. Thus, it was now sequentiallyanalyzed the impact <strong>of</strong> n-3 fatty acids on prostaglandin and leukotriene synthesis innecrotizing pancreatitis in 198 Sprague-Dawley rats (11 groups, n=18) who underwentintraductal glycodesoxycholat instillation and 6-hour cerulein infusion. Afterward, saline wasinfused in groups 2, 4, 6, 8, and 10, whereas groups 3, 5, 7, 9, and 11 received infusion richin n-3 fatty acids. Animals were killed after 6 (group 1), 10 (groups 2 and 3), 14 (groups 4and 5), 18 (groups 6 and 7), 22 (groups 8 and 9), and 26 hours (groups 10 and 11). The

pancreas was histopathologically examined, and the pancreatic eicosanoid metabolism(prostaglandin E2, prostaglandin F1-alpha [PGF1-alpha]], and leukotrienes) and lipidperoxidation (thiobarbituric acid-reactive substance, superoxide dismutase, and glutathioneperoxidase) were analyzed. Between the 14th and 26th hours, histopathologic scores(edema, inflammation, bleeding, and necrosis) were reduced in the n-3 fatty acid groupcompared with the corresponding saline group. Pancreatic prostaglandin E2 and PGF1-alphawere decreased between the 10th and 18th hour by n-3 fatty acids; PGF1-alpha wasreduced after 26 hours compared with the corresponding saline group. Lipid peroxidationwas decreased by n-3 fatty acids after 14 hours (thiobarbituric acid-reactive substance);however, there was no difference concerning lipid peroxidation protective enzymes(glutathione peroxidase and superoxide dismutase). It was concluded that parenteral therapywith n-3 fatty acids decreased histopathologic severity in necrotizing pancreatitis in rats byearly inhibition <strong>of</strong> prostaglandin (E2 and F1-alpha) synthesis and reduction <strong>of</strong> lipidperoxidation [242].High-mobility group box 1To investigate the effects <strong>of</strong> high-mobility group box 1 (HMGB1) A box in experimentalsevere acute pancreatitis (SAP) severe acute pancreatitis was induced by 20 percent l-arginine abdominal cavity injection in mice. The serum levels <strong>of</strong> HMGB1, amylase, lipase,and biochemical indicators were measured 24 and 48 hours after induction <strong>of</strong> SAP. Thepathological changes <strong>of</strong> the pancreas, lung, kidney, and liver for both SAP group andtreatment group were observed and compared, as well as survival rate and surviving time. Abox significantly improved the elevation <strong>of</strong> the serum levels <strong>of</strong> HMGB1, amylase, lipase, andbiochemical indicators in SAP. The pathological changes <strong>of</strong> pancreas and organ injury intreatment group were more alleviated than that in SAP group. The mice survival rate <strong>of</strong> thetreatment group (67 %) was significantly higher than that <strong>of</strong> the SAP group (27 %). It wasconcluded that a box has remarkable protective effect against pancreatitis and associatedorgan injury; HMGB1 probably participates in the inflammatory reaction and organ injury <strong>of</strong>severe acute pancreatitis as a late-acting mediator <strong>of</strong> inflammation [243].PAF-antagonistsPlatelet-activating factor (PAF) is an important mediator <strong>of</strong> inflammation and postulated to beinvolved in the pathogenesis <strong>of</strong> acute pancreatitis. In one study, we evaluated the therapeuticeffect <strong>of</strong> PAF antagonist WEB 2086 in acute experimental pancreatitis <strong>of</strong> graded severity inrats. According to a block design, 64 animals were randomly allocated to 8 groups. Severenecrotizing pancreatitis was induced by intraductal infusion <strong>of</strong> taurocholic acid (4 %, 0.4 mL),and the combination <strong>of</strong> glycodeoxycholic acid (10 mmol/L, 1.0 mL/kg, intraductal infusion)and cerulein (5 microg/kg per hour, intravenous) was applied to induce intermediatepancreatitis, or cerulein alone (5 microg/kg per hour, intravenous) to establish edematouspancreatitis. WEB 2086 was given 15 minutes after beginning the induction <strong>of</strong> pancreatitis.Pancreatic microcirculation was analyzed in vivo with an epiluminescent microscope.Histopathology was evaluated by a validated score. Trypsinogen-activating peptide andserum amylase were analyzed sequentially. WEB 2086 had no significant influence on thebreakdown <strong>of</strong> microcirculation, leukocyte adherence, histopathological damage, and amylaselevels in severe necrotizing pancreatitis, intermediate pancreatitis, and edematouspancreatitis. Only in intermediate pancreatitis was there a significant reduction <strong>of</strong>trypsinogen-activating peptide levels [244].

Epidemiology and demographyChinaCHRONIC PANCREATITISA multicenter study was initiated by the Chinese Chronic Pancreatitis Study Group todetermine the nature and magnitude <strong>of</strong> chronic pancreatitis in China. Twenty-two hospitalsrepresenting all 6 urban health care regions in China participated in the study. The surveycovered a 10-year period from 1994 to 2004. Multiple logistic regression was used foranalyses. Results: The analysis included 2008 patients (65 % were men, mean age, 49years). Chronic pancreatitis prevalence increased yearly from 1996 to 2003: 3.08, 3.91, 5.28,7.61, 10.43, 11.92, 12.84, and 13.52 per 100,000 inhabitants. Chronic pancreatitis etiologieswere alcohol (35 %), biliary stones (34 %), hereditary (7 %), and idiopathic chronicpancreatitis (13 %). Clinical feature were pain (76 %), maldigestion (36 %), jaundice (13 %),and steatorrhea (7 %). Complications were pseudocyst (26 %), diabetes (22 %), bile ductstrictures (13 %), and ascites (2 %). With regard to the diagnosis, the sensitivity andspecificity <strong>of</strong> endoscopic ultrasonography and endoscopic retrograde cholangiopancreatographywere 88 and 93 percent, and 87 and 93 percent, respectively. Threehundred ninety-one patients (19 %) received endoscopic therapy. Surgery was performed in239 patients (12 %). It was concluded that in China, the incidence <strong>of</strong> chronic pancreatitis isrising rapidly [245].IndiaTropical pancreatitis, an idiopathic chronic pancreatitis (ICP) with unique features, has beendescribed in south and north India. It was investigated the clinical pr<strong>of</strong>ile <strong>of</strong> ICP patients innorth India. Detailed demographic data was recorded and hematological and biochemicalinvestigations were performed on 155 patients that had been diagnosed with chronicpancreatitis. Ultrasonography and computed tomography were performed in all patients.Magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography,glucose tolerance test and fecal fat studies were performed on some patients.Patients were divided in to early or lateonset ICP (before or after 35 years <strong>of</strong> age). ICP wasreported in 41 percent <strong>of</strong> patients, followed by alcoholic chronic pancreatitis (38 %). Themean age <strong>of</strong> ICP patients was 33 years and the mean duration <strong>of</strong> symptoms at the time <strong>of</strong>presentation was 40 months. Pain was the dominant symptom in both early- (95 %) and lateonset(100 %) ICP; pseudocyst was the most common local complication. Diabetes wasobserved in 17 percent <strong>of</strong> patients with early-onset ICP and 35 percent with late-onset ICP.Pancreatic calcification was noted in 46 percent <strong>of</strong> patients with early-onset and 48 percentwith late-onset ICP. Pseudocyst and segmental portal hypertension occurred more frequentlyin non-calcific ICP whereas diabetes mellitus and abnormal fecal fat excretion occurred morefrequently in patients with calcific ICP. It was concluded that ICP <strong>of</strong> north India appears to bedifferent from classical tropical pancreatitis described in the <strong>literature</strong> and is associated witha higher prevalence <strong>of</strong> pain, lower frequencies <strong>of</strong> diabetes, calcification and intraductalcalculi [246].Risk <strong>of</strong> cancerIt was monitored 223 patients with chronic pancreatitis on a systematic basis from 1992 to2005. During this 14-year period, we monitored the number <strong>of</strong> cigarettes smoked per year inaddition to standard parametres measured by biochemical methods, endosonography, CTand ERCP exams, and assigned the alcoholic form <strong>of</strong> chronic pancreatitis to patientsconsuming more than 80g <strong>of</strong> alcohol per day on a systematic basis for more than 5 years in

the case <strong>of</strong> men, and 50 g <strong>of</strong> alcohol per day in the case <strong>of</strong> women, and classed the patientsaccording the TIGARO classification. Alcoholic etiology was proven in 73 percent <strong>of</strong> theexamined patients, chronic obstructive form <strong>of</strong> pancreatitis was diagnosed in 22 percent <strong>of</strong>patients, and only 5 percent <strong>of</strong> patients were classified into the idiopathic pancreatitis group.Pancreatic carcinoma in the region <strong>of</strong> chronic pancreatitis was found in 13 patients (6 %);stomach carcinoma was diagnosed in 3 patients with chronic pancreatitis, and oesophagealcarcinoma in 1 patient <strong>of</strong> the total <strong>of</strong> patients monitored. Malignant pancreatic disease wasdiagnosed primarily in patients with alcoholic pancreatitis (5 %). During the period <strong>of</strong> 14years, 11 patients died, 8 <strong>of</strong> the deaths being associated with pancreatic carcinoma. It wasconcluded that both pancreatic and extrapancreatic carcinoma in gastrointestinal location is aserious complication <strong>of</strong> protracted chronic, non-hereditary pancreatitis. Systematicidentification and treatment <strong>of</strong> patients with chronic pancreatitis is therefore necessary fortimely diagnosis <strong>of</strong> gastrointestinal and pancreatic malignancies [247].GeneticsCFTRDNA analyses <strong>of</strong> the cystic fibrosis transmembrane conductance regulator (CFTR) gene inJapanese patients with idiopathic chronic pancreatitis (ICP) were performed to determine therelationship between the CFTR mutation and ICP. The study included patients with alcoholicpancreatitis (n = 20), patients with ICP (n = 20) and healthy volunteers (controls; n=110). Thepoly-T region in intron 8 <strong>of</strong> the CFTR gene was analysed by direct sequencing. The CFTRcoding region was screened using single-strand conformational polymorphism and directsequencing. In the controls, frequencies <strong>of</strong> the 5T genotype and 5T allele were 4.5 and 3.6percent, respectively. The frequency <strong>of</strong> the 5T genotype was significantly higher in the ICPgroup (20 %) versus controls, but was not significantly different in alcoholic chronicpancreatitis patients (5 %). Thus, the CFTR gene mutation, especially the 5T genotype,appears to have some relationship to ICP prevalence in Japanese patients independent <strong>of</strong>cystic fibrosis [248].Chymotrypsin CVariations and haplotypes <strong>of</strong> the chymotrypsin C (CTRC) gene in Chinese patients withchronic pancreatitis and control subjects with genotype-phenotype correlation wereinvestigated. One hundred and twenty-six patients with chronic pancreatitis were analyzed.The entire sequence <strong>of</strong> coding regions <strong>of</strong> exons 2, 3 and 7 and their neighboring intronicregions in introns 1, 2 and 6 <strong>of</strong> the CTRC gene were analyzed using PCR sequence-specificprimers and direct sequencing. The exonic region <strong>of</strong> exon 7 and the neighboring intronicregion <strong>of</strong> intron 6 were also analyzed in 90 geographically matched healthy control subjects.In total, 4 novel variations were identified in exons 2, 3 and 7 in 3 CP patients. A total <strong>of</strong> 2.3percent (3/126) <strong>of</strong> our chronic pancreatitis patients carried variations <strong>of</strong> the CTRC gene. Itwas also first identified six new intronic variations in intron 6 which had not been reportedbefore. The GAGGGG, GAGGAG and GAGTAG haplotypes assembled by six locus intronicvariations c.640-41/c.640-40/c.640-39/c.640-37/c.640-36/c.640-35 in intron 6 wereassociated with a significantly higher susceptibility risk <strong>of</strong> CP (OR 66.75, 37.00, and 9.37,respectively). Novel CTRC gene variations and haplotypes are associated with CP in aChinese population [249].SpainMutations in the PRSS1 and the SPINK1 genes have variably been associated with alcoholrelated,idiopathic and hereditary chronic pancreatitis. The aim <strong>of</strong> one study was to determine

for the first time the significance <strong>of</strong> PRSS1, SPINK1 mutations and genetic variants <strong>of</strong> AAT ina group <strong>of</strong> Spanish patients with chronic pancreatitis. One hundred and four consecutivepatients with chronic pancreatitis were included, as well as 84 healthy control subjects. TheR122H and N29I mutations in the PRSS1 gene, the N34S mutation in the SPINK1 gene andPiS and PiZ mutations in the AAT gene were analyzed by RFLP-PCR methods. No R122Hmutation was found in the PRSS1 gene, and N29I mutation was detected in 8 percent <strong>of</strong>chronic pancreatitis patients. A N29I mutation was observed in 4 percent <strong>of</strong> patients withalcohol-related pancreatitis. A total <strong>of</strong> 6 percent <strong>of</strong> chronic pancreatitis patients wereidentified with the N34S mutation. Genotype MS, SS and MZ were detected in 18.3, 3.8 and1.3 percent <strong>of</strong> patients, respectively. It was concluded that the percentage <strong>of</strong> N29I mutationsin alcohol-related pancreatitis patients was higher than that reported in other studies, whilethe percentage <strong>of</strong> N34S and AAT mutations in alcohol-related pancreatitis and idiopathicchronic pancreatitis patients was similar [250].Possible etiological factorsChronic pancreatitis is an inflammatory disease followed by structural alterations –inflammation, fibrosis and acinar atrophy – pain emergence, exocrine and endocrinepancreatic insufficiency, severe alteration <strong>of</strong> quality <strong>of</strong> life. The pathogenetic mechanismscharacteristic to this disease are not thoroughly known, but the identification <strong>of</strong> some geneticand autoimmune factors in certain entities has elucidated several pathogenetic links. Theetiologic risk factors for chronic pancreatitis may associate each other and may causedifferent evolutions to the disease. By tracing out the risk factors and their typical workingmechanisms, further pathogenetic treatments may occur, taking place precociously andpreventing the evolution <strong>of</strong> the disease towards exocrine and endocrine pancreaticinsufficiency [251].HomocysteinemiaHomocysteine has been implicated in vascular dysfunction and thrombosis, as well asinflammatory conditions. One study was aimed to find out whether chronic pancreatitis isassociated with hyperhomocysteinemia and derangements <strong>of</strong> transmethylation andtranssulfuration pathways. It was estimated homocysteine and its metabolites in 45 alcoholicchronic pancreatitis patients, 45 tropical chronic pancreatitis patients, and 48 healthycontrols. Significant increases in plasma total homocysteine and decreases in red blood cellfolate, reduced glutathione, plasma methionine, cysteine, and urinary inorganicsulfate/creatinine ratio were observed in both alcoholic and tropical chronic pancreatitispatients in comparison with healthy controls. Red blood cell glutathione and plasma cysteinelevels were significantly lower in alcoholic than in tropical chronic pancreatitis patients.However, plasma vitamin B12 levels were comparable between chronic pancreatitis patientsand controls. No significant differences in these parameters were observed between diabeticpatients and nondiabetic patients. Multivariate regression analysis showed a significantnegative correlation between homocysteine and folate and a positive correlation betweenglutathione and cysteine levels. It was concluded that pancreatitis is associated withhyperhomocysteinemia and derangements in transmethylation and transsulfurationpathways. Low folate levels observed in these patients seem to have a key role in thisderangement [252].Changes in neurohormonesIt was measured content <strong>of</strong> neuromediators (acetylcholine, serotonin) and gastrointestinalhormones (cholecystokinine and secretin) in the blood serum <strong>of</strong> patients with chronicpancreatitis to study protective properties <strong>of</strong> the mucus in the duodenum. In alcoholic

pancreatitis patients the response <strong>of</strong> biologically active substrates to standard meal changed:serotonin concentration rose from 0.40 + 0.07 to 0.55 + 0.05 mcg/ml (a statistically significantdifference) while acetylcholin dropped from 1.7 + 0.3 to 1.6 + 0.3 mmol/l (not statisticallysignificant). Biliary pancreatitis patients responded to the standard meal with a significantserotonin concentration rise from 0.28 + 0.04 to 0.43 + 0.05 mcg/ml, acetylcholin changedinsignificantly from 1.5 + 0.12 to 1.45 + 0.21 mmol/l, respectively. CCK after standard mealsignificantly rose both in both types <strong>of</strong> patients, and both types had strong direct correlationbetween concentrations <strong>of</strong> serotonin and CCK and weak negative correlation withacetylcholin level. Reduction <strong>of</strong> secretin secretion diminished secretion <strong>of</strong> bicarbonates andmucus with simultaneous change in the quality <strong>of</strong> mucous gel. It was concluded that inchronic pancreatitis <strong>of</strong> various etiology there are changes in the level and proportions <strong>of</strong>neuromediators and hormones causing alterations in the regulation system. These disorderscorrelate with disturbances in pancreatic excretory function and destructive tissue changes.Bicarbonates secretion decreases and changes quality <strong>of</strong> the secreted mucus [253].Amino acidsThe circulating amino acid levels were determined in 12 patients with chronic pancreatitis, 12pancreatic cancer patients, and 12 controls. Total amino acid concentrations were 2850 + 71micromol/L in controls, 2640 + 96 micromol/L in chronic pancreatitis patients, and 2210 + 123micromol/L in cancer patients, which was statistically significantly different. In chronicpancreatitis patients, significant reductions in the concentrations <strong>of</strong> citrulline, gammaaminobutyricacid, taurine, and aspartic acid were found, whereas in pancreatic cancerpatients, the levels <strong>of</strong> phosphoethanolamine, gamma-aminobutyric acid, aspartic acid,taurine, arginine, threonine, alanine, citrulline, and tryptophan were reduced. There was asignificant inverse relationship between the total amino acid levels and the white blood cellcounts. The mechanisms underlying these defects may involve intestinal malabsorption aswell as systemic inflammation. Providing selective amino acid supplementation to suchpatients may minimize the excess morbidity and mortality associated with protein malnutrition[254].DiagnosticsSymptomsPancreatic panniculitis is rare form <strong>of</strong> panniculitis with associated pancreatic disease. Theskin manifestations can occur at any time <strong>of</strong> the pancreatic pathology. It was now reported acase <strong>of</strong> pancreatic panniculitis associated with underlying chronic pancreatitis. The patientpresented with painful subcutaneous nodules and the histology revealed the characteristicfeatures <strong>of</strong> pancreatic panniculitis [255].Endocopic ultrasography (EUS)To provide histologic correlation <strong>of</strong> endoscopic ultrasound (EUS) findings believed torepresent chronic pancreatitis 18 postmortem pancreatic specimens in patients dying <strong>of</strong> allcauses were examined in vitro by EUS for features <strong>of</strong> chronic pancreatitis: echogenic foci,hypoechoic foci, echogenic main pancreatic duct (MPD), accentuated lobular pattern, cysts,irregular MPD, dilated MPD, side branch dilation, and calculi. The pancreata were thenexamined by two pathologists (blinded to the EUS/clinical findings) for histopathologicfeatures <strong>of</strong> chronic pancreatitis. Six specimens were autolyzed, and in 1 specimen, MPDcould not be seen by EUS. In the other 11 patients, 10 had evidence <strong>of</strong> chronic pancreatitisby EUS (>3 features) and by histopathologic examination (>2 features). One patient did nothave chronic pancreatitis by either EUS or histologic examination. It was concluded that

endoscopic ultrasound accurately detected chronic pancreatitis, when compared withhistopathologic examination. The presence <strong>of</strong> 3 or more features <strong>of</strong> chronic pancreatitiscorrelates with the histologic diagnosis <strong>of</strong> chronic pancreatitis, however, up to 3 features arefrequently present in elderly patients dying <strong>of</strong> all causes [256].The endoscopic ultrasound (EUS) diagnosis <strong>of</strong> chronic pancreatitis relies on the presence <strong>of</strong>up to nine distinct pancreatic parenchymal and ductal abnormalities, without consideringother factors such as age, duration <strong>of</strong> disease or clinical symptoms. The goal <strong>of</strong> one studywas to examine the impact <strong>of</strong> patient symptoms on EUS findings in patients with chronicpancreatitis. All patients with previously suspected chronic pancreatitis who had symptomaticdisease referred to a medical center for pancreatic EUS were identified. Patients werestratified into two groups based on their clinical symptoms – pain only and steatorrhea ±pain. Groups were compared using two-tailed comparative testing. Fifty-three patients (group1) with pain only and 27 patients with steatorrhea ± pain (group 2) were identified. Patients ingroup 1 were younger and more likely female. Compared to group 1 (pain only), group 2(steatorrhea ± pain) had significantly more total (5.4 vs 3.3) and ductal abnormalities (2.6 vs0.8), although the number <strong>of</strong> parenchymal abnormalities between groups 1 and 2 was notdifferent. The presence <strong>of</strong> steatorrhea ± pain in patients with chronic pancreatitis undergoingpancreatic EUS examination is associated with more total and ductal abnormalities.Stratification based on underlying patient symptoms may be valuable as an adjunct toendosonographic findings in making or excluding the diagnosis <strong>of</strong> chronic pancreatitis [258].ERCP in childrenTo evaluate indications, findings, therapies, safety, and technical success <strong>of</strong> endoscopicretrograde cholangiopancreatography (ERCP) in children <strong>of</strong> a Children's Hospital inAmsterdam, the Netherlands a retrospective analysis by medical records was done. Successwas defined as obtaining accurate diagnostic information or succeeding in endoscopictherapy. Sixty-one children (age 3 days to 17 years, mean age 7 years) underwent a total <strong>of</strong>99 ERCPs. Of those patients, 51 percent (31/61) were younger than 1 year, 84 percent hadbiliary indications, and 16 percent had pancreatic indications for the performance <strong>of</strong> ERCP.The complication rate was 4 percent (4/99) and included substantial pancreatitis and mildirritated pancreas. No complications occurred in children younger than 1 year. Indications forERCP are different for children and adults. A laparotomy could be prevented in 12 percent <strong>of</strong>children with suspicion <strong>of</strong> biliary atresia [259].Breath testsAlthough the fecal elastase-1 test is a satisfactory pancreatic exocrine function test, breathtests that use stable isotopes have been developed recently as alternatives. We evaluatedthe usefulness <strong>of</strong> a 13 C-labeled mixed triglyceride breath test for assessing pancreaticexocrine function after pancreatic surgery. The breath test and the fecal elastase-1 test wereperformed on 7 healthy volunteers, 10 patients with chronic pancreatitis, and 95 patientsafter pancreatic surgery. The breath test was analyzed with isotope ratio mass spectrometryand the cumulative recovery <strong>of</strong> 13 CO 2 at 7 hours (% dose 13 C cum 7h) was calculated. Thefecal elastase-1 concentration was determined immunoenzymatically. Both the fecalelastase-1 concentration and the % dose 13 C cum 7h <strong>of</strong> chronic pancreatitis patients andpancreatic resection patients were less than those <strong>of</strong> healthy volunteers. In all subjects, %dose 13 C cum 7h correlated with the fecal elastase-1 concentration. Accuracy rates forclinical symptoms, including clinical steatorrhea, for the fecal test and the breath test were 62and 88 percent, respectively. It was concluded that the 13 C-labeled mixed triglyceride breathtest might be more useful than the fecal elastase-1 test for evaluating pancreatic exocrinefunction after pancreatic resection [260].

Association with liver diseaseAlthough chronic pancreatitis and liver cirrhosis are common sequelae <strong>of</strong> excess alcoholconsumption, the two conditions are rarely associated. It was studied the prevalence <strong>of</strong>simultaneous liver cirrhosis and chronic pancreatitis by post-mortem autopsy data from 620individuals with a history <strong>of</strong> excess alcohol consumption and 100 non-alcoholics (controls).The individuals were classified into groups based on macroscopic observations <strong>of</strong> pancreas(no injury, acute pancreatitis, fibrosis and chronic pancreatitis) and liver (no injury, moderatesteatosis, severe steatosis, and cirrhosis). The same classification system was used forhistological data, which was used to confirm and correlate macroscopic results. Out <strong>of</strong> the183 patients with liver cirrhosis, 33 (18 %) had chronic pancreatitis and 93 (51 %) pancreaticfibrosis. Out <strong>of</strong> the 230 patients with severe steatosis, 37 (16 %) had chronic pancreatitis and97 (42 %) were found to have a pancreatic fibrosis. Thirty-three (39 %) with chronicpancreatitis also showed liver cirrhosis and 37 (44 %) severe steatosis. Thirty-eight percent<strong>of</strong> the patients with a pancreatic fibrosis were found to have also liver cirrhosis and in another40 percent severe steatosis. Thirty-five patients showed neither hepatic nor pancreatic injury.It was found no chronic pancreatitis or liver cirrhosis in the control group (n=100). It wasconcluded that contrary to common believe there is a close association between pancreaticand hepatic injury in patients with increased alcohol consumption, and the degree <strong>of</strong> organdamage between the two organs correlate [261].Alcohol-induced chronic pancreatitisChronic pancreatitis is a progressive inflammatory condition characterized by repeatedattacks <strong>of</strong> abdominal pain, and the destruction and fibrosis <strong>of</strong> the pancreatic parenchymawhich causes to reduced exocrine and endocrine functions. Alcohol is the most commoncause <strong>of</strong> chronic pancreatitis. Although abstinence is usually considered a prerequisite forsuccessful treatment <strong>of</strong> alcoholic chronic pancreatitis, one <strong>of</strong>ten encounter patients who haverepeated attacks from the compensated stage through the transitional stage. In alcoholicchronic pancreatitis, continued alcohol consumption causes changes in the digestivehormones and vagal nerve function that induce the pancreatic acinar cells to oversecreteprotein, increasing the protein concentration and viscosity <strong>of</strong> the pancreatic juice. Thisinduces protein sedimentation from the pancreatic juice and formation <strong>of</strong> protein plugs withinthe pancreatic duct, triggering repeated attacks <strong>of</strong> acute pancreatitis. The treatment <strong>of</strong>alcoholic chronic pancreatitis includes alleviation <strong>of</strong> symptoms, particularly abdominal pain,elimination <strong>of</strong> trigger factors, prevention <strong>of</strong> recurrence and disease progression, adjuvanttherapies for pancreatic exocrine and endocrine failure. Recently, the main constituentproteins in these protein plugs have been identified, enabling trials <strong>of</strong> several therapies, suchas the administration <strong>of</strong> secretin formulations and endoscopic removal. Bromhexinehydrochloride, a bronchial mucolytic, has an affinity for the pancreatic acinar cells, inducingthem to secrete pancreatic juice <strong>of</strong> low viscosity. In one <strong>review</strong>, it was summarized the mostrecent thoughts about alcoholic chronic pancreatitis, and the new treatments, and inparticular, it was presented our findings concerning the efficacy <strong>of</strong> bromhexine hydrochloridein the treatment <strong>of</strong> this disease [262].Seventy percent <strong>of</strong> pancreatitis cases are considered to be induced by alcohol in Finland.Half <strong>of</strong> those fallen ill with alcohol-induced acute pancreatitis will have relapses. Aprospective follow-up study showed that the level <strong>of</strong> dependence on alcohol constitutes themost important risk factor. Continued drinking was shown to be a dose-responsive risk factorfor relapse; abstinence provided for a complete protection against renewed pancreatitis. In arandomized study, a semi-annual meeting with a healthcare pr<strong>of</strong>essional specialized insubstance abuse problems significantly reduced new episodes <strong>of</strong> acute pancreatitis. It is thus

possible to at least reduce relapses by intervening in the risk factors [263].Groove pancreatitisGroove pancreatitis is an uncommon form <strong>of</strong> focal chronic pancreatitis that involves theduodenal wall or "groove" area (between the pancreas, common bile duct, and duodenum). Itremains largely an unfamiliar entity to most physicians and is <strong>of</strong>ten misdiagnosed aspancreatic malignancy or autoimmune pancreatitis because <strong>of</strong> its "pseudotumor" formation.In one case series, it was presented four cases <strong>of</strong> groove pancreatitis which highlightimportant clinical aspects <strong>of</strong> this disease entity [264].PainTheories on investigations <strong>of</strong> pain in patients with chronic pancreatitisA total pancreatectomy for pain relief in chronic pancreatitis has been proposed as ultimaratio, but the rationale for such a mutilating option has not been defined, and the discussionon indication, results, and outcome <strong>of</strong> this procedure remains contradictory. There areseveral major problems why series <strong>of</strong> chronic pancreatitis from different centers regardingsuccess <strong>of</strong> therapeutic interventions are not comparable. In particular, the pathomechanism<strong>of</strong> pain in chronic pancreatitis is poorly understood; there is no generally accepted pain scoresystem, and in most series, nature and cause <strong>of</strong> pain are not adequately documented.Moreover, reliable data on the long-term pain pr<strong>of</strong>ile <strong>of</strong> chronic pancreatitis should be basedon prospective studies <strong>of</strong> mixed medical-surgical series <strong>of</strong> chronic pancreatitis <strong>of</strong> variousetiology, primarily because data <strong>of</strong> surgical series are biased excluding approximately 50percent <strong>of</strong> chronic pancreatitis patients who never required surgical intervention for pain relief[265].Types <strong>of</strong> painAbdominal pain in chronic pancreatitis is difficult to treat and appropriate choice <strong>of</strong> treatmentis controversial. It has been suggested that patients with chronic pancreatitis particularly fromalcohol (ACP) with intermittent attack <strong>of</strong> abdominal pain (type A pain) should be managedconservatively because pain relief will be achieved in most cases. Data <strong>of</strong> all patients withchronic pancreatitis with type A pain, who were followed-up and managed conservativelyduring 2004-2008 were analyzed. Pain relief was defined by the absence <strong>of</strong> abdominal painfor more than 1 year. Twenty-two patients were followed-up with a median duration <strong>of</strong> 31months (range 5-96 months). The etiology <strong>of</strong> chronic pancreatitis was alcoholic (ACP) in 12(56 %), early-onset idiopathic (E-ICP) in 5 (22 %) and late-onset idiopathic (L-ICP) in 5 (22%). Alcohol abstinence was successful in every ACP patient. Overall, 18 patients (82 %) hadpain relief with a median duration <strong>of</strong> 39 months (range 16-167 months) from the onset <strong>of</strong> painor 14 months (range 11-57 months) from the time <strong>of</strong> diagnosis <strong>of</strong> chronic pancreatitis. Painrelief was achieved at a higher level mainly in ACP (100 %) and L-ICP (80 %) but was only40 % in E-ICP Median duration from onset until pain relief were 28 months (range 16-167months) for ACP, 36 months (range 16-39 months) for L-ICP and 120 months (range 42-120months) for E-ICP. The difference was statistically significant between L-ICP and E-ICP, butnot between ACP and E-ICP and not between ACP and L-ICP. Median duration from thetime <strong>of</strong> diagnosis <strong>of</strong> chronic pancreatitis until pain relief was only 14 months for ACP 13months for L-ICP but was 52 months for E-ICP. None <strong>of</strong> the patients required narcotics,endoscopic therapy or surgery. The authors concluded that conservative management wasfeasible and effective in most patients with chronic pancreatitis and type A pain, particularlyACP after alcohol abstinence, and L-ICP Conservative treatment was not effective in E-ICP

[266].The chemokine fractalkine induces migration <strong>of</strong> inflammatory cells into inflamed tissues,thereby aggravating inflammatory tissue damage and fibrosis. Furthermore, fractalkineincreases neuropathic pain through glial activation, which can be diminished by blocking <strong>of</strong>its receptor, CX3CR1, through neutralizing antibodies. As chronic pancreatitis ischaracterized by tissue infiltration <strong>of</strong> inflammatory cells, fibrosis, pancreatic neuritis andsevere pain, the roles <strong>of</strong> fractalkine and CX3CR1 were investigated in CP (n=61) and normalpancreas (NP, n=21) by QRT-PCR, western blot and immunohistochemistry analyses. Theirexpression correlated with the severity <strong>of</strong> pancreatic neuritis, fibrosis, intrapancreatic nervefiber density and hypertrophy, pain, CP duration and with the amount <strong>of</strong> inflammatory cellinfiltrate immuno-positive for CD45 and CD68. Advanced fibrosis was associated withincreased fractalkine expression, whereas in vitro fractalkine had no significant impact oncollagen-1 and alpha-SMA expressions in hPSCs. Therefore, pancreatic fractalkineexpression appears to be linked to visceral pain and to the recruitment <strong>of</strong> inflammatory cellsinto the pancreatic tissue and nerve fibers, with subsequent pancreatic neuritis. However,pancreatic fibrogenesis is probably indirectly influenced by fractalkine. Taken together, thesenovel findings suggest that CX3CR1 represents a potential novel therapeutic target to reduceinflammation and modulate pain in chronic pancreatitis [267].Medical pain treatmentThe aim <strong>of</strong> one study was to evaluate the efficacy <strong>of</strong> intrathecal narcotics pump (ITNP) as analternative treatment for patients with pain from chronic pancreatitis. ITNP <strong>of</strong>fers theadvantages <strong>of</strong> reversibility, lower total narcotic dose, and the pancreas remaining intact.Thirteen patients (8 female, 5 male), with mean age 41 years, who had experiencedintractable upper abdominal pain from chronic pancreatitis were <strong>review</strong>ed. Each patient hadmultiple other failed treatment modalities, including partial pancreatic resection (n=6). Theywere <strong>of</strong>fered ITNP after a successful intraspinal opioid trial. Etiologies <strong>of</strong> the pancreatitisincluded idiopathy (n=3), cystic fibrosis (n=2), alcohol (n=2), and pancreas divisum (n=6).The median duration <strong>of</strong> severe, intractable pain prior to ITNP was 6 years (2-22 years). Themedian follow-up time after ITNP was 29 months (range, 7-94 months). The ITNP was in situfor a mean duration <strong>of</strong> 29 months (range, 0.5-94 months). Seven patients had pumpexchange or removal for various reasons; improvement <strong>of</strong> pain at month 53 (n=1), meningitis(n=1), meningitis with subsequent replacement (n=1), pump failure at month 31, 68, 79, and84 (n=4). There were no deaths. The mean pain score prior to implantation was significantlyhigher than 1 year after and last follow-up. The median oral narcotic dose before and 1 yearafter ITNP were morphine sulfate equivalents 338 mg per day (range, 68-1320) and 40 mgper day (range, 0-1680), respectively. Two patients were considered failures, as they stillrequire a high dosage <strong>of</strong> both oral and intrathecal medications to control their pain, despitesignificant pain-score improvement. One patient who was excluded due to meningitis wasalso considered a failure. Therefore, the overall success rate <strong>of</strong> ITNP based on an intentionto-treatanalysis was 77 percent (10/13). The major complications <strong>of</strong> ITNP were centralnervous system infection requiring pump removal (n=1), cerebrospinal fluid leak requiringlaminectomy (n=1), and perispinal abscess with bacterial meningitis requiring pump removal(n=1) [268].Pancreatic enzymes as treatment for painThe multiple possible etiologies <strong>of</strong> painful chronic pancreatitis combined with the likelihoodthat many patients with the condition are addicted to alcohol (and possibly continue to abusealcohol) make clinical research in this field particularly challenging. Additionally, the biologicbasis <strong>of</strong> pain in chronic pancreatitis remains somewhat controversial. Multiple other

etiologies have been proposed and are <strong>review</strong>ed elsewhere; some experts have evenpostulated that pain in chronic pancreatitis may actually be centrally mediated, rather thanmediated by inflammation <strong>of</strong> the pancreas itself. It has been proposed that administeringsupplemental porcine pancreatic extracts to patients with painful chronic pancreatitisstimulates receptors in the proximal small intestine and triggers a negative-feedback loopwhich suppresses baseline pancreatic enzyme secretion, decreasing ductal pressures,thereby decreasing pain. Many patients receive a therapeutic trial <strong>of</strong> pancreatic enzymesupplementation at some point in the course <strong>of</strong> their disease, but it is unclear what theexpected outcome <strong>of</strong> such a trial should be and whether or not all patients should receive atrial <strong>of</strong> pancreatic enzymes. It should be noted, however, that other proposedpathophysiological mechanisms for pain exist, including chronic perineural inflammation andfibrosis, uninhibited cholinergic stimulation <strong>of</strong> pancreatic secretion and colonic hypermotilitydue to malabsorption and steatorrhea. Of these alternative proposed etiologies, only colonichypermotility due to steatorrhea and malabsorption would potentially respond to pancreaticenzyme supplementation. It was searched PubMed for all studies <strong>of</strong> pancreatic enzymesupplementation for painful chronic pancreatitis from 1980 to 2009. In 1998, a technical<strong>review</strong> published by the American Gastroenterological Association (AGA) found that “the role<strong>of</strong> pancreatic enzymes in reducing pain in chronic pancreatitis … remains unclear”. However,an AGA medical position statement appearing in the same issue <strong>of</strong> Gastroenterologyrecommended routine use <strong>of</strong> pancreatic enzyme supplements for painful chronic pancreatitis.The AGA medical position statement does advocate the routine use <strong>of</strong> a quality-<strong>of</strong>-life (QOL)questionnaire though the AGA makes no specific recommendation as to which one. Ninestudies (6 articles and 3 abstracts) <strong>of</strong> pancreatic enzyme supplementation for the treatment<strong>of</strong> pain in chronic pancreatitis have been undertaken or reported, with widely varying results.The published clinical trials <strong>of</strong> enzyme replacement for pain relief in painful chronicpancreatitis are plagued by a number <strong>of</strong> methodological and design flaws. These include, butare not limited to, lack <strong>of</strong> a priori power analysis, failure to use validated instruments toassess pain or health-related quality <strong>of</strong> life, use <strong>of</strong> crossover designs, selection <strong>of</strong> studypopulations which are not generalizable to clinical patient populations, and use <strong>of</strong> coatedpancreatic enzymes rather than uncoated forms (only 2 studies have evaluated uncoatedenzymes). Five <strong>of</strong> the studies noted no improvement in pain with treatment, but all failed toreport whether an a priori power analysis was done, raising the possibility <strong>of</strong> type 2 error –sufficient numbers <strong>of</strong> patients may not have been studied to detect a significant difference.Further, even though 4 <strong>of</strong> the 9 published studies reported improvement in pain (statisticallysignificant p-values) with pancreatic enzyme supplements, they also failed to report havingdone an a priori power analysis. All studies reported significant placebo responses. Failure touse validated instruments or to systematically assess health-related quality <strong>of</strong> life (HRQOL)is another common problem with the published studies. Only 2 <strong>of</strong> the 9 studies assessedHRQOL in a systematic fashion, using published, validated instruments. Seven <strong>of</strong> the 9published clinical trials also made use <strong>of</strong> crossover designs. Crossover designs arebeneficial in reducing confounding because each patient serves as his own control and theyreduce the required number <strong>of</strong> participants. However, numerous problems exist withcrossover designs – carryover effects, assignment sequence, and dropouts in particular.Finally, selection <strong>of</strong> patients in the published studies is nonuniform and is poorly described,particularly with regard to rigorous screening for alcohol abuse, a potential confounder. One<strong>of</strong> the most important issues in the treatment <strong>of</strong> patients with painful and nonpainful chronicpancreatitis is alcohol abstinence. Achieving alcohol abstinence is difficult in the bestcircumstances and may be made more complicated by a chronic pain condition such aspainful chronic pancreatitis. What is not clear, however, is what to do with patients whocontinue to abuse alcohol or relapse during treatment. It is clear that the current publishedstudies have not definitively answered the question <strong>of</strong> whether or not pancreatic enzymesupplementation is useful in painful chronic pancreatitis. Based upon the published studies,the authors would recommend that clinicians follow the general guidelines proposed by theAGA. They would, however, add the following caveats for the use <strong>of</strong> pancreatic enzymes inpainful chronic pancreatitis [269]:

- pain should be assessed in a standardized and repeatable fashion prior to initiating atherapeutic trial <strong>of</strong> pancreatic enzymes. This could be as simple as using a 10-cmvisual-analog pain scale which is widely available and takes just seconds for a patientto fill out- therapeutic trials should be limited in time to 6 weeks with uncoated enzymes andconcurrent acid suppression, at which point another standardized pain measurementquestionnaire should be filled out- if the clinician feels that narcotics should be a part <strong>of</strong> the pain management strategyfor a patient, pill counts should be part <strong>of</strong> routine pain assessment at clinic visits- alcohol rehabilitation should be considered for any patient with ongoing alcohol abuse– before beginning therapy with enzyme supplements- since only one study has shown significant reductions in pain with coated pancreaticenzymes they would not recommend their use in painful chronic pancreatitis ingeneralSafety <strong>of</strong> pancreatic enzyme supplementationTo evaluate the efficacy and safety <strong>of</strong> a pancreatic enzyme preparation specificallydeveloped for infants and small children with cystic fibrosis (CF) 12 patients with CF youngerthan 24 months with pancreatic exocrine insufficiency and a coefficient <strong>of</strong> fat absorption(CFA) less than 70 percent were treated with Creon for Children (Solvay PharmaceuticalsGmbH, Hannover, Germany) minimicrospheres for 8 weeks. The primary end point was themean change from baseline in the CFA after 2 weeks <strong>of</strong> treatment, based on 72-hour fatbalance assessments. Two weeks' treatment with Creon for Children resulted in a significantincrease in the mean CFA from 58 percent at baseline to 85 percent in the full analysissample. There was a significant reduction <strong>of</strong> mean stool fat and mean fecal energy loss at 2weeks. Dietary fat intake did not change, whereas an improvement was observed in stoolfrequency and characteristics. Patient weight and height increased over 8 weeks <strong>of</strong>treatment. No serious adverse event was reported [270].Surgical interventionsOutcome <strong>of</strong> pancreatoduodenectomyPancreatic resection can be performed to ameliorate the sequelae <strong>of</strong> chronic pancreatitis inselected patients. The perceived risk <strong>of</strong> pancreatectomy may limit its use. Using a nationaldatabase, this study compared mortality after pancreatic resections for chronic pancreatitiswith those performed for neoplasm. Patient discharges with chronic pancreatitis or pancreaticneoplasm were queried from the Nationwide Inpatient Sample, 1998 to 2006. To account forthe Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used.There were 11,048 pancreatic resections. Malignant neoplasms represented 64 percent <strong>of</strong>the sample; benign neoplasms and pancreatitis comprised 17 percent and 19 percent,respectively. In-hospital mortality rates were 2.2 percent and 1.7 percent for the pancreatitisand benign tumor cohorts, respectively, compared with 5.9 percent for the malignancycohort, which was a significant difference. A multivariable logistic regression examineddifferences in mortality among diagnoses while adjusting for patient and hospitalcharacteristics; covariates included patient gender, race, age, comorbidities, type <strong>of</strong>pancreatectomy, payor, hospital teaching status, hospital size, and hospital volume. Afteradjustment, patients undergoing resection for pancreatitis were at a significantly lower risk <strong>of</strong>in-hospital mortality when compared with those with malignant neoplasm (odds ratio, 0.43;95 % confidence interval 0.28 to 0.67). Pancreatectomies for chronic pancreatitis have lowerin-hospital mortality than those performed for malignancy and similar rates as resection forbenign tumors. Pancreatic resection, which can improve quality <strong>of</strong> life in chronic pancreatitis

patients, can be performed with moderate mortality rates and should be considered inappropriate patients [271].PancreatogastrostomyPancreaticogastrostomy is a less used operation for drainage. In one seriespancreaticogastrostomy was done in 37 patients with dilated ducts during the period from2002-2008. Anastomosis <strong>of</strong> the pancreas to the posterior wall <strong>of</strong> stomach was performedusing pancreatic duct to gastric mucosa technique. The cases were followed up and it wasseen that pancreaticogastrostomy was an effective operation for chronic pancreatitis. Mostpatients (89 %) got relieved <strong>of</strong> pain for first several years. It is also a less time takingprocedure to perform as no Roux-en-y construction is needed [272].Longitudinal pancreatodjejunostomyObstruction <strong>of</strong> the main pancreatic duct in chronic pancreatitis (CP) leads to an increasedintraductal and intraparenchymal pressure causing pain. In one study it was evaluated theoutcome <strong>of</strong> surgical treatment <strong>of</strong> CP including the quality <strong>of</strong> life following Partington-Rochellepancreaticojejunostomy performed for intractable pain. Between 2002 and 2008, PRP themethod was performed in 17 patients in whom the diameter <strong>of</strong> the main pancreatic ductexceeded 7 mm and there was no inflammatory tumor in the pancreatic head. Perioperativemorbidity and mortality were analyzed in all patients. The long term outcome including thequality <strong>of</strong> life (Karn<strong>of</strong>sky index) was evaluated in 9 patients who were followed with a mean28 (range 13-60) months since surgery. Complications in the postoperative period werefound in 3 (18 %) patients including 1 death due to a myocardial infarction shortly aftersurgery. All patients submitted to the long-term evaluation reported a significant painreduction by an average <strong>of</strong> 6 (5-8) points in a 10-points visual analogue scale. The Karn<strong>of</strong>skyindex increased significantly from a mean 52 percent (40-70 %) before surgery up to 82percent (70-90 %) following surgery and long-term [273].Islet transplantationTransplantation <strong>of</strong> the whole pancreas or islet <strong>of</strong> Langerhans transplantation are alternativesto intensive insulin treatment, which decreases long-term complications at the cost <strong>of</strong> anincrease <strong>of</strong> severe hyoglycemia. Pancreas transplantation, indicated mainly to diabeticpatients with simultaneous kidney transplantation, has a high success rate, but isaccompanied by high morbidity due to general surgery. Islet transplantation, a cell-therapyfor type 1 diabetes, is in full development. It is mainly indicated as islet transplant alone inpatients suffering from brittle diabetes, and is associated with a very low risk due to minimallyinvasive technique, but a lower rate <strong>of</strong> long-term success. New potential sources <strong>of</strong> beta cellreplacement are beta-cell lines, stem cells and xenotransplantation [274].Intraportal autotransplantationThe probability <strong>of</strong> insulin independence after intraportal islet autotransplantation (IAT) forchronic pancreatitis treated by total pancreatectomy relates to the number <strong>of</strong> islets isolatedfrom the excised pancreas. The goal <strong>of</strong> one study was to correlate the islet yield with thehistopathologic findings and the clinical parameters in pediatric (age,

surgeries also had a strong negative correlation. Islet yield was better in younger (preteen)children and in those with pancreatitis <strong>of</strong> shorter duration. It was concluded that forpreserving beta cell mass, it is best to perform total pancreatectomy and intraportalautotransplantation early in the course <strong>of</strong> chronic pancreatitis in children, and prior drainageprocedures should be avoided to maximize the number <strong>of</strong> islets available, especially inhereditary disease [275].The only clinically acceptable radical treatment for patients with insulin-dependent diabetesmellitus is a whole pancreas transplantation, or alternatively an infusion <strong>of</strong> isolated islet cellsinto the hepatic portal venous system. Allogeneic transplantation <strong>of</strong> isolated islet cells is aprocedure used only in a highly specific group <strong>of</strong> recipients, whereas intensive insulintreatment still remains the best therapy to achieve glycemia control in most patients with type1 diabetes. Two groups <strong>of</strong> allograft recipients should be taken into consideration whenscheduled for islet cell transplantation. The first group comprises allogeneic kidney recipientswith a stabilized graft function for >6 months who receive chronic immunosuppression andrequire transplantation for end-stage renal disease caused by diabetic nephropathy. Thesecond group consists <strong>of</strong> patients with unsatisfactory glycemic control despite insulintherapy, life-threatening hypoglycemic episodes and a rapid progression <strong>of</strong> long-termcomplications. Despite increasingly beneficial outcomes, islet cell transplantation has severallimitations. Maintaining normoglycemia without exogenous insulin administration andappropriate selection <strong>of</strong> immunosuppressive agents to prolong graft survival are the majorchallenges. The aim <strong>of</strong> related studies has been to optimize all phases <strong>of</strong> islet celltransplantation in order to achieve total insulin independence and prolong graft survival [276].Open islet cell transplantationOne study examined 85 consecutive patients undergoing total pancreatectomy (+ islet celltransplant), examining pain relief, insulin requirements, and glycemic control postoperatively.A prospective database <strong>of</strong> all patients undergoing total pancreatectomy for chronicpancreatitis was used to record preoperative and postoperative details from 1996 to 2006.There were 3 postoperative deaths (1 islet recipient and 2 nonislet patients). The mediannumber <strong>of</strong> acute admissions for pain fell from 5 to 2 after pancreatectomy, and the medianlength <strong>of</strong> stay from 6.2 days to 3.3 days. At 12 months postoperatively, the number <strong>of</strong>patients on regular opiate analgesia fell from 91 to 40 percent and by 5 years to 16 percent.There was a significant reduction in the patients' visual analogue pain score after surgeryfrom 9.7 to 3.7. Five patients were insulin independent at 5 years. Median 24-hour insulinrequirements were significantly lower in the islet group (16 vs 40 units at 5 yearspostoperatively). It was concluded that total pancreatectomy is effective in reducing pain anddependence on opioid analgesia in patients with chronic pancreatitis. The addition <strong>of</strong> an isletcell transplant results in a reduction in 24-hour insulin demands, as well as potentiallyachieving insulin independence [277].Other interventions agains painPancreatic duct stentingEndoscopic therapy with pancreatic duct stenting in painful chronic pancreatitis is effective atreducing pain. Few studies have compared response to different pancreatic duct stentdiameters. In one study, it was retrospectively analyzed the effect <strong>of</strong> pancreatic duct stentdiameter on hospitalization for abdominal pain in chronic pancreatitis. An existing databasewas queried to identify individuals who received pancreatic duct stenting for chronicpancreatitis. Each patient was grouped according to stent diameter: (1) 8.5 F stents orsmaller and (2) 10 F stents. The main outcome was number <strong>of</strong> hospitalizations adjusting forvarying follow-up time and controlling for age, sex, and etiology <strong>of</strong> pancreatitis using a

negative binomial model. One hundred sixty-three patients underwent pancreatic duct stentplacement for chronic pancreatitis from 1995 to 2007. One hundred twenty-nine patients (79%) received predominantly pancreatic duct stents 8.5 F or smaller in diameter, and 34patients (21 %) received predominantly pancreatic duct stents 10 F in diameter. There wasno statistically significant difference in population characteristics between the two groups.The 10 F stent group had a statistically significant lower rate <strong>of</strong> hospitalization. It wasconcluded that patients who received larger diameter pancreatic duct stents had fewerhospitalizations for abdominal pain [278].To assess the long-term outcomes <strong>of</strong> endoscopic minor papilla therapy in a spectrum <strong>of</strong>symptomatic patients with pancreas divisum patients with pancreas divisum coded in aprospective database as having had minor papilla endotherapy (1997-2003, n=145) weregrouped into 3 categories: acute recurrent pancreatitis, chronic pancreatitis, andchronic/recurrent epigastric pain. Telephone follow-up was conducted (78 % <strong>of</strong> patients),including quesions regarding interval co-interventions and narcotic use. Primary success wasdefined as clinical improvement (better or cured on a Likert scale), without needing narcotics,after one therapeutic endoscopic retrograde cholangiopancreatography. Primary successrates in acute recurrent pancreatitis, chronic pancreatitis, and chronic/recurrent epigastricpain were achieved in 53, 18, and 41 percent, respectively; and secondary success rates (

endoscopic solution <strong>of</strong> mentioned problem is very important. The purpose <strong>of</strong> one publicationis presentation the case <strong>of</strong> proximal migration "pig tail" pancreatic stent and endoscopictechnique removal it [282].Plexus blockEndoscopic ultrasound (EUS)-guided celiac plexus block/neurolysis (CPB/N) can beperformed by injecting at the base (central) or on either side (bilateral) <strong>of</strong> the celiac axis.Central CPB/N is easier and possibly safer. Bilateral CPB/N is more difficult but may be moreeffective as it reaches more ganglia. The aim <strong>of</strong> one study was to compare the short-termsafety and efficacy <strong>of</strong> central and bilateral CPB/N. Central CPB/N was used in the first half <strong>of</strong>the study period and bilateral CPB/N in the last half. The primary outcome was the percentreduction in visual analog pain scores at day 7. A total <strong>of</strong> 184 patients were eligible. Out <strong>of</strong>them, 24 (13 %) were excluded for incomplete data. A total <strong>of</strong> 160 were left (71 central, 89bilateral). The groups were similar for all cogent variables. Bilateral CPB/N was significantlymore effective than central CPB/N (mean percent pain reduction 70 % (61-80) vs 46 % (33-57)). The only predictor <strong>of</strong> a >50 percent pain reduction was bilateral CPB/N (odds ratio 3.6,1.7-7.3). Only one complication was noted: self-limited bleeding because <strong>of</strong> laceration <strong>of</strong> theadrenal artery following bilateral celiac plexus block in an anticoagulated patient [283].RadiotherapyIt was reasoned that anti-inflammatory radiotherapy, which has proven useful to alleviateother painful inflammatory painful disorders, might prove valuable for severely symptomaticpatients with chronic pancreatitis. It was prospectively studied the efficacy <strong>of</strong> single-doseanti-inflammatory radiotherapy in 15 consecutive patients with chronic pancreatitis wh<strong>of</strong>ulfilled the following criteria: either two flare-ups <strong>of</strong> pancreatitis in the previous 6 monthsand/or continuous pain for more than 3 months. Treatment consisted <strong>of</strong> a single radiationdose <strong>of</strong> 8 Gy to the pancreas. Exocrine function (fecal elastase), endocrine function (cpeptide), quality <strong>of</strong> life (EuroQol questionnaire), and clinical outcome were assessed beforeand after radiation. Response was defined as no further pain or flare-ups <strong>of</strong> pancreatitis.During follow-up (median: 39 months; range: 4-72 months), 12 patients had no further pain orflare-ups. One patient required a second radiation dose 1 year after the initial treatment, buthe has remained well ever since (50 months). Two other patients did not respond toradiotherapy. After radiotherapy either exocrine or endocrine pancreatic function, or both,deteriorated in three patients. Patients who responded to treatment (13/15) gained 4-20 kg inbody weight during follow-up (median 4 kg) and EuroQol improved significantly from 0.58 to0.86. It was concluded that radiotherapy for severe symptomatic chronic pancreatitis appearsto be a useful and effective therapeutic choice that could potentially substitute for or delaysurgery [284].Hal<strong>of</strong>unginol as prevention <strong>of</strong> fibrosisChronic pancreatitis is characterized by inflammation and fibrosis. It was evaluated theefficacy <strong>of</strong> hal<strong>of</strong>uginone, an inhibitor <strong>of</strong> collagen synthesis and my<strong>of</strong>ibroblast activation, inpreventing cerulein-induced pancreas fibrosis. Collagen synthesis was evaluated by in situhybridization and staining. Levels <strong>of</strong> prolyl 4-hydroxylase-beta (P4H-beta), cytoglobin/stellatecell activation-associated protein (Cygb/STAP), transgelin, tissue inhibitors <strong>of</strong>metalloproteinases, serum response factor, transforming growth factor-beta (TGF-beta),Smad3, and pancreatitis-associated protein 1 (PAP-1) were determined byimmunohistochemistry. Metalloproteinase activity was evaluated by zymography.Hal<strong>of</strong>uginone prevented cerulein-dependent increase in collagen synthesis, collagen crosslinkingenzyme P4H-beta, Cygb/STAP, and tissue inhibitors <strong>of</strong> metalloproteinase 2.

Hal<strong>of</strong>uginone did not affect TGF-beta levels in cerulein-treated mice but inhibited serumresponse factor synthesis and Smad3 phosphorylation. In culture, hal<strong>of</strong>uginone inhibitedpancreatic stellate cell proliferation and TGF-beta-dependent increase in Cygb/STAP andtransgelin synthesis and metalloproteinase 2 activity. Hal<strong>of</strong>uginone increased c-Jun N-terminal kinase phosphorylation in pancreatic stellate cells derived from cerulein-treatedmice. Hal<strong>of</strong>uginone prevented the increase in acinar cell proliferation and further increasedthe cerulein-dependent PAP-1 synthesis. It was concluded that hal<strong>of</strong>uginone inhibits Smad3phosphorylation and increases c-Jun N-terminal kinase phosphorylation, leading to theinhibition <strong>of</strong> pancreatic stellate cell activation and consequent prevention <strong>of</strong> fibrosis.Hal<strong>of</strong>uginone increased the synthesis <strong>of</strong> PAP-1, which further reduces pancreas fibrosis.Thus, hal<strong>of</strong>uginone might serve as a novel therapy for pancreas fibrosis [285].Pancreatopleural fistulaePancreaticopleural fistula (PPF) is an unusual complication <strong>of</strong> chronic pancreatitis. Itsdiagnosis is obscured by predominance <strong>of</strong> pulmonary symptoms. A <strong>review</strong> <strong>of</strong> clinicalpresentation, etiology, diagnostic, and treatment modalities is presented in context <strong>of</strong> twocases from one institution. Case reports and case series <strong>of</strong> PPFs in the English <strong>literature</strong>from 1960 to 2007 were identified in the PubMed, OVID, and EMBASE search engines. Fiftytwocases <strong>of</strong> pancreaticopleural fistula were identified. Common presenting complaint wasdyspnea (65 %) followed by abdominal pain (29 %), cough (27 %) and chest pain (23 %).Computed tomography scanning diagnosed PPF in 8 (47 %) <strong>of</strong> 17 patients, endoscopicretrograde cholangiopancreatography diagnosed PPF in 25 (78 %) <strong>of</strong> 32 patients, andmagnetic resonance cholangiopancreatography diagnosed PPF in 8 (80 %) <strong>of</strong> 10 patients.Twenty-one patients (65 %) improved with conservative management alone. Interventionaltherapy (5 endoscopic and 6 surgical interventions) was eventually needed in 35 percent <strong>of</strong>the patients after failing conservative management. Magnetic resonancecholangiopancreatography is the better initial choice for being a noninvasive procedure andfor better demonstration <strong>of</strong> complete main pancreatic duct obstruction. Restoring anatomiccontinuity is important if conservative approach fails [286].Maldigestion and nutritionVitaminsThe main clinical manifestations <strong>of</strong> exocrine pancreatic insufficiency are fat malabsorption,known as steatorrhea, which consists <strong>of</strong> fecal excretion <strong>of</strong> more than 6 g <strong>of</strong> fat per day,weight loss, abdominal discomfort and abdominal swelling sensation. Fat malabsorption alsoresults in a deficit <strong>of</strong> fat-soluble vitamins (A, D, E and K) with consequent clinicalmanifestations. The relationships between pancreatic maldigestion, intestinal ecology andintestinal inflammation have not received particular attention, even if in clinical practice thesemechanisms may be responsible for the low efficacy <strong>of</strong> pancreatic extracts in abolishingsteatorrhea in some patients. The best treatments for pancreatic maldigestion should be reevaluated,taking into account not only the correction <strong>of</strong> pancreatic insufficiency usingpancreatic extracts and the best duodenal pH to permit optimal efficacy <strong>of</strong> these extracts, butwe also need to consider other therapeutic approaches including the decontamination <strong>of</strong>intestinal lumen, supplementation <strong>of</strong> bile acids and, probably, the use <strong>of</strong> probiotics whichmay attenuate intestinal inflammation in chronic pancreatitis patients [287].Nutritional support

Chronic pancreatitis is associated with a substantial morbidity, including malnutrition,malabsorption, pseudocysts, metabolic disturbances, and intractable abdominal pain.Approximately 5 percent <strong>of</strong> patients with chronic pancreatitis are refractory to nutritionalsupport and opiate analgesia, making management challenging. Pancreatic rest can providesymptomatic relief. However, achieving simultaneous pancreatic rest and adequatenutritional support in these patients is difficult. It was describe a technique for providingnutritional support and pancreatic rest in patients with intractable symptomatic in 3 patients.All 3 patients had masses associated with the pancreas. Symptom relief and adequatenutritional support were achieved by inserting a long-term nasojejunal tube (FlocareBengmark, Nutricia Clinical Care, United Kingdom) under ambulatory endoscopic guidance.The long-term nasojejunal tube feeding achieved pancreatic rest and significant symptomaticrelief while delivering adequate nutritional support. Pseudocyst size decreased substantiallyin 2 patients. The third patient was found to have pancreatic carcinoma afterpancreaticoduodenectomy [288].Influence <strong>of</strong> colostrumsExocrine pancreatic secretion contributes to limit pathogenic bacteria-associated diarrhea.Bovine colostrum, used in the treatment <strong>of</strong> diarrhea, reduces symptoms originating from gutpathogenic bacteria overgrowth. It was hypothesized that bovine colostrum may stimulate theexocrine pancreatic secretion. Eighteen piglets fitted with 2 permanent catheters (forpancreatic juice collection and reintroduction) were allocated to 1 <strong>of</strong> the following 2 dietarytreatments for 5 days: a control diet or a diet supplemented with defatted bovine colostrum.Pancreatic juice was collected daily, and digestive enzyme activities and antibacterial activitywere determined. The prandial pancreatic juice outflow, the basal and prandial lipase output,and the basal secretion <strong>of</strong> the antibacterial activity were, respectively, 60 percent, 154percent, 92 percent, and 72 percent higher in piglets fed a diet supplemented with defattedbovine colostrum. It was concluded that with defatted bovine colostrum, the increasedantibacterial activity secretion against Escherichia coli may limit pathogenic bacteriaovergrowth <strong>of</strong> the gut and reduce diarrheal episodes. The role <strong>of</strong> secretin in the increasedpancreatic juice flow and lipase secretion was considered [289].Diabetes in chronic pancreatitisIn consequence <strong>of</strong> the close anatomical and functional links between the exocrine andendocrine pancreas, any disease affecting one <strong>of</strong> these parts will inevitably affect the other.Pancreatic conditions which might cause diabetes mellitus include acute and chronicpancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development <strong>of</strong>diabetes greatly influences the prognosis and quality <strong>of</strong> life <strong>of</strong> patients with exocrinepancreatic diseases. It may cause lifethreatening complications, such as hypoglycemia, dueto the lack <strong>of</strong> glucagon and the impaired absorption <strong>of</strong> nutrients, or the micro- andmacrovascular complications may impair the organ functions. Temporary hyperglycemia canbe observed in around 50 percent <strong>of</strong> patients with acute pancreatitis; persisting diabetesmellitus may affect 1-15 percent. The prevalence <strong>of</strong> diabetes in chronic pancreatitis variesbetween 30 and 83 percent. Overall, exocrine pancreatic diseases are believed to beresponsible for diabetes in only about 0.5-1.7 percent <strong>of</strong> the cases, but in as many as 15-20percent <strong>of</strong> diabetes mellitus patients in Southeast Asia, where tropical pancreatitis isendemic. The incidence <strong>of</strong> pancreatic diabetes depends on several factors, such as theetiology and duration <strong>of</strong> chronic pancreatitis, and the presence <strong>of</strong> pancreatic calcification.The endocrine function is more disturbed in alcoholic chronic pancreatitis than innonalcoholic pancreatitis. Both insulin and glucagon secretion are more strongly impaired inpatients with calcified chronic pancreatitis than in those with noncalcified chronic pancreatitis.In two recent follow-up studies <strong>of</strong> patients with chronic pancreatitis over a period <strong>of</strong> 7.7 and 8

years, the risk <strong>of</strong> diabetes was increased 3.2- and 1.3-fold, respectively, after the onset <strong>of</strong>pancreatic calcification. Clinically manifest diabetes usually appears in the advanced stages<strong>of</strong> the disease, generally 8-10 years after the onset. The longer the duration <strong>of</strong> pancreatitis,the higher the number <strong>of</strong> patients who develop diabetes. The annual rate <strong>of</strong> diabetes inchronic pancreatitis calculated by means <strong>of</strong> linear regression was 3.5 percent and thecumulative rate <strong>of</strong> diabetes 25 years after the onset <strong>of</strong> chronic pancreatitis was 83 percent.Distal pancreatectomy was associated with a higher rate <strong>of</strong> diabetes as compared with othertypes <strong>of</strong> surgical procedures (pancreaticoduodenectomy, or pancreatic drainage) or withpatients who were never treated surgically. This result is consistent with the distribution <strong>of</strong>Langerhans’ islets in the pancreatic gland: the islet concentration <strong>of</strong> the tail is significantlygreater than the concentration in the head and body. There is a regional distribution <strong>of</strong> theglucagon-producing delta-cell and pancreatic polypeptide (PP)-producing cell, based on theembryologic derivation <strong>of</strong> the pancreas from distinct dorsal and ventral anlagen. The dorsalpancreas contains the glucagon-rich islets, whereas the ventral pancreas (most <strong>of</strong> the headand the uncinate process) is PP-rich. The role <strong>of</strong> PP deficiency in the pathogenesis <strong>of</strong>pancreatic diabetes suggests that conservation <strong>of</strong> the PP-rich ventral pancreas may beimportant for improved outcome after surgical treatment <strong>of</strong> pancreatic disease. Around 70percent <strong>of</strong> patients with pancreatic cancer already have an impaired glucose tolerance orfrank diabetes. In nearly 60 percent <strong>of</strong> these, the impaired glucose tolerance or diabetesimproves after surgery, whereas diabetes does not develop during a short-term follow-up.The reasons for the impaired glucose metabolism in pancreatic cancer are the alterationscaused in the islet cell functions by diabetogenic substances released by the cancer cells.On the other hand, 30 percent <strong>of</strong> the patients with a benign form <strong>of</strong> the disease and normalpreoperative glucose tolerance become diabetic after surgery. The primary hormonalabnormality in pancreatic diabetes is decreased insulin secretion. In chronic pancreatitis, theprogressive fibrosis destroys the beta-cells and reduces their functional capacity, leading to adeficiency <strong>of</strong> insulin secretion. Furthermore, the fibrosis impairs the circulation in the islets,which may result in an impaired delivery <strong>of</strong> secretagogues and blunted hormonal responses<strong>of</strong> the islets. Moreover, pancreatic diabetes is considered to be a result not merely <strong>of</strong> animpaired insulin production, but also <strong>of</strong> coexisting insulin resistance and alterations in insulinaction. The loss <strong>of</strong> hepatic insulin receptor expression caused by PP deficiency andimpairment <strong>of</strong> combined insulin receptor and glucagonlike peptide 2 endocytosis after insulinbinding in chronic pancreatitis was recently demonstrated to contribute to the development <strong>of</strong>diabetes. The greater the reduction in beta-cell mass, the more the insulin secretion isimpaired and the more the glucose tolerance is reduced. As long as 20-40 percent <strong>of</strong> thebeta-cell mass is preserved, the fasting plasma glucose and insulin levels are <strong>of</strong>ten normal.Nevertheless, at this stage, the functional exhaustion <strong>of</strong> the endocrine pancreas may berevealed by stimulatory tests: the insulin responses following the ingestion <strong>of</strong> an oral glucoseload or arginine or glucagon infusion are already delayed and reduced. Only when around 80percent <strong>of</strong> the beta-cells have been destroyed does fasting hyperglycemia develop.However, pancreatic diabetes has distinct clinical characteristics: the wide fluctuations inplasma glucose and frequent, severe and unpredictable hypoglycemic episodes which maybe lethal. This is particularly true for patients with pancreatic diabetes caused by total orsubtotal pancreatectomy due to:- basal glucagon secretion is significantly lower in those with pancreatic diabetes ascompared with patients with primary diabetes or healthy controls due to the reductionin beta-cell mass. The hypoglycemia and the arginine-stimulated glucagon responseare lower in pancreatic diabetes. The effects <strong>of</strong> insulin therefore remain unopposeddue to impaired glucagon secretion- the maldigestion <strong>of</strong> carbohydrates due to the coexisting pancreatic exocrineinsufficiency- concomitant alcohol consumption and hepatic disease- the lack <strong>of</strong> compliance with the prescribed diet and medical therapy- enhanced intestinal transit

Unlike hypoglycemia, the development <strong>of</strong> diabetic ketoacidosis and coma are uncommon inpancreatic diabetes, and are mainly seen in situations <strong>of</strong> marked stress such as infections orsurgery. This can be explained by the fact that the secretion <strong>of</strong> insulin is markedly impaired inpancreatic diabetes, but, except for total pancreatectomy, never completely absent. Thedevelopment <strong>of</strong> early microvascular complications in pancreatic diabetes is similar to that inother forms <strong>of</strong> diabetes. The prevalence and severity <strong>of</strong> diabetic retinopathy and neuropathyin pancreatic diabetes patients do not differ from those in patients with insulin-dependentdiabetes, and depend on the duration <strong>of</strong> the diabetes and on the degree <strong>of</strong> adequacy <strong>of</strong>glycemic control. The prevalence <strong>of</strong> more advanced stages <strong>of</strong> diabetic microvascularcomplications is not well known because <strong>of</strong> the high mortality <strong>of</strong> patients with chronicpancreatitis. The prevalence <strong>of</strong> neuropathy may be observed in 30 percent <strong>of</strong> the patientswith pancreatic diabetes, but an early onset suggests that the peripheral nerves had alreadybeen damaged by longterm alcohol abuse. The prevalence <strong>of</strong> diabetes in patients withautoimmune pancreatitis is quite high as compared with that in patients with ordinary chronicpancreatitis and is diagnosed before or simultaneously with autoimmune pancreatitis in 85percent <strong>of</strong> the patients. Steroid therapy reduces the symptoms <strong>of</strong> diabetes in approximately50 percent <strong>of</strong> patients with autoimmune pancreatitis. Diabetes is caused by cytokines from T-cells and macrophages, which suppress the function <strong>of</strong> the islet beta-cells. This suppressionmay be downregulated by steroids. On the other hand, 14 percent <strong>of</strong> the patients, andparticularly older patients, exhibit newly developed diabetes or exacerbation <strong>of</strong> diabetes aftersteroid therapy as steroids counteract the effects <strong>of</strong> insulin. The treatment <strong>of</strong> pancreaticdiabetes, a distinct metabolic and clinical form <strong>of</strong> diabetes, requires special knowledge. Dietand pancreatic enzyme replacement therapy may be sufficient in the early stages. Oralantidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemicgoals, insulin treatment with multiple injections is required. The goal <strong>of</strong> treatment inpancreatic diabetes is therefore to achieve a HbA 1C level as close as possible to normal inthe absence <strong>of</strong> hypoglycemia. However, this goal may be difficult to achieve with the presenttherapies. The irregular lifestyle <strong>of</strong> patients with pancreatic diabetes, their random eatinghabits, the lack <strong>of</strong> compliance, maldigestion and alcohol consumption severely hamper theirtreatment. Alcohol abstinence and appropriate enzyme substitution are essential to reducethe metabolic instability. The absorption <strong>of</strong> nutriments is unpredictable without adequateenzyme replacement therapy; the glucose-lowering effect <strong>of</strong> insulin occurs earlier than theglucose-elevating effect <strong>of</strong> nutriments, thereby leading to hypoglycemia. The basic principles<strong>of</strong> nutrition therapy are the same as those applied in other forms <strong>of</strong> diabetes: the dailycarbohydrate and energy intake should be based on the body weight and physical activityand meals should be rich in vegetable fibers and low in fat. Eating frequent small-volumemeals, at least six times per day, is recommended in pancreatic diabetes. The intake <strong>of</strong>saturated fatty acids from animal sources must be reduced, but decreasing the use <strong>of</strong>vegetable oil is also suggested. Milk and dairy products with reduced fat contents arerecommended. The intake <strong>of</strong> gross fibers is not advised as they may cause gastrointestinalsymptoms due to the exocrine pancreatic insufficiency. The application <strong>of</strong> oral antidiabeticdrugs in pancreatic diabetes is not recommended. Insulin sensitizers (biguanides andglitazones) and the carbohydrate absorption inhibitor glucosidase inhibitors should beavoided in pancreatic diabetes since the major pathogenetic defect is the lack <strong>of</strong> insulin andbecause <strong>of</strong> the coexisting maldigestion and consequent leanness. Although patients withpancreatic diabetes may occasionally be capable <strong>of</strong> insulin secretion, the use <strong>of</strong>sulfonylureas is likewise not recommended, because they can accelerate the exhaustion <strong>of</strong>beta-cells. Furthermore, they are <strong>of</strong>ten contraindicated due to the accompanying liverdisease. Appropriate glycemic control can be achieved in pancreatic diabetes by theadministration <strong>of</strong> short-acting insulin three times per day and an intermediate insulin injectionbefore sleep. The dosage <strong>of</strong> this bedtime insulin is usually much less than that in type 1diabetes. The administration <strong>of</strong> long-acting insulin twice a day is not recommended inpancreatic diabetes, because <strong>of</strong> the possibility <strong>of</strong> interference and the danger <strong>of</strong> severehypoglycemia. Treatment with oral pancreatic enzymes is therefore indicated in diabetes

patients with a proven exocrine pancreatic insufficiency [290].Function in diabetes mellitusRecently it has been shown that there is not only endocrine insufficiency in diabetic patients,but a frequent co-morbidity <strong>of</strong> both, the endocrine and exocrine pancreas. The records <strong>of</strong>1992 patients with diabetes mellitus who had been treated in one hospital during a 2-yearperiod were re-evaluated. Defined parameters were documented in standardized datasheets. Records were further checked for the results <strong>of</strong> imaging procedures <strong>of</strong> the pancreas.In 307 patients fecal elastase-1 concentrations had been performed and documented. Onlythese patients were included in further evaluation. Fecal elastase-1 concentrations wereinversely correlated with diabetes duration and HbA1c-levels but not with age. C-peptidelevels correlated positively with fecal elastase-1 concentrations. BMI and fecal elastase-1concentrations were also significantly correlated. There was no correlation between diabetestherapy and exocrine pancreatic function as there was no correlation with any concomitantmedication. The presence <strong>of</strong> diabetes-associated antibodies was not related to fecalelastase-1 concentrations. According to the documented data 38 were classified as type-1diabetes (12 %), 167 as type-2 (54 %), and 88 patients met the diagnostic criteria <strong>of</strong> type-3(29 %). Fourteen patients could not be classified because <strong>of</strong> lacking information (5 %). Theauthors concluded that exocrine insufficiency might be explained as a complication <strong>of</strong>diabetes mellitus. However, it is more likely that type-3 diabetes is much more frequent thanpreviously believed. Consequently the evaluation <strong>of</strong> exocrine function and morphologyshould be included into the clinical workup <strong>of</strong> any diabetic patient at least at the time <strong>of</strong>manifestation [291].Pancreas divisumTo assess the long-term outcomes <strong>of</strong> endoscopic minor papilla therapy in a spectrum <strong>of</strong>symptomatic patients with pancreas divisum. Patients with pancreas divisum coded in aprospective database as having had minor papilla endotherapy (1997- 2003, n=145) weregrouped into 3 categories: (1) acute recurrent pancreatitis, (2) chronic pancreatitis, and (3)chronic/recurrent epigastric pain. Telephone follow-up was conducted (78 % <strong>of</strong> patients),including quesions regarding interval co-interventions and narcotic use. Primary success wasdefined as clinical improvement (better or cured on a Likert scale), without needing narcotics,after one therapeutic endoscopic retrograde cholangiopancreatography. Primary successrates in acute recurrent pancreatitis, chronic pancreatitis, and chronic/recurrent epigastricpain were achieved in 53 percentage, 18 percent, and 41 percent, respectively; andsecondary success rates (< 2 additional endoscopic retrograde cholangiopancreatographies),71 percent, 46 percent, and 55 percent, respectively (median follow-up, 43months; range, 14-116 months). Younger age (median age, 47 years [no success] vs 58years [success]) and chronic pancreatitis (odds ratio, 0.10; 95 % confidence interval 0.03 to0.39) independently predicted a lower chance <strong>of</strong> success. It was concluded that significantlong-term improvement can be achieved with endoscopic therapy in selected patients withpancreas divisum, although many require multiple procedures. Older patients, withoutchronic pancreatitis, were most likely to respond [292].Pancreatic stellate cellsPancreatitis and pancreatic cancer represent two major diseases <strong>of</strong> the exocrine pancreas.Pancreatitis exhibits both acute and chronic manifestations. The commonest causes <strong>of</strong> acutepancreatitis are gallstones and alcohol abuse; the latter is also the predominant cause <strong>of</strong>chronic pancreatitis. Recent evidence indicates that endotoxinemia, which occurs in

alcoholics due to increased gut permeability, may trigger overt necroinflammation <strong>of</strong> thepancreas in alcoholics and one that may also play a critical role in progression to chronicpancreatitis (acinar atrophy and fibrosis) via activation <strong>of</strong> pancreatic stellate cells (PSCs).Chronic pancreatitis is a major risk factor for the development <strong>of</strong> pancreatic cancer, which isthe fourth leading cause <strong>of</strong> cancer-related deaths in humans. Increasing attention has beenpaid in recent years to the role <strong>of</strong> the stroma in pancreatic cancer progression. It is now wellestablished that PSCs play a key role in the production <strong>of</strong> cancer stroma and that theyinteract closely with cancer cells to create a tumor facilitatory environment that stimulateslocal tumor growth and distant metastasis. One <strong>review</strong> summarized recent advances in theunderstanding <strong>of</strong> the pathogenesis <strong>of</strong> alcoholic pancreatitis and pancreatic cancer, withparticular reference to the central role played by PSCs in both diseases. An improvedknowledge <strong>of</strong> PSC biology has the potential to provide an insight into pathways that may betherapeutically targeted to inhibit PSC activation, thereby inhibiting the development <strong>of</strong>fibrosis in chronic pancreatitis and interrupting stellate cell-cancer cell interactions so as toretard cancer progression [293].Pancreatic duct stonesAlthough radiopaque pancreatic duct stones can be targeted by extracorporeal shock wavelithotripsy (ESWL) and extracted by ERCP, large and radiolucent stones remain atherapeutic challenge. Four symptomatic patients with large (> 1 cm) radiolucent stonesoccluding the main pancreatic duct that could not be retrieved by standard endoscopicmaneuvers. Pancreatic sphincterotomy followed by balloon dilation <strong>of</strong> the pancreatic orificeto aid retrieval <strong>of</strong> large radiolucent stones occluding the main pancreatic duct was performed.Technical success was defined as the ability to achieve pancreatic duct clearance in oneendoscopic encounter. The procedure was technically successful in all 4 patients. Pancreaticduct clearance was achieved in all 4 patients in 1 endoscopy session with complete symptomrelief at 12-month follow-up. Mild post-ERCP pancreatitis developed in 1 patient, and minorbleeding developed in another patient; both were managed conservatively. It was concludedthat endoscopic balloon dilation <strong>of</strong> the pancreatic orifice after sphincterotomy is a safetechnique that facilitates the removal <strong>of</strong> large radiolucent stones from the main pancreaticduct in [294].Duodenal dystrophyOne paper presented the morphological characteristics <strong>of</strong> intraoperative specimens takenfrom patients with duodenal dystrophy characterized by cystic changes in the elements <strong>of</strong>pancreatic heterotopic tissue in the duodenal wall. It is emphasized that the development <strong>of</strong>cysts may be associated with that <strong>of</strong> an inflammatory process in the pancreatic heterotopictissue in young persons or may be caused by chronic alcoholic pancreatitis [295].On the basis <strong>of</strong> a <strong>review</strong> <strong>of</strong> the <strong>literature</strong> and description <strong>of</strong> a clinical case, the aim <strong>of</strong> onepaper was to evaluate the role <strong>of</strong> pancreaticoduodenectomy as the primary therapeuticchoice in a rare, serious condition such as cystic dystrophy <strong>of</strong> the duodenal wall inheterotopic pancreas. The diagnosis is difficult because <strong>of</strong> the non-specific clinicalmanifestations, and radiological and endoscopic imaging are decisive. Computedtomography and magnetic resonance are very useful for demonstrating the presence <strong>of</strong> cystsin a thickened duodenal wall but endoscopic ultrasonography is the most useful imagingexamination. The choice <strong>of</strong> therapeutic option is still debated. Although some authors haveproposed a medical approach using octreotide or endoscopic treatment for selected patients,pancreaticoduodenectomy is usually proposed for symptomatic patients. When surgery isneeded, pancreaticoduodenectomy should be preferred, reserving by-pass procedures for

high-risk patients [296].Cystic fibrosisCystic fibrosis is an autosomal recessive disorder, which is caused by a mutation in theCFTR protein, a chloride channel in epithelial cell membranes. More than 1500 mutations areknown. The incidence is 1/2.000-3.000 in nations <strong>of</strong> European origin. The CFTR mutationinfluences the secretion and absorption by epithelium in various organs. The consequencesare different depending on the organ, but there is a global tendency for obstruction <strong>of</strong>secretory glands. The primary organs affected are the respiratory tract, pancreas,gastrointestinal tract and sweat glands. The disease is most <strong>of</strong>ten diagnosed during the firstmonths <strong>of</strong> life, with a common presentation <strong>of</strong> salty tasting sweat, failure to thrive and diversefaecal problems. Possible diagnostic tools are sweat test and DNA testing. Respiratorysymptoms cause most morbidity, with chronic infections and an exaggerated inflammatoryresponse. Abnormal water and electrolyte composition leads to thicker respiratory secretionscompared to that <strong>of</strong> healthy individuals. The interaction <strong>of</strong> pathogens with the epitheliumcauses S. aureus, and later P. aeuruginosa, to transform into a mucoid form which is muchmore difficult to eradicate with antibiotics, making them a significant part <strong>of</strong> the diseaseburden <strong>of</strong> cystic fibrosis. The main respiratory medications are antibiotics, bronchodilators,mucolytic agents and anti-inflammatory agents. Ninty percent <strong>of</strong> cystic fibrosis patients havepancreas insufficiency which is treated with pancreas enzymes. A good nutritional status is anecessary basis for any further treatment. The prognosis <strong>of</strong> cystic fibrosis patients hasimproved greatly over the last few decades in parallel with increased knowledge, and theaverage survival is currently 37 years in the United States [297].

AUTOIMMUNE PANCREATITISAutoimmune pancreatitis is a systemic disease with a wide range <strong>of</strong> pancreatic andextrapancreatic imaging findings. These findings can mimic those <strong>of</strong> other diseases in thepancreas or other organs and therefore are commonly misdiagnosed and mistreated. It isimportant for radiologists to understand both the pancreatic and extrapancreatic imagingfindings <strong>of</strong> autoimmune pancreatitis to make accurate and timely diagnoses [298].PathogenesisTumor growth factor-beta (TGF-beta) is an immunosuppressive cytokine and has beenimplicated in a variety <strong>of</strong> disease processes, including those in autoimmune disease. Tumorgrowth factor-beta is also involved in fibrosis by regulating matrix metalloproteinases (MMPs)and the tissue inhibitor <strong>of</strong> MP (TIMP). The purpose <strong>of</strong> one study was to compare theexpression patterns <strong>of</strong> TGF-beta1, MMP-2, and TIMP-2 between autoimmune chronicpancreatitis (AIP) and alcoholic chronic pancreatitis (ACP) by immunohistochemical staining<strong>of</strong> pancreatic tissue specimens. Pancreatic tissue specimens were obtained from 16 <strong>of</strong> 57patients who had a diagnosis <strong>of</strong> AIP. Pancreatic tissue specimens <strong>of</strong> ACP were obtainedfrom 10 patients who were surgically treated. The degree <strong>of</strong> immunohistochemical stainingfor TGF-beta1 was significantly weaker in AIP than in ACP in the pancreatic ductal epithelialand mononuclear cells. This finding suggests that there may be a defect in the function <strong>of</strong>regulatory T (Treg) cells, which normally prevents autoimmune disease progression via asuppressor mechanism. Further studies are needed to identify the type <strong>of</strong> regulatory T cellinvolved in this process [299].Inflammatory pseudotumor (IPT) is a heterogeneous group <strong>of</strong> lesions occurring in variousorgans, which is histologically characterized by fibroblastic and my<strong>of</strong>ibroblastic proliferationwith inflammatory infiltrate. Inflammatory my<strong>of</strong>ibroblastic tumor (IMT) is a neoplasticcounterpart <strong>of</strong> IPT, which shows aberrant expression <strong>of</strong> ALK and its gene translocation. Incontrast, the concept "immunoglobulin (Ig)G4-related IPT" in the lung, liver, and pancreashas recently been proposed as a member <strong>of</strong> IgG4-related sclerosing disease. In one study, itwas compared the histopathologic features with an emphasis on IgG4 expression between22 cases <strong>of</strong> IMT and 16 cases <strong>of</strong> IgG4-related sclerosing disease, including chronicsclerosing sialadenitis (n=8), mass-forming autoimmune pancreatitis (n=3), sclerosingcholangitis (n=1), retroperitoneal fibrosis (n=2), and chronic sclerosing dacryoadenitis (n=2).Bland-looking spindle cell proliferation with fibrosis and inflammatory infiltrate <strong>of</strong> lymphocytesand plasma cells was the common morphologic feature in both lesions. Obstructive phlebitiswas observed in all <strong>of</strong> the IgG4-related sclerosing lesions, but in only 1/22 <strong>of</strong> IMT. Theimmunohistochemical expression <strong>of</strong> ALK was observed in 15/22 (68 %) <strong>of</strong> IMT and 0/16 (0%) <strong>of</strong> IgG4-related sclerosing disease. The number <strong>of</strong> IgG4-positive plasma cells and theratio <strong>of</strong> IgG4+/ IgG+ plasma cells were each significantly lower in IMT than in IgG4-relatedsclerosing disease. The results suggest that IgG4 does not play an important role in thepathogenesis <strong>of</strong> IMT. In addition, the evaluation <strong>of</strong> IgG4+ plasma cells and the ratio <strong>of</strong>IgG4+/IgG+ plasma cells and the presence <strong>of</strong> obstructive phlebitis may be useful for thedifferential diagnosis between IMT and IgG4-related sclerosing disease [300].Association with Helicobacter pyloriIt was studied the frequency <strong>of</strong> peptic ulcer, the association <strong>of</strong> peptic ulcer with Helicobacterpylori and host TNF-alpha promoter haplotype in autoimmune pancreatitis (AIP) andnonautoimmune chronic pancreatitis. Esophagogastroduodenoscopy (EGD) was performedin 40 patients with AIP and 113 patients with nonautoimmune chronic pancreatitis. The status<strong>of</strong> H. pylori infection was determined. Genotyping and 5-locus haplotype assembly <strong>of</strong> the

TNF-alpha promoter were performed. The correlation between clinical characteristics,endoscopic findings, Helicobacter pylori infection status, and TNF-alpha promoterpolymorphism and haplotype was analyzed. The frequencies <strong>of</strong> gastric ulcer (GU) weresignificantly higher in patients with autoimmune pancreatitis compared with patients withnonautoimmune CP (23 % vs 4 %). Duodenal ulcer (DU) was more prevalent than GU inboth patients with AIP and patients with nonautoimmune chronic pancreatitis. There was nodifference in the positive status <strong>of</strong> Helicobacter pylori and TNF-alpha promoterpolymorphism/haplotype. The results demonstrated that gastric ulcer was more prevalent inAIP compared with nonautoimmune chronic pancreatitis. Positive H. pylori status and hostTNF-alpha promoter susceptibility could not explain the pathogenesis <strong>of</strong> higher gastric ulcerprevalence and pathogenesis <strong>of</strong> autoimmune pancreatitis in a selected population [301].Association with eosinophiliaThe purpose <strong>of</strong> one study was to investigate the clinical significance and causes <strong>of</strong>eosinophilia (>0.5 x 10 9 /L eosinophils in the peripheral blood) by analyzing the features <strong>of</strong>chronic pancreatitis cases with eosinophilia. It was retrospectively analyzed the clinicalfeatures <strong>of</strong> chronic pancreatitis patients with eosinophilia and compared them with chronicpancreatitis patients without eosinophilia. There were 28 cases (16 %) with eosinophiliaamong 180 patients with chronic pancreatitis. The peak value <strong>of</strong> eosinophils in the patients'peripheral blood was 0.935 + 0.600 x 10 9 /L. The incidence <strong>of</strong> eosinophilia in autoimmunepancreatitis was significantly higher than in non-autoimmune pancreatitis chronic pancreatitiscases. The incidence <strong>of</strong> pancreatic ascites, pancreatic enlargement, or jaundice in witheosinophilia was significantly higher than in those without eosinophilia. There was no obviousinfiltration <strong>of</strong> eosinophils in the pancreatic tissues <strong>of</strong> 16 pathology or cytology specimens. Itwas concluded that the occurrence <strong>of</strong> eosinophilia during the course <strong>of</strong> chronic pancreatitis isnot unusual. This may be related to autoimmune mechanisms, serous membrane response,or the progression <strong>of</strong> pancreatic inflammation and fibrosis [302].Definitions and differential diagnosisThree committees (the pr<strong>of</strong>essional committee for making clinical questions and statementsby Japanese specialists, the expert panelist committee for rating statements by the modifiedDelphi method, and the evaluating committee by moderators) were organized. Fifteenspecialists for Japanese clinical guidelines for autoimmune pancreatitis extracted the specificclinical statements from a total <strong>of</strong> 871 <strong>literature</strong>s by PubMed search (~1963-2008) and from asecondary database and made the clinical questions and statements. The expert panelistsindividually rated these clinical statements using a modified Delphi approach, in which aclinical statement receiving a median score greater than 7 on a 9-point scale from the panelwas regarded as valid. The pr<strong>of</strong>essional committee made 13, 6, 6, and 11 clinical questionsand statements for the concept and diagnosis, extrapancreatic lesions, differential diagnosis,and treatment, respectively. The expert panelists regarded them as valid after a 2-roundmodified Delphi approach. After evaluation by the moderators, the Japanese clinicalguideline for AIP has been established [303].The new Japanese clinical guidelines for autoimmune pancreatitis (JCGAIP) reflect a careful,consensus-building effort to guide and standardize the diagnosis and treatment <strong>of</strong> patientswith autoimmune pancreatitis in Japan. The guidelines provide an effective <strong>review</strong> <strong>of</strong>autoimmune pancreatitis and merit attention and careful consideration regarding theirapplication internationally. The most basic issue is the question <strong>of</strong> whether there is more thanone form <strong>of</strong> autoimmune pancreatitis in regard to pancreatic pathology, clinical features, andpathogenetic mechanisms. The JCGAIP focus on patients with the histopathologic changescalled lymphoplasmacytic sclerosing pancreatitis (LPSP), most <strong>of</strong> whom have elevations <strong>of</strong>plasma immunoglobulins, and specifically <strong>of</strong> IgG4. It has been proposed that AIP is a

manifestation <strong>of</strong> a systemic IgG4-related autoimmune disease. These patients are typicallyolder than 50 years and male. Large series reported from Europe and the United Statesconsistently identify a second set <strong>of</strong> patients with slightly different histopathologic changesthat have been called idiopathic duct-centric chronic pancreatitis (IDCP) or AIP withgranulocytic epithelial lesions (GELs). This subgroup <strong>of</strong> patients is more diverse in age,includes a higher fraction <strong>of</strong> female patients, and characteristically does not have elevatedplasma IgG4. These patients may have chronic inflammatory bowel disease such asulcerative colitis, but typically lack evidence <strong>of</strong> extrapancreatic involvement <strong>of</strong> the organstypical <strong>of</strong> IgG4-related autoimmune disease. More recently, these two patterns have beendesignated as AIP types 1 and 2. In the United States and Europe, type 1 AIP (LPSP) ismore common than type 2 (IDCP/AIP with GELs) in series that identify both types. Bothtypes <strong>of</strong> AIP share a number <strong>of</strong> histopathologic features most notably a periductallymphoplasmacytic infiltrate and a phlebitis. Only the concomitant duct infiltration byneutrophilic granulocytes, the GEL, and a less marked phlebitis distinguish the histologicalchanges <strong>of</strong> type 2 from type 1 AIP. A fraction <strong>of</strong> patients with type 2 AIP also hasinflammatory bowel disease, and one had multiple sclerosis (some forms <strong>of</strong> multiple sclerosisare considered to be <strong>of</strong> autoimmune origin). Type 2 AIP patients may also show biliaryinvolvement similar to that seen in type 1 AIP. Finally, both types 1 and 2 AIP cases reveal asimilar increase in the numbers <strong>of</strong> CD4 and CD lymphocytes that infiltrate the pancreas. Inaggregate, these observations provide a significant support for an autoimmune mechanismin the pathogenesis <strong>of</strong> type 2 AIP. The issue <strong>of</strong> core biopsies to diagnose AIP has been apoint <strong>of</strong> contention. Whereas the Mayo group has published on the technical aspects andusefulness <strong>of</strong> endoscopic ultrasoundguided pancreatic core biopsies and routinely uses it toestablish the diagnosis <strong>of</strong> AIP, others have not found it as helpful in its ability to get sufficienttissue to make the diagnosis <strong>of</strong> either AIP or nonfocal chronic pancreatitis. The Americancriteria also differ sigificantly from the Japanese and Asian criteria in the use <strong>of</strong> serologicalmarkers. Whereas the American criteria use only serum IgG4, the Japanese and Asiancriteria use any one <strong>of</strong> immunoglobulin G, immunoglobulin G4, and autoantibodies such asantinuclear antibody and rheumatoid factor. However, unlike the American criteria, in theJapanese or Asian criteria, other organ involvement cannot be used as collateral evidence todiagnose AIP.It is believe that the presence <strong>of</strong> other organ involvement can be as helpful as,if not more helpful than, serological abnormalities in the diagnosis <strong>of</strong> AIP and should beincluded in the diagnostic armamentarium as suggested by the JCGAIP. In conclusion, thenew Japanese guidelines reflect progress in standardizing the diagnosis and treatment AIP.The recommendations also reveal differences in the experience <strong>of</strong> Japanese and Westernclinicians and pathologists that may require additional consideration for their applicationinternationally, or slight revision to create guidelines that are applicable worldwide [304].A new antibodyAutoimmune pancreatitis is characterized by an inflammatory process that leads to organdysfunction. The cause <strong>of</strong> the disease is unknown. Its autoimmune origin has beensuggested but never proved, and little is known about the pathogenesis <strong>of</strong> this condition. Toidentify pathogenetically relevant autoantigen targets, it was screened a random peptidelibrary with pooled IgG obtained from 20 patients with autoimmune pancreatitis. Peptidespecificantibodies were detected in serum specimens obtained from the patients. Among thedetected peptides, peptide AIP(1-7) was recognized by the serum specimens from 18 <strong>of</strong> 20patients with autoimmune pancreatitis and by serum specimens from 4 <strong>of</strong> 40 patients withpancreatic cancer, but not by serum specimens from healthy controls. The peptide showedhomology with an amino acid sequence <strong>of</strong> plasminogen-binding protein (PBP) <strong>of</strong>Helicobacter pylori and with ubiquitin-protein ligase E3 component n-recognin 2 (UBR2), anenzyme highly expressed in acinar cells <strong>of</strong> the pancreas. Antibodies against the PBP peptidewere detected in 19 <strong>of</strong> 20 patients with autoimmune pancreatitis (95 %) and in 4 <strong>of</strong> 40patients with pancreatic cancer (10 %). Such reactivity was not detected in patients withalcohol-induced chronic pancreatitis or intraductal papillary mucinous neoplasm. The results

were validated in another series <strong>of</strong> patients with autoimmune pancreatitis or pancreaticcancer: 14 <strong>of</strong> 15 patients with autoimmune pancreatitis (93 %) and 1 <strong>of</strong> 70 patients withpancreatic cancer (1 %) had a positive test for anti-PBP peptide antibodies. When thetraining and validation groups were combined, the test was positive in 33 <strong>of</strong> 35 patients withautoimmune pancreatitis (94 %) and in 5 <strong>of</strong> 110 patients with pancreatic cancer (5 %). It wasconcluded that the antibody that was identified was detected in most patients withautoimmune pancreatitis but also in a few patients with pancreatic cancer, making it animperfect test to distinguish between these two conditions [305].Possible etiological factorsK-rasTo assess the relationship between autoimmune pancreatitis (AIP) and pancreatic cancer, itwas analyzed K-ras mutation in the pancreatobiliary tissues <strong>of</strong> patients with AIP. An analysis<strong>of</strong> K-ras mutation and an immunohistochemical study were performed on the pancreas <strong>of</strong> 8patients with autoimmune pancreatitis and 10 patients with chronic alcoholic pancreatitis andon the common bile duct and the gallbladder <strong>of</strong> 9 patients with AIP. K-ras mutation wasanalyzed in the pure pancreatic juice from 3 patients with AIP. High-frequency K-ras mutation(2+ or 3+) was detected in the pancreas <strong>of</strong> all the 8 patients and in the pancreatic juice <strong>of</strong> theother 2 patients. The mutation in codon 12 <strong>of</strong> the ras gene was GAT in all the 10 patients.High-frequency K-ras mutation was detected in the common bile duct <strong>of</strong> 5 patients withautoimmune pancreatitis and in the gallbladder epithelium <strong>of</strong> 4 patients with AIP. The K-rasmutation was detected in the fibroinflammatory pancreas, the bile duct, and the gallbladder,with abundant infiltrating IgG4-positive plasma and Foxp3-positive cells <strong>of</strong> patients with AIPwith elevated serum IgG4 levels. It was concluded that significant K-ras mutation occursmost frequently in the pancreatobiliary regions <strong>of</strong> patients with AIP. Autoimmune pancreatitismay be a risk factor <strong>of</strong> pancreatobiliary cancer [306].TGF-beta1Tumor growth factor-beta (TGF-beta) is an immunosuppressive cytokine and has beenimplicated in a variety <strong>of</strong> disease processes, including those in autoimmune disease. Tumorgrowth factor [beta] is also involved in fibrosis by regulating matrix metalloproteinases(MMPs) and the tissue inhibitor <strong>of</strong> MP (TIMP). The purpose <strong>of</strong> one study was to compare theexpression patterns <strong>of</strong> TGF-beta1, MMP-2, and TIMP-2 between autoimmune chronicpancreatitis (AIP) and alcoholic chronic pancreatitis (ACP) by immunohistochemical staining<strong>of</strong> pancreatic tissue specimens. Pancreatic tissue specimens were obtained from 16 <strong>of</strong> 57patients who had a diagnosis <strong>of</strong> AIP. Pancreatic tissue specimens <strong>of</strong> alcoholic chronicpancreatitis were obtained from 10 patients who were surgically treated. The degree <strong>of</strong>immunohistochemical staining for TGF-beta1 was significantly weaker in AIP than inalcoholic chronic pancreatitis in the pancreatic ductal epithelial and mononuclear cells. Thisfinding suggests that there may be a defect in the function <strong>of</strong> regulatory T (Treg) cells, whichnormally prevents autoimmune disease progression via a suppressor mechanism. Furtherstudies are needed to identify the type <strong>of</strong> regulatory T cell involved in this process [307].Extrapancreatic manifestationsThe frequency and clinical characteristics <strong>of</strong> extrapancreatic lesions during the clinical course<strong>of</strong> autoimmune pancreatitis were investigated retrospectively in 64 patients with autoimmunepancreatitis. The predictive factors for relapse <strong>of</strong> autoimmune pancreatitis at clinical onset

were also examined. Extrapancreatic lesions occurred in 95 percent (61/64) during theclinical course <strong>of</strong> autoimmune pancreatitis. The frequencies <strong>of</strong> sclerosing cholangitis,sclerosing sialadenitis, retroperitoneal fibrosis, and mediastinal or hilar lymphadenopathywere 84 percent (54/64), 23 percent (15/64), 16 percent (10/64), and 77 percent (27/35),respectively. Patients with sclerosing sialadenitis or extrapancreatic bile duct sclerosingcholangitis had a significantly higher serum immunoglobulin G concentration than thosewithout). Univariate analysis revealed that sclerosing sialadenitis, diffuse pancreatic ductalchanges, and a high serum immunoglobulin G concentration at clinical onset <strong>of</strong> autoimmunepancreatitis were significant predictive factors for relapse. Multivariate analysis revealed thatdiffuse pancreatic ductal changes and sclerosing sialadenitis were significant independentpredictive factors for relapse <strong>of</strong> autoimmune pancreatitis. It was thus concluded that thefrequency <strong>of</strong> extrapancreatic lesions with autoimmune pancreatitis during the clinical coursewas high. The presence <strong>of</strong> sclerosing sialadenitis at clinical onset is a significant predictivefactor for relapse <strong>of</strong> autoimmune pancreatitis [308].Mikulicz diseasePatients with autoimmune pancreatitis sometimes present with Mikulicz disease; however,the clinical features regarding these autoimmune pancreatitis patients with Mikulicz diseasehave not yet been fully elucidated. The aim <strong>of</strong> one study was to study the clinical differencesbetween autoimmune pancreatitis with and without Mikulicz disease. Twenty-eightautoimmune pancreatitis patients were divided into 2 groups, one with Mikulicz disease andone without it. The following factors having a possible association with the presence orabsence <strong>of</strong> Mikulicz disease were investigated: gender; serum IgG and IgG4 levels; thepresence or absence <strong>of</strong> antinuclear autoantibodies, jaundice, diabetes mellitus, swollenduodenal papilla, diffuse pancreatic swelling, spontaneous remission, and relapse. TheMikulicz disease and non-Mikulicz disease groups consisted <strong>of</strong> 5 autoimmune pancreatitisand 23 autoimmune pancreatitis patients, respectively. The results <strong>of</strong> univariate analysisrevealed that autoimmune pancreatitis patients presenting with Mikulicz disease weresignificantly associated with a younger onset, female predominance, high serum IgG4 titer,and diffuse pancreatic swelling. In 4 <strong>of</strong> the Mikulicz disease patients, onset precededpancreatitis. It was concluded that autoimmune pancreatitis patients presenting with Mikuliczdisease tended to have different clinical features from the non-Mikulicz disease autoimmunepancreatitis patients, such as having an earlier onset, female tendency, and diffusepancreatic swelling with a high titer <strong>of</strong> serum IgG4. Autoimmune pancreatitis with Mikuliczdisease tended to precede gastroenterological events [309].Sclerosing cholangitisIt was assessed the clinical, computed tomography, and pathological findings in patients withlymphoplasmacytic sclerosing cholangitis in 15 consecutive patients (four women and 11men, mean age 71 years) with lymphoplasmacytic sclerosing cholangitis and without thecharacteristic features <strong>of</strong> underlying disorders causing benign biliary strictures wereretrospectively recruited. Two radiologists evaluated multiphase contrast-enhanced CTimages acquired with 0.5 or 1-mm collimation. One pathologist performed all histologicalexaminations, including IgG4 immunostaining. The intrahepatic biliary ducts showeddilatation in all 15 patients, but only seven presented with jaundice. Although laboratory datawere not available in all patients, serum gammaglobulin and IgG levels were elevated in five<strong>of</strong> six patients and six <strong>of</strong> eight patients, respectively. Anti-nuclear antibody was detected inthree <strong>of</strong> six patients. The involved biliary ducts showed the following CT findings:involvement <strong>of</strong> the hilar biliary duct (14/15), a mean wall thickness <strong>of</strong> 4.9 mm, a smoothmargin (10/15), a narrow but visible lumen (6/15), hyper-attenuation during the late arterialphase (9/15), homogeneous hyper-attenuation during the delayed phase (11/11), and no

vascular invasion (14/15). Abnormal findings in the pancreas and urinary tract were detectedin eight <strong>of</strong> 15 patients. In 13 patients with adequate specimens, moderate to severelymphoplasmacytic infiltration associated with dense fibrosis was observed. Infiltration <strong>of</strong>IgG4-positive plasma cells was moderate or severe in nine patients and minimal or absent infour patients. It was concluded that lymphoplasmacytic sclerosing cholangitis exhibitsrelatively characteristic clinical and CT findings, although they are not sufficiently specific fordifferentiation from other biliary diseases [310].Retroperitoneal fibrosisIt was presented a case <strong>of</strong> retroperitoneal fibrosis (RPF) in a 72-year-old man who previouslyreceived pancreatectomy for autoimmune pancreatitis. He had earlier received colectomy forearly colon cancer. During the routine follow-up for colon cancer, a swollen pancreas tail wasdetected on enhanced CT. He received distal pancreatectomy under the diagnosis <strong>of</strong>pancreas cancer two years later. Pathological diagnosis revealed the autoimmunepancreatitis. Eight months later, right hydronephrosis was observed in an abdominalultrasonographic study, and at the same time, right hydroureterosis due to retroperitoneals<strong>of</strong>t tissue mass around the bifurcation was detected on enhanced CT. He was treated withpredonisolone aiming at the diagnosis and therapy. Twelve weeks later, right hydronephrosishad disappeared and retroperitoneal mass had shrunken. Now, it is thought that autoimmunepancreatitis is a systemic sclerosing disease accompanied with extra-pancreatic pathologicchanges such as RPF [311].A 74-year-old male patient presented with progressive anorexia, cholestatic liver functiontests, and a diffuse enlarged pancreas suggestive <strong>of</strong> a pancreatic carcinoma. There was amarked elevation <strong>of</strong> total immunoglobulin G4 (IgG4) in serum. Further investigation led to thediagnosis <strong>of</strong> IgG4-related sclerosing disease with involvement <strong>of</strong> the pancreas,retroperitoneal fibrosis, and bilateral focal nephritis. This was the first report on these threeclinical entities occurring in the same patient. A short <strong>review</strong> <strong>of</strong> the <strong>literature</strong> concerningautoimmune pancreatitis and retroperitoneal fibrosis is made, with special interest to theconcept <strong>of</strong> IgG4-related pathology. This systemic disease can have several clinicalmanifestations: IgG4-positivity not only can be found in the pancreas, but also at the level <strong>of</strong>extrahepatic biliary ducts, gallbladder, salivary glands, retroperitoneal tissue, kidneys,ureters, and lymph nodes [312].DiagnosticsCTIt was investigated the clinical and radiological features <strong>of</strong> focal mass-forming autoimmunepancreatitis (FMF AIP) to help physicians avoid performing unnecessary surgery because <strong>of</strong>an improper diagnosis. It was evaluated 23 patients with chronic inflammatory pancreaticmasses and who underwent pancreatectomy for presumed pancreatic cancer from 1995 to2005. These patients were distinguished into 8 FMF AIP patients and 15 ordinary chronicpancreatitis patients through a histological <strong>review</strong>, along with considering the immunoglobulinG4 staining. Twenty-six randomly selected pancreatic cancer patients were also evaluatedas a control group. On the portal venous phase <strong>of</strong> computed tomography, 6 (86 %) <strong>of</strong> 7 FMFAIP patients showed homogeneous enhancement, whereas only 3 chronic pancreatitispatients (25 %) and none <strong>of</strong> the pancreatic cancer patients showed homogeneousenhancement. None <strong>of</strong> the FMF AIP patients showed upstream main pancreatic ductdilatation greater than 5 mm or proximal pancreatic atrophy. It was concluded that forpatients with a pancreatic mass, if their radiological images show homogeneous

enhancement on the portal venous phase, the absence <strong>of</strong> significant upstream mainpancreatic duct dilatation greater than 5 mm, and the absence <strong>of</strong> proximal pancreaticatrophy, then conducting further evaluations should be considered to avoid performingunnecessary surgery [313].The purposes <strong>of</strong> one study were to define the pancreatic enhancement <strong>of</strong> autoimmunepancreatitis at dual-phase CT and to compare it with that <strong>of</strong> pancreatic carcinoma and anormal pancreas. Dual-phase CT scans <strong>of</strong> 101 patients (43 with autoimmune pancreatitis, 13cases <strong>of</strong> which were focal; 33 with pancreatic carcinoma, and 25 with a normal pancreas)were evaluated. One radiologist measured the CT attenuation <strong>of</strong> the pancreatic parenchymaand pancreatic masses in both the pancreatic and hepatic phases <strong>of</strong> imaging. The mean CTattenuation value <strong>of</strong> the pancreatic parenchyma in patients with autoimmune pancreatitis wascompared with that in patients with a normal pancreas. The mean CT attenuation value <strong>of</strong>the focal masses in the focal form <strong>of</strong> autoimmune pancreatitis was compared with that <strong>of</strong>carcinomas. In the pancreatic phase, the mean CT attenuation value <strong>of</strong> the pancreaticparenchyma in patients with autoimmune pancreatitis was significantly lower than that inpatients with a normal pancreas (autoimmune pancreatitis, 85 HU; normal pancreas, 104HU). In the hepatic phase, however, the mean CT attenuation values were not significantlydifferent (autoimmune pancreatitis, 96 HU; normal pancreas, 89 HU). In the pancreaticphase, the mean CT attenuation value <strong>of</strong> the mass in autoimmune pancreatitis was notsignificantly different from that <strong>of</strong> carcinoma (autoimmune pancreatitis, 71 HU; carcinoma, 59HU), but in the hepatic phase, the value was significantly higher than that <strong>of</strong> carcinoma(autoimmune pancreatitis, 90 HU; carcinoma, 64 HU). It was concluded that at dual-phaseCT, the enhancement patterns <strong>of</strong> the pancreas and pancreatic masses in patients withautoimmune pancreatitis are different from those <strong>of</strong> pancreatic carcinoma and normalpancreas [314].PET-CT for differential diagnosisOne study was conducted to evaluate the clinical usefulness <strong>of</strong> PET/CT in differentiatingautoimmune pancreatitis from pancreatic cancer. It was analyzed the cases <strong>of</strong> 17 patientswith autoimmune pancreatitis and atypical pancreatic imaging findings who underwentintegrated PET/CT. The PET/CT findings on the 17 patients with autoimmune pancreatitiswere compared with those <strong>of</strong> 151 patients with pancreatic cancer. Fluorine-18 FDG uptakeby the pancreas was found in all patients with autoimmune pancreatitis and in 82 percent(124/151) <strong>of</strong> patients with pancreatic cancer. Diffuse uptake by the pancreas wassignificantly more frequent in patients with autoimmune pancreatitis (53 % vs 3 %). FDGuptake by the salivary glands and kidneys was seen only in patients with autoimmunepancreatitis, the former reaching statistical significance. Follow-up PET/CT after steroidtherapy was performed for eight patients with autoimmune pancreatitis. After steroid therapy,none <strong>of</strong> the patients had intense FDG uptake by the pancreas or extrapancreatic organs. Itwas concluded that in difficult cases, at PET/CT the presence <strong>of</strong> diffuse uptake <strong>of</strong> FDG bythe pancreas or concomitant extrapancreatic uptake by the salivary glands can be used toaid in differentiation <strong>of</strong> autoimmune pancreatitis and pancreatic cancer [315].Positrone emission tomographyThe aim <strong>of</strong> one study was to analyze the usefulness <strong>of</strong> positron emission tomography with18 F-fluorodeoxyglucose (FDG-PET) in the evaluation <strong>of</strong> distribution and activity <strong>of</strong> systemiclesions <strong>of</strong> AIP during steroid therapy. Eleven cases <strong>of</strong> autoimmune pancreatitis had theirFDG-PET images evaluated before and 3 months after steroid therapy and another 2 casesonly before therapy. AIP activity was determined by the level <strong>of</strong> serum markers, IgG andIgG4, and compared with findings <strong>of</strong> PET. In all 13 cases <strong>of</strong> AIP, a moderate to intense level<strong>of</strong> FDG accumulation was recognized in the pancreatic lesion before steroid therapy. Of 13patients, 11 (85 %) showed FDG accumulation in the multiple organs, such as mediastinal

and other lymph nodes, salivary gland, biliary tract, prostate, and aortic wall. In 11 patientswho underwent PET before and after steroid therapy, FDG accumulation was diminished inalmost all systemic lesions, with a mean <strong>of</strong> maximum standardized uptake value (SUV max ) inthe pancreatic lesion from 5.1 to 2.7. Similar to the SUV level, serum IgG and IgG4 weredecreased in most <strong>of</strong> the cases after steroid therapy. It was concluded that FDG-PET is aneffective modality to evaluate the response <strong>of</strong> steroid therapy and the distribution and activity<strong>of</strong> various systemic lesions <strong>of</strong> autoimmune pancreatitis [316].MissdiagnosisAutoimmune pancreatitis (AIP) is a chronic inflammatory disease <strong>of</strong> the pancreas that isincreasingly encountered worldwide. It has generated considerable interest, in part becausethe inflammatory process usually responds dramatically to corticosteroid therapy. The mostcommon presentation mimics that <strong>of</strong> pancreatic cancer; thus, a correct diagnosis <strong>of</strong> AIP canavoid major surgery. However, the diagnosis is challenging, because its incidence is farlower than that <strong>of</strong> the diseases it mimics and there is no single diagnostic clinical feature ortest that can identify the full spectrum <strong>of</strong> AIP. Therefore, there has been increasinglyencountering patients misdiagnosed as having AIP. The misdiagnosis typically occurs inthree scenarios:- treatment <strong>of</strong> pancreatic or biliary malignancy with corticosteroids and/orimmunomodulators- treatment <strong>of</strong> chronic abdominal pain with corticosteroids and/or immunomodulators- performance <strong>of</strong> operative resection for autoimmune disease.This growing clinical problem must be reinforced by use <strong>of</strong> published guidelines for thediagnosis and management <strong>of</strong> autoimmune pancreatitis [317].Concomittant cancerAn asymptomatic 59-year-old man underwent pancreatoduodenectomy for a pancreaticmass that was discovered during a health check-up. Histopathology indicated typical features<strong>of</strong> CLPSP) or autoimmune pancreatitis along with the presence <strong>of</strong> abundant IgG4-positiveplasma cells throughout the mass. A small invasive ductal adenocarcinoma was observed inthe center <strong>of</strong> the area affected by LPSP [318].Case reportsIgG4-related sclerosing disease is a distinctive mass-forming lesion with frequent systemicinvolvement, most frequently the pancreas, salivary glands, and lacrimal glands. One reportdescribed a case manifesting with a previously unrecognized form <strong>of</strong> central nervous systeminvolvement. The 37-year-old man presented with signs and symptoms <strong>of</strong> spinal cordcompression at the thoracic level 9. Magnetic resonance imaging revealed an elongateddural mass extending from the fifth to tenth thoracic vertebra. Laminectomy and excision <strong>of</strong>the mass revealed dura expanded by a dense lymphoplasmacytic infiltrate accompanied bystromal fibrosis and phlebitis. IgG4+ plasma cells were increased and the proportion <strong>of</strong>IgG4+/IgG+ plasma cells was 85 percent. The patient also had a 1-year history <strong>of</strong> bilateralsubmandibular swelling due to chronic sialadenitis. Thus, IgG4-related sclerosingpachymeningitis represents a new member <strong>of</strong> the IgG4-related sclerosing disease familyaffecting the central nervous system. It seems that at least a proportion <strong>of</strong> cases described inthe <strong>literature</strong> as idiopathic hypertrophic pachymeningitis belong to this disease, especially as

some patients have other clinical manifestations compatible with IgG4-related sclerosingdisease, such as cholangitis and orbital pseudotumor [319].A 38-year old man presented himself for further clarification <strong>of</strong> a previously discoveredcircumscribed stenosis <strong>of</strong> the pancreatic duct. He had experienced several episodes <strong>of</strong>pancreatitis characterized by abdominal pain and increased lipase values. An endoscopicretrograde cholangiopancreatography demonstrated a "double duct" sign with correspondingstenosis <strong>of</strong> the bile and pancreatic ducts. No space-occupying mass was identified. Therewas no evidence <strong>of</strong> chronic pancreatitis. Post-inflammatory stenosis <strong>of</strong> the pancreatic ductwas suspected. As the patient requested definitive diagnosis Whipple's operation wasperformed. It confirmed that the changes were benign. Histologic examination revealedchanges <strong>of</strong> an autoimmune pancreatitis. It was concluded that circumscribed changes in thepancreatic duct, especially in young patients, should be clarified with all modern invasive andnoninvasive modes <strong>of</strong> investigation to exclude with certainty a malignancy and avoidunnecessary resection [320].It was reported a case <strong>of</strong> a man who simultaneously presented with autoimmune pancreatitisassociated with retroperitonal fibrosis, and a lesion <strong>of</strong> the extrapancreatic bile duct, with totalresponse to corticosteroid treatment for 4 months and absence <strong>of</strong> recurrence after 24 months<strong>of</strong> follow-up. Autoimmune pancreatitis is a kind <strong>of</strong> chronic pancreatitis that is probably a part<strong>of</strong> a systemic autoimmune disease, with retroperitoneal fibrosis and extrapancreatic bile ductlesion being the most commonly associated extrapancreatic lesions. A correct diagnosis andearly treatment <strong>of</strong> this disease may aid in the total resolution <strong>of</strong> lesions, especially in caseswith a low activity grade [321].

HEREDITARY PANCREATITISPatients with hereditary pancreatitis bear a high risk <strong>of</strong> pancreatic adenocarcinoma, but theirlife expectancy remains unknown. The objective <strong>of</strong> the study was to assess whether the highrisk <strong>of</strong> cancer decreases survival. Inclusion criteria were the presence <strong>of</strong> a PRSS1 mutationwith pancreatic symptoms or chronic pancreatitis in at least two first-degree relatives or threesecond-degree relatives without another cause. Survival rates were assessed according torisk factors. Excess mortality compared with the general French population was calculatedfor two periods (20-50 and 50-70 years), according to several risk factors. The cohortcomprised 189 patients. PRSS1 mutations were found in 66 percent. A total <strong>of</strong> 19 patientsdied at the median age <strong>of</strong> 60. In all, 10 deaths were attributable to hereditary pancreatitis,including 8 to pancreatic adenocarcinoma. Median overall survival for the whole cohort was74 years (95 % confidence interval 71 to 79). The presence <strong>of</strong> R122H mutation, gender,tobacco consumption in patients older than 18 years, and diabetes mellitus were notassociated with differences in survival. Only patients with pancreatic cancer had decreasedsurvival. Excess mortality risk compared with the general population was 0.02 percentbetween 20 and 50 years, and 0.61 percent between 50 and 70 years (a statistically nonsignificantdifference). Gender, R122H mutation, diabetes, and tobacco use were notassociated with excess mortality in these two periods. The authors concluded that despitetheir high risk <strong>of</strong> cancer, patients with hereditary pancreatitis do not have excess mortalityrisk compared with the general population, irrespective <strong>of</strong> gender, tobacco use, or diabetesmellitus [322].The N34S mutation in the serine protease inhibitor Kazal type I (SPINK1) gene has beenassociated with chronic pancreatitis. Clinical data about the phenotypic expression <strong>of</strong>alcoholic chronic pancreatitis with the N34S variant are limited. The prevalence <strong>of</strong> the N34Smutation in patients with chronic pancreatitis and healthy individuals from Eastern Europe isunknown. It was studied Romanian patients with chronic pancreatitis and investigated theclinical presentation in patients with N34S mutation. The SPINK1 N34S variant was analysedin 94 chronic pancreatitis patients and 96 healthy controls by an allele specific PCR methodand a restriction fragment length polymorphism method. A meta-analysis was conducted withprevious N34S association studies. The clinical course <strong>of</strong> alcoholic pancreatitis wasevaluated according to the severity criteria <strong>of</strong> the M-ANNHEIM classification system <strong>of</strong>chronic pancreatitis. A heterozygous N34S mutation was found in 1 <strong>of</strong> 96 healthy individuals(1 %) and in 4 <strong>of</strong> 80 patients (5 %) with alcoholic chronic pancreatitis. The meta-analysisconfirmed the status <strong>of</strong> N34S as a risk factor for the development <strong>of</strong> alcoholic chronicpancreatitis (odds ratio 5.3). However, the clinical course <strong>of</strong> the disease was similar inpatients with and without N34S mutation. It was thus concluded that N34S mutation is aweak risk factor for alcoholic chronic pancreatitis [323].PRSS1 and SPINK1 are 2 important genes in the defense mechanism guarding against thedevelopment <strong>of</strong> pancreatitis. One study aimed to evaluate the prevalence <strong>of</strong> PRSS1 andSPINK1 mutations and to explore the presence <strong>of</strong> any ethnic specificity in Korean patients. Atotal <strong>of</strong> 47 patients from 40 families including 37 patients with idiopathic pancreatitis and 10patients with familial pancreatitis were prospectively enrolled. Fifty healthy controls wereincluded for analysis <strong>of</strong> SPINK1 IVS3+2T site. PRSS1 mutations were observed in 6 patientsfrom 2 families and SPINK1 mutations in 13 patients from 11 families, respectively. In case <strong>of</strong>SPINK1 mutations, N34S and IVS3+2T>C were identified in 3 and 11 patients, respectively,including one with compound N34S/IVS3+2T>C heterozygote. The prevalence <strong>of</strong> SPINK1IVS3+2T>C mutations was 27 percent among 41 patients without PRSS1 mutations,whereas the prevalence among 50 healthy controls was 0 percent. Only PRSS1 R122H wasidentified. Late onset <strong>of</strong> symptoms at the age <strong>of</strong> 36 years and absence <strong>of</strong> symptoms at theage <strong>of</strong> 47 years were observed in 2 patients with PRSS1 mutations. It was concluded thatPRSS1 and SPINK1 mutations were not rare in Korean patients with idiopathic and familial

pancreatitis. SPINK1 IVS3+2T>C was a prevalent mutation in this population [324].Case reportA 72-year-old woman with Mikulicz disease with pathogically proven sclerosing sialadenitisshowed systemic abnormal F-18 FDG uptake in the bilateral lacrimal and submandibularglands, pancreas, abdominal aortic wall, and a retroperitoneal fibroid mass on PET/CT scan,with marked elevation <strong>of</strong> the serum IgG4 level. This case supports Mikulicz disease beingincluded as 1 <strong>of</strong> the disorders associated with a new clinical entity <strong>of</strong> systemic IgG4-relatedplasmacytic syndrome. A whole-body FDG-PET/CT scan can be expected as a useful toolfor detecting systemic involvement in systemic IgG4-related plasmacytic syndrome [325].

Classification <strong>of</strong> pancreatic tumorsPANCREATIC CANCERThe recent sequencing <strong>of</strong> the pancreatic cancer genome provides unprecedented insight intothe fundamental nature <strong>of</strong> this deadly malignancy. Although much work still needs to bedone, a molecular classification <strong>of</strong> neoplasms <strong>of</strong> the pancreas is emerging. Moleculargenetics have been used to identify unique clinical subtypes <strong>of</strong> pancreatic cancer, to guidethe clinical diagnosis <strong>of</strong> pancreatic tumors, and to identify targeted therapies for selectpancreatic neoplasms. A new classification does not ignore previous histology-basedclassification systems but instead embraces them, creating an integrated histologicalmolecularclassification [326].Demography and epidemiologyStatistics in theoryActuarial 5-year survival rates exceeding 20 percent are <strong>of</strong>ten reported for patientsundergoing pancreatoduodenectomy for ductal adenocarcinoma <strong>of</strong> the head <strong>of</strong> the pancreas.In contrast, when actual long-term patient survival rates following pancreatoduodenectomyfor ductal adenocarcinoma have been reported, they have been disappointingly lower thanthe optimistic survival results predicted by those studies using actuarial analysis. Thisdiscrepancy between actuarial estimation <strong>of</strong> patient survival and actual patient survivalfollowing pancreatoduodenectomy for pancreatic ductal adenocarcinoma has been explainedaway by some puckish observers as resulting from "the magic <strong>of</strong> Kaplan-Meier." A moreprecise explanation <strong>of</strong> the discrepancy lies in the fact that Kaplan-Meier calculations arestatistical estimates and become artificially inflated either if shorter-term survival patients arealso included in the analysis, or if patients are lost to follow-up. Accordingly, actual survivalrates represent the gold standard for measuring operative success, particularly in long-termstudies [327].Importance <strong>of</strong> raceAfrican Americans have a poorer survival from gastrointestinal cancers. It was hypothesizedthat socioeconomic status may explain much <strong>of</strong> this disparity. Four years <strong>of</strong> population-basedMedicare and Medicaid administrative claims files were merged with the Michigan TumorRegistry. Data were identified for 18,260 patients with colorectal (n=13,001), pancreatic(n=2,427), gastric (n=1,739), and esophageal (n=1,093) cancer. Three outcomes werestudied: the likelihood <strong>of</strong> late stage diagnosis, the likelihood <strong>of</strong> surgery after diagnosis, andsurvival. Bivariate analysis was used to compare stage and operation between African-American and Caucasian patients. In unadjusted analyses, relative to Caucasian patients,African-American patients with colorectal and esophageal cancer were more likely to presentwith metastatic disease, were significantly less likely to have surgery, and were less likely tosurvive during the study period. No racial differences in survival were observed amongpatients with esophagus, gastric, or pancreatic cancer. It was concluded that race has littleinfluence on survival <strong>of</strong> patients with pancreatic cancer [328].SwedenThe aim <strong>of</strong> one study was to characterise the familial association <strong>of</strong> pancreatic cancer withother malignancies. Relative risks (RRs) <strong>of</strong> pancreatic cancer according to family history <strong>of</strong>cancer were calculated using the updated Swedish Family-Cancer Database, which includes

over 11.5 million individuals. Estimates were based on Poisson regression. RRs <strong>of</strong> tumoursfor individuals with a parental history <strong>of</strong> pancreatic cancer were also estimated. The risk <strong>of</strong>pancreatic cancer was elevated in individuals with a parental history <strong>of</strong> cancers <strong>of</strong> the liver(RR 1.41; 95 % confidence interval 1.10 to 1.81), kidney (RR 1.37; 95 % confidence interval1.06 to 1.76), lung (RR 1.50; 95 % confidence interval 1.27 to 1.79) and larynx (RR 1.98; 95% confidence interval 1.19 to 3.28). Associations were also found between parental history <strong>of</strong>pancreatic cancer and cancers <strong>of</strong> the small intestine, colon, breast, lung, testis and cervix in<strong>of</strong>fspring. There was an increased risk <strong>of</strong> pancreatic cancer associated with early-onsetbreast cancer in siblings. Pancreatic cancer aggregates in families with several types <strong>of</strong>cancer. Smoking may contribute to the familial aggregation <strong>of</strong> pancreatic and lung tumours,and the familial clustering <strong>of</strong> pancreatic and breast cancer could be partially explained byinherited mutations in the BRCA2 gene [329].DanmarkIt was reported the incidence rates <strong>of</strong> pancreatic cancer in Denmark during 61 years <strong>of</strong> dataregistration, from 1943 to 2003 and it was calculated age-standardized, period-specificincidence rates <strong>of</strong> pancreatic cancer. A total <strong>of</strong> 32,654 incident cases <strong>of</strong> pancreatic cancerwere evaluated (male-female ratio, 1.4). The age-standardized incidence rate <strong>of</strong> pancreaticcancer increased steadily in the beginning <strong>of</strong> the study period from 3.75/100,000 personyearsin 1943 to 1947 to the maximum <strong>of</strong> 9.96/100,000 person-years in 1968 to 1972 amongmen and from 2.95 in 1943 to 1947 to the maximum <strong>of</strong> 7.04 in 1978 to 1982 among women.The incidence rates declined between 1968 to 1972 and 1988 to 1992 for men and between1978 to 1982 and 2003 for women. More than 40 percent <strong>of</strong> the tumors were located in thehead <strong>of</strong> the pancreas; 14 percent were localized, 21 percent were regionally spread, and 36percent were metastatic at the time <strong>of</strong> diagnosis. During the period 1978 to 2003, thepercentages <strong>of</strong> histologically or cytologically verified adenocarcinomas remained relativelysteady, approximately 30 percent [330].FranceIn 2006, a total number <strong>of</strong> 149,000 cancer deaths were observed in France, 88,500 in themale population and 60,500 in the female population. In 2005, the number <strong>of</strong> new diagnoses<strong>of</strong> cancer is estimated to be 319,000, 183,000 among men and 136,000 among women. Agestandardisedmortality rates are decreasing for most frequent cancer sites, at least in recentyears, the main exceptions being lung in the female population, and pancreas in both maleand female populations [331].KoreaUsing the population-based cancer registry in Jejudo, it was found that Jejudo had lowerincidence in stomach cancer than other regions in Korea. The aim <strong>of</strong> one study was toevaluate reasons for this difference. Citrus is the leading agricultural production in Jejudo,suggesting that lower cancer incidence in Jejudo could be explained by citrus fruit intake. Itwas evaluated this hypothesis with quantitative systematic <strong>review</strong> (QSR). Stomach cancerincidence was significantly lower, with a summary odds ratio (SOR) after QSR <strong>of</strong> 0.72. Inaddition, the SOR <strong>of</strong> pancreatic cancer tended to be lower at 0.83 (95 % confidence interval0.70 to 0.98). It was suggested that lower cancer incidence in Jejudo could be explained byintake <strong>of</strong> citrus fruits [332].Arctic pancreatic cancerLittle information is available on the incidence and mortality <strong>of</strong> cancer among the Aboriginalpopulation in the Province <strong>of</strong> Québec, Canada. Cancer was likely rare in this population

historically, but recent life-style changes suggest that this may no longer be the case. Thepurpose <strong>of</strong> this study was to estimate incidence and mortality rates among Aboriginal peopleliving on reserves and in northern villages in Québec during the period 1988-2004, and tocompare these estimates with those <strong>of</strong> the general population. Aboriginal people wereidentified based on geographic residence codes. Population data were taken from theCanadian census <strong>of</strong> 1991, 1996 and 2001. Incidence and mortality rates were calculated andage-standardized according to the World Standard Population. The Aboriginal incidence andmortality rates for cancer, all sites combined, was 322 per 100,000 (95 % confidence interval305 to 339) and 160 per 100,000 (95 % CI 148-173), respectively. These rates are notsignificantly different from those <strong>of</strong> the general population <strong>of</strong> Québec. However, there aredifferences according to cancer site and sex. Aboriginal men had a higher risk for liver, lungand kidney cancers and a lower risk for prostate, bladder, leukemia and non-Hodgkin'slymphoma cancers, whereas Aboriginal women had a higher risk for colorectal, lung, cervixand kidney cancers, and a lower risk for breast, uterus, bladder, brain, leukemia, stomachand pancreas cancers [333].Nenetskij Avtonomnyj Okrug (NAO), a part <strong>of</strong> Arkhangelskaja Oblast in north-west Russia,has a population <strong>of</strong> 42,000 inhabitants. The central oncological hospital <strong>of</strong> the oblastregisters all new cases <strong>of</strong> cancer. All new cases recorded in the study period among <strong>of</strong>ficialresidents <strong>of</strong> NAO were included in the study, except for secondary malignant neoplasm,cases revealed by autopsy and cancers diagnosed within 6 months <strong>of</strong> a previous cancerdiagnosis. The census and annual sex and age-group-specific population figures for NAOwere obtained from the regional statistics <strong>of</strong>fice. Crude and age-adjusted incidence rates (tothe world standard population) were estimated. The average crude cancer incidence per yearwas 204/100,000 among men and 194/100,000 among women. Adjusted for age, theincidence was 322/100,000 and 182/100,000, respectively. The most frequent primary site <strong>of</strong>cancer was trachea, bronchus and lung, which constituted 17 percent <strong>of</strong> all cases (<strong>of</strong> which87 % were among men), followed by stomach cancer (13 %). Breast cancer constituted 18percent <strong>of</strong> all cases among women. The results are consistent with reports <strong>of</strong> a low cancerrisk among women compared with men in Russia and compared with women in Westerncountries and with results that point out that public health measures are needed to curb thelung cancer epidemic among men in Russia. The high risks <strong>of</strong> pancreas, kidney andoesophagus cancers among men should be investigated further [334].Pancreatic compared to peripancreatic cancersCarcinomas co-occur in the pancreas, extrahepatic bile ducts, and ampulla <strong>of</strong> Vater. It wasinvestigated whether cancers originating in these sites represent a field effect similar to thatobserved in the lung and upper aerodigestive tract. To determine whether a field effect forcarcinogenesis exists in the ampulla <strong>of</strong> Vater, extrahepatic bile ducts, gallbladder, andpancreas data were obtained from National Cancer Institute's Surveillance Epidemiology andEnd Results Program from 1973 through 2005. Cases were compared by age frequencydensity plots, age-specific incidence rates, and logarithmic plots <strong>of</strong> the age-specific incidencerates and age <strong>of</strong> diagnosis. Incidence rates were 11.71, 1.43, 0.88, and 0.49 per 100,000persons at risk for pancreatic, gallbladder, extrahepatic bile ducts, and ampullarycarcinomas, respectively. Age frequency density plots were congruent for cancers originatingin all 4 sites. Logarithmic plots <strong>of</strong> the age-specific incidence rates with age <strong>of</strong> diagnosisproduced parallel linear rate patterns for the 4 sites indicative <strong>of</strong> similar populations for tumordevelopment. However, density and logarithmic plots <strong>of</strong> pancreatic endocrine carcinomas, atumor <strong>of</strong> different cellular differentiation and carcinogenic pathway, served as a comparison.The endocrine carcinomas showed a different age distribution and nonparallel rate patternswith ductal carcinomas. It was concluded that carcinomas <strong>of</strong> the pancreas, gallbladder,extrahepatic bile ducts, and ampulla have a common embryonic cellular ancestry,differentiation pathways, mucosal histologic patterns, and population-related tumor

development indicating a field effect in carcinogenesis. Parallel linear rate patterns indicatethat the rate <strong>of</strong> cancer development is similar in all four sites even though the absoluteincidence rates vary and, regardless <strong>of</strong> location, the ductal epithelium is equally susceptibleto malignant transformation. If carcinogenic pathways to cancer are similar, then the differentincidence rates seen clinically may depend on the relative surface area <strong>of</strong> the ductal systemin these sites. Pancreatic cancers are most common because the surface area <strong>of</strong> thepancreas' ductal system is greater than that <strong>of</strong> the gallbladder, extrahepatic bile ducts, andampulla [335].Death at homeThe purpose <strong>of</strong> one study was to confirm the recent trends in home deaths among cancerdeaths in Osaka Prefecture. The number <strong>of</strong> home deaths (the proportion <strong>of</strong> home deathsamong cancer deaths) has continuously increased from 875 (4.6 %) in 1995 to 1,544 (6.6 %)in 2006. The proportions increased gradually in most second-level medical-care areas. Since2004, the proportion in the Toyono medical-care area has increased rapidly and reached10.6 percent in 2006. The proportions <strong>of</strong> cancers <strong>of</strong> the lung, colorectum, stomach, pancreasand breast gradually increased from around 5 percent in 1995 to around 7 percent in 2006[336].Etiological factorsAlthough mounting evidence suggests that insulin resistance is involved in pancreaticcarcinogenesis, few epidemiologic studies have comprehensively investigated the role <strong>of</strong>lifestyle factors influencing this metabolic disorder in the etiology <strong>of</strong> pancreatic cancer. It wasnow sought to examine this problem in a case-control study conducted in 1994-1998 inMinnesota. Cases (n=186), aged 20 years or older, were ascertained from all hospitals in themetropolitan area <strong>of</strong> the Twin Cities and the Mayo Clinic; from the latter, only cases residingin the Upper Midwest <strong>of</strong> the United States were recruited. Controls (n=554) were randomlyselected from the general population and frequency matched to cases by age (within 5years) and sex. Odds ratios (OR) and 95 % confidence intervals were estimated usingunconditional logistic regression. After adjustment for confounders, physical activity wasassociated with a reduced risk, but this protective effect was confined to light activity andmoderate activity only (OR 0.55, 95 % confidence interval 0.30 to 0.97; and OR 0.51, 95 %confidence interval 0.28 to 0.93, for highest vs. lowest quartile, respectively). An increasedrisk was found for dietary intakes <strong>of</strong> energy and fat but was statistically significant forsaturated and polyunsaturated fat only. Of note, no appreciable difference in the magnitude<strong>of</strong> the associations existed between saturated, monounsaturated, and polyunsaturated fat.Compared with individuals in the lowest quartile <strong>of</strong> fiber intake, the risk was approximatelyhalved for those in the third (OR 0.49, 95 % confidence interval 0.26 to 0.94) and the highestquartile (OR 0.52, 95 % confidence interval 0.21 to 1.30). The study lends support to thehypothesis that dietary and other lifestyle factors influencing insulin resistance modulatepancreatic cancer risk [337].Read meat and risk <strong>of</strong> cancerHigh intake <strong>of</strong> meat, particularly red and processed meat, has been associated with anincreased risk <strong>of</strong> a number <strong>of</strong> common cancers such as breast, colorectum, and prostate inmany epidemiological studies. Heterocyclic amines (HCAs) are a group <strong>of</strong> mutageniccompounds found in cooked meats, particularly well-done meats. HCAs are some <strong>of</strong> mostpotent mutagens detected using the Ames/salmonella tests and have been clearly shown toinduce tumors in experimental animal models. Over the past 10 years, an increasing number<strong>of</strong> epidemiological studies have evaluated the association <strong>of</strong> well-done meat intake and meat

carcinogen exposure with cancer risk. The results from these epidemiologic studies wereevaluated and summarized in this <strong>review</strong>. The majority <strong>of</strong> these studies have shown that highintake <strong>of</strong> well-done meat and high exposure to meat carcinogens, particularly HCAs, mayincrease the risk <strong>of</strong> human cancer [338].SmokingCigarette smoking doubles the risk <strong>of</strong> pancreatic cancer, and smoking accounts for 20 to 25percent <strong>of</strong> pancreatic cancers. The recent sequencing <strong>of</strong> the pancreatic cancer genomeprovides an unprecedented opportunity to identify mutational patterns associated withsmoking. It was previously sequenced >750 million bp DNA from 23,219 transcripts in 24adenocarcinomas <strong>of</strong> the pancreas (discovery screen). In this previous study, the 39 genesthat were mutated more than once in the discovery screen were sequenced in an additional90 adenocarcinomas <strong>of</strong> the pancreas (validation screen). Now, it was compared the somaticmutations in the cancers obtained from individuals who ever smoked cigarettes (n=64) to thesomatic mutations in the cancers obtained from individuals who never smoked cigarettes(n=50). When adjusted for age and gender, analyses <strong>of</strong> the discovery screen revealedsignificantly more nonsynonymous mutations in the carcinomas obtained from ever smokers(mean, 53 mutations per tumor) than in the carcinomas obtained from never smokers (mean,38.5). The difference between smokers and nonsmokers was not driven by mutations inknown driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), butinstead was predominantly observed in genes mutated at lower frequency. No differenceswere observed in mutations in carcinomas from the head versus tail <strong>of</strong> the gland. Pancreaticcarcinomas from cigarette smokers harbor more mutations than do carcinomas from neversmokers [339].A meta-analysis <strong>of</strong> observational studies on association between cigarette smoking andpancreatic cancer was performed to focus, particularly, on the role <strong>of</strong> the studies' quality inaffecting meta-analysis results. A bibliographic search was carried out on PubMed andEMBASE databases until February 15, 2008. Key words were "pancreatic neoplasms,""pancreatic cancer," "smoking," "smoke," "cigarette," "case-control studies," and "cohortstudies." Studies about cigarette smoking and pancreatic cancer were selected andassessed on quality. Six cohort studies and 24 case-control studies were selected, withmedian quality scores <strong>of</strong> 8 (range, 3) and 10 (range, 8), respectively. Pooled case-controlstudies' odds ratio (OR) and cohort studies' risk ratio were, respectively, 1.45 (95 %confidence interval 1.33 to 1.57) and 1.78 (95% CI, 1.64-1.92). After stratifying for qualityscoring, high-quality-scored case-control studies yielded an odds ratio <strong>of</strong> 1.38 (95 %confidence interval 1.27 to 1.49), whereas the others gave an odds ratio <strong>of</strong> 1.52 (95 %confidence interval 1.34 to 1.73). The results <strong>of</strong> meta-analysis for cohort studies showed arisk ratio <strong>of</strong> 1.74 (95 % confidence interval 1.61 to 1.90) and <strong>of</strong> 2.10 (95 % confidenceinterval 1.64 to 2.67), respectively, for high- and low-quality score studies. It was thusconcluded that here is evidence that cigarette smoking is an important risk factor forpancreatic cancer, but the estimate <strong>of</strong> the association greatly relies on the studies' quality[340].To evaluate the effects <strong>of</strong> nicotine and cigarette smoke exposure on mice submitted to 7,12-dimethylbenzanthracene (DMBA) model <strong>of</strong> pancreatic carcinogenesis. One hundred fourteenmale mice were divided into the DMBA-n and DMBA-s groups: the DMBA-n group was given2 mg/kg per dose <strong>of</strong> nicotine subcutaneously for 45 days, and the DMBA-s group wasexposed to 100 mg/m 3 <strong>of</strong> cigarette smoke. At day 16, 1 mg <strong>of</strong> DMBA crystals was implantedin the pancreatic head <strong>of</strong> both groups. Euthanasia was performed in all mice 30 days afterthe surgery. The specimens were evaluated according to the following criteria: normal ducts,reactive hyperplasia, pancreatic intraepithelial neoplasm 3 (PanIN-3), and carcinoma. Thefrequency <strong>of</strong> PanIN in the 3 groups was almost the same when considering the higher-grade

lesions: controls (67 %), DMBA-s (67 %), and DMBA-n (44 %). Pancreatic adenocarcinomahas a higher frequency in the DMBA-n group (52 %) than in the controls (17 %) and DMBA-s(13 %) groups. The DMBA-s group has the highest score <strong>of</strong> PanIN-3 (40 %). The differencesamong the groups were statistically significant. It was concluded that nicotine but notcigarette smoke promotes pancreatic DMBA carcinogenesis in mice. Pancreaticadenocarcinomas and PanINs have the same phenotypic appearance as those that occur inhumans [341].Alcohol and smokingThe association between alcohol consumption and pancreatic cancer is not clear. One studyinvestigates different prediagnostic measurements <strong>of</strong> alcohol consumption, a laboratorymarker (gamma-glutamyltransferase), and a score measuring alcohol addiction (Mm-MAST),in relation to the risk <strong>of</strong> pancreatic cancer. Furthermore, the study investigated whethersmoking and alcohol consumption interact with each other, or if the risk <strong>of</strong> pancreatic cancerassociated with these factors is modified by obesity or weight gain. A cohort <strong>of</strong> 33,346subjects provided prediagnostic information on the above factors. During a mean follow-up <strong>of</strong>22 years, 183 cases <strong>of</strong> pancreatic cancer occurred. The highest gamma-GT quartile wasassociated with a high risk <strong>of</strong> pancreatic cancer (RR = 2.15, 95% CI = 1.34-3.44), and thisassociation was even stronger in subjects that reported a previous weight gain (RR = 3.61,95% CI = 1.29-10.09). A high Mm-MAST score was also associated with pancreatic cancer(p = 0.02). Current smoking was associated with pancreatic cancer (RR = 2.34, 95% CI =1.60-3.43), and obese smokers had an even higher risk (RR = 7.45, 95% CI = 1.65-33.64).Conclusion: High alcohol intake is associated with subsequent risk <strong>of</strong> pancreatic cancer andthis risk may be higher following weight gain. The risk associated with smoking may be evenhigher in obese subjects [342].Life-style factorsSmoking, alcohol use, diet, body mass index, and physical activity have been studiedindependently in relation to pancreatic cancer. It was generated a healthy lifestyle score toinvestigate their joint effect on risk <strong>of</strong> pancreatic cancer. In the prospective National Institutes<strong>of</strong> Health-AARP Diet and Health Study, a total <strong>of</strong> 450 416 participants aged 50 to 71 yearscompleted the baseline food frequency questionnaire (1995-1996) eliciting diet and lifestyleinformation and were followed up through December 31, 2003. It was identified 1057 eligibleincident pancreatic cancer cases. Participants were scored on 5 modifiable lifestyle factorsas unhealthy (0 points) or healthy (1 point) on the basis <strong>of</strong> current epidemiologic evidence.Participants received 1 point for each respective lifestyle factor: nonsmoking, limited alcoholuse, adherence to the Mediterranean dietary pattern, body mass index (>18 and

the risk <strong>of</strong> pancreatic cancer. It was followed the participants in the NIH-AARP Diet andHealth Study from 1995/1996 through 2003. A baseline self-administered food frequencyquestionnaire was used to assess the dietary intake and exposure information. A total <strong>of</strong>1,151 exocrine pancreatic cancer cases were identified from 482,362 participants afterexcluding first-year <strong>of</strong> follow-up. There were no associations between glycemic index, total oravailable carbohydrates, gycemic load, and pancreatic cancer risk. Participants with high freefructose and glucose intake were at a greater risk <strong>of</strong> developing pancreatic cancer. Therewere no statistically significant interactions by body mass index, physical activity, or smokingstatus. The results do not support an association between glycemic index, total or availablecarbohydrate intake, and glycemic load and pancreatic cancer risk. The higher riskassociated with high free fructose intake needs further confirmation and elucidation [344].FructoseUsing fructose dehydrogenase-catalyzed conversion <strong>of</strong> d-fructose to 5-ket<strong>of</strong>ructose, followedby quantitation <strong>of</strong> MTT [3-(4,5-dimethylthiaze-syl)-2,5-diphenyltetrazolium bromide] formazanproduction by direct spectrophotometry, an assay to measure serum fructose concentrationwas developed, and assay sensitivity and specificity were tested. Validity <strong>of</strong> the assay wasconfirmed by gas chromatography-mass spectroscopy, and the assay was tested in healthysubjects and pancreatic cancer patients. The assay was highly specific, exhibiting no crossreactivitywith other sugars. Mean serum fructose concentration in fasting healthy volunteerswas 1.9 + 0.4 mM and after ingestion <strong>of</strong> a fructose and glucose-containing drink rose to 16.3+ 1.2 mM at 15 minutes and peaked at 30 minutes when serum fructose was 17.2 + 1.1 mM.Mean fasting serum fructose level was significantly higher at 5.7 + 2.5 mM in patients withpancreatic cancer than those with no pancreatic cancer. The fructose dehydrogenase-basedenzymatic assay correlated highly with gas chromatography-mass spectroscopic analysis <strong>of</strong>serum fructose with a correlation coefficient <strong>of</strong> 0.94. It was concluded that measurement <strong>of</strong>serum fructose concentration may provide insight into the relationship between refinedfructose intake and diseases including pancreatic cancer [345].Citrus fruitsThe purpose <strong>of</strong> one systematic <strong>review</strong> was to investigate the association between dietaryintake <strong>of</strong> citrus fruits and pancreatic cancer risk. The authors searched electronic databasesand the reference lists <strong>of</strong> publications <strong>of</strong> studies addressing diet and pancreatic cancer up toDecember 2007. All <strong>of</strong> the epidemiological studies that obtained individual data on dietaryintake <strong>of</strong> citrus fruits and presented risk estimates <strong>of</strong> the association between intake <strong>of</strong> citrusfruits and risk <strong>of</strong> pancreatic cancer were identified and included. Using general variancebasedmethods, study-specific odds ratios (ORs)/relative risk and associated confidenceinterval (CI)/SE for highest versus lowest intake <strong>of</strong> citrus fruits level were extracted from eacharticle. Nine articles including 4 case-control studies and 5 cohort studies proved eligible.Overall summary OR using random effect model suggested an inverse association in risk <strong>of</strong>pancreatic caner with intake <strong>of</strong> citrus fruits (summary odds ratio, 0.83) with largeheterogeneity across studies. It was concluded that pooled results from observational studiesshowed an inverse association between intake <strong>of</strong> citrus fruits and the risk <strong>of</strong> pancreaticcancer, although results vary substantially across studies, and the apparent effect isrestricted to the weaker study design (case-control studies) [346].PollutionTo describe the mortality pr<strong>of</strong>ile <strong>of</strong> the population resident in the polluted area <strong>of</strong> nationalconcern "Laguna di Grado e Marano" Friuli-Venezia-Giulia region, in the period 1997-2001and to examine mortality temporal trends between 1981 and 2001 a small-areaepidemiological study based on descriptive statistics, socioeconomic deprivation variables,

analysis <strong>of</strong> spatial heterogeneity disease mapping and time trend analysis was carried out.Compared to regional averages, standardised mortality ratios in the region were significantlyhigher for lung and stomach cancer in men and for ovarian cancer in women. Standardisedmortality ratios were instead significantly lower for all causes <strong>of</strong> death (8.7 %), respiratoryand cardiovascular diseases, liver (51%) and pancreas (47 %) cancer in men and forcardiovascular diseases in women. These results did not change after adjustment bysocioeconomic status [347].RadonIt was correlated radon exposure with the incidence <strong>of</strong> pancreatic cancer and to ascertain theinfluence <strong>of</strong> race in this correlation. Age-standardized incidence rates (SIRs) <strong>of</strong> pancreaticcancer from 1992 to 2002, segregated by race, were obtained from the Surveillance,Epidemiology, and End Results database. The mean radon levels for each county wereobtained from the Environmental Protection Agency map, which assigns each county to 1 <strong>of</strong>3 categories based on radon potential. The SIRs <strong>of</strong> pancreatic cancer in the United Statesranged from 1.4 to 21.8/100,000 person-years. The highest rates for whites (19.6/100,000person-years) and American Indians (594/100,000 person-years) were found in GuadalupeCounty, New Mexico; for African Americans (4845/100,000 person-years) in Worth County,Iowa; and for Asian Americans (3177/100,000 person-years) in Monroe County, Iowa. Therewas an insignificant correlation between radon exposure and overall incidence <strong>of</strong> pancreaticcancer. A significant correlation existed between radon exposure and incidence <strong>of</strong> pancreaticcancer in African Americans, American Indians, and Asian Americans, but not in whites. Theauthors concluded that radon exposure may be a significant risk factor for pancreatic cancerin African Americans, American Indians, and Asian Americans [348].Vitamine DExperimental evidence suggests that vitamin D has anticarcinogenic properties; however, anested case-control study conducted in a population <strong>of</strong> male Finnish smokers found thathigher 25-hydroxyvitamin D [25(OH)D], the best indicator <strong>of</strong> vitamin D status as determinedby the sun and diet, was associated with a significant 3-fold increased risk for pancreaticcancer. It was conducted a nested case-control study in the Prostate, Lung, Colorectal, andOvarian Screening Trial cohort <strong>of</strong> men and women 55 to 74 years <strong>of</strong> age at baseline to testwhether prediagnostic serum 25(OH)D concentrations were associated with pancreaticcancer risk. Between 1994 and 2006, 184 incident cases <strong>of</strong> pancreatic adenocarcinomaoccurred (follow-up to 12 years). Two controls (n=368) who were alive at the time the casewas diagnosed were selected for each case and matched by age, race, sex, and calendardate <strong>of</strong> blood draw (to control for seasonal variation). It was calculated odds ratios and 95percent confidence intervals using conditional logistic regression, adjusting for smoking andbody mass index. Vitamin D concentrations were not associated with pancreatic canceroverall (highest versus lowest quintile, >82 vs

conducted a cohort analysis <strong>of</strong> prediagnostic vitamin E intake (4 tocopherols, 4 tocotrienols),serum alpha-tocopherol concentrations, and pancreatic cancer in the Alpha-Tocopherol,Beta-Carotene Cancer Prevention (ATBC) Study <strong>of</strong> male Finnish smokers aged 50-69 yearsat baseline. During follow-up from 1985 to 2004 (maximum: 19 years; median: 16 yeras), 318incident cases were diagnosed among cohort participants with complete serum samples(n=29,092); 306 cases had complete dietary data (n=27,111). Higher alpha-tocopherolconcentrations were associated with signifikant lower pancreatic cancer risk.Polyunsaturated fat, a putative prooxidant nutrient, modified the association such that theinverse alpha-tocopherol association was most pronounced in subjects with a highpolyunsaturated fat intake. No associations were observed for dietary tocopherols andtocotrienols. The results support the hypothesis that higher alpha-tocopherol concentrationsmay play a protective role in pancreatic carcinogenesis in male smokers [350].Nitrate in drinking waterA matched case-control and nitrate ecology study was used to investigate the associationbetween mortality attributed to pancreatic cancer and nitrate exposure from Taiwan's drinkingwater. All pancreatic cancer deaths <strong>of</strong> Taiwan residents from 2000 through 2006 wereobtained from the Bureau <strong>of</strong> Vital Statistics <strong>of</strong> the Taiwan Provincial Department <strong>of</strong> Health.Controls were deaths from other causes and were pair-matched to the cases by gender, year<strong>of</strong> birth, and year <strong>of</strong> death. Each matched control was selected randomly from the set <strong>of</strong>possible controls for each case. Data on nitrate-nitrogen (NO 3 -N) levels <strong>of</strong> drinking waterthroughout Taiwan were collected from Taiwan Water Supply Corporation. The municipality<strong>of</strong> residence for cancer cases and controls was assumed to be the source <strong>of</strong> the subject'snitrate exposure via drinking water. The adjusted odds ratios and confidence limits forpancreatic cancer death for those with high nitrate levels in their drinking water, as comparedto the lowest tertile, were 1.03 (0.9-1.18) and 1.1 (0.96-1.27), respectively. The results <strong>of</strong> thepresent study show that there was no statistically significant association between the levels<strong>of</strong> nitrate in drinking water and increased risk <strong>of</strong> death from pancreatic cancer [351].PerfluorooctanoatePerfluorooctanoate and perfluorooctanesulfonate are used in many industrial products andhave been widely detected in human blood. Both chemicals are associated with tumordevelopment in animal studies, but data on carcinogenic potential in humans are sparse. Itwas investigated the association between plasma levels <strong>of</strong> perfluorooctanoate andperfluorooctanesulfonate and cancer risk within a prospective Danish cohort <strong>of</strong> participantswith no previous cancer diagnosis at enrollment. From enrollment, between 1993 and 1997,and through, 2006, it was identified 713 participants with prostate cancer, 332 with bladdercancer, 128 with pancreatic cancer, and 67 with liver cancer in the entire cohort and it wasselected a comparison subcohort <strong>of</strong> 772. Plasma concentrations <strong>of</strong> perfluorooctanoate andperfluorooctanesulfonate were measured in each participant by use <strong>of</strong> high-pressure liquidchromatography coupled to tandem mass spectrometry. It was found no clear differences inincidence rate ratios for these cancers in relation to plasma concentrations <strong>of</strong>perfluorooctanoate or perfluorooctanesulfonate. A 30-40 percent increase in risk estimatesfor prostate cancer was observed for the three upper quartiles <strong>of</strong> perfluorooctanesulfonateconcentration compared with the lowest quartile. Plasma concentrations <strong>of</strong>perfluorooctanoate and perfluorooctanesulfonate in the general Danish population appearnot to be associated with risk <strong>of</strong> prostate, bladder, pancreatic, or liver cancer [352].PsoriasisIt was examined overall and specific cancer risks among Swedish subjects who had beenhospitalised one or more times for psoriasis. A database was created by identifying such

patients from the Swedish Hospital Discharge Register and linking them with the NationalCancer Registry. Follow-up <strong>of</strong> patients was carried out from the last hospitalisation through2004. A total <strong>of</strong> 15 858 patients were hospitalised for psoriasis during 1965-2004, <strong>of</strong> whom1408 developed cancer, giving an overall standardised incidence ratios (SIRs) <strong>of</strong> 1.33. Asignificant excess was noted for squamous cell skin cancer, and for cancers <strong>of</strong> the upperaerodigestive tract, oesophagus, stomach, liver, pancreas, lung, kidney and bladder as wellas non-Hodgkin lymphoma. Many <strong>of</strong> these may reflect the effects <strong>of</strong> alcohol drinking andtobacco smoking [353].Genetic aspectsPancreatic cancer, like many other complex diseases, has genetic and environmentalcomponents to its etiology. It is likely that relatively common genetic variants with modesteffects on pancreatic cancer risk play an important role in both familial and sporadic forms <strong>of</strong>the disease, either individually or in interaction with environmental factors. The relatively highfrequency <strong>of</strong> such variants means that they could potentially explain a substantial portion <strong>of</strong>disease risk. In general, very few low-penetrance variants have been identified and thosethat have require replication in independent studies. Possible gene-environment interactionsarising from these studies also require replication. More comprehensive approaches areneeded to make progress, including global analyses <strong>of</strong> biologically sound pathways andgenome-wide association studies. Large sample sizes are required to do this appropriatelyand multi-study consortia make this possible. A number <strong>of</strong> consortia <strong>of</strong> pre-existing studieshave already been formed, and these will facilitate the identification <strong>of</strong> further low-penetrancevariants and gene-environment interaction. However, these approaches do not substitute forthe design <strong>of</strong> novel, sufficiently powered studies that apply uniform criteria to case selection,the acquisition <strong>of</strong> environmental exposure information, and to biological sample collection[354].Hereditary pancreatic cancer comprises about 10 percent <strong>of</strong> pancreatic cancer cases.Multiple causative mutations have been identified. It was described a pancreatitis/pancreaticcancer family, which demonstrates pancreatitis and pancreatic cancer resulting from anuncharacterized mutation. Family members completed evaluations to determine signs <strong>of</strong>mutation status. Select patients were screened for mutations associated with hereditarypancreatic diseases. In generation II, 12 siblings exhibit 6 cases <strong>of</strong> pancreatitis, 3 pancreaticcancer, and 2 obligate carrier status. The average age at pancreatitis diagnosis <strong>of</strong> enrolledmembers is 33 years; average age at pancreatic cancer diagnosis is 59 years. There is noassociation with known cancer syndromes. Those affected generally present with mildepigastric pain, and CT scans demonstrate characteristic fatty infiltration <strong>of</strong> the pancreaticbody and tail with sparing <strong>of</strong> the head and neck. Full sequence analysis <strong>of</strong> genes associatedwith hereditary pancreatic disease failed to demonstrate known mutations or polymorphisms.Based upon pedigree evaluation and preliminary DNA analysis, it was believed that thefamily members with pancreatitis/pancreatic cancer carry a novel genetic mutation resultingin hereditary pancreatitis. This mutation is autosomal dominant, expressed with highpenetrance, and is part <strong>of</strong> a unique hereditary syndrome that significantly increasespancreatic cancer risk [355].ScreeningSeveral masses and premalignant lesions have been detected, but the detection <strong>of</strong> the firstpancreatic cancer through an organised study <strong>of</strong> screening has yet to be published. Therehas been progress in risk stratification. A mutation in the palladin gene was found tosegregate with the disease in a family with a clear predisposition for pancreatic cancer,though this has yet to be found in other such kindreds. This means that significant challenges

emain to be solved in screening for early pancreatic cancer. Risk stratification needs to beimproved and high-risk patients included in research-based screening programmes. It will beimpossible to confirm that screening can detect cancers early enough for curative treatmentuntil the results <strong>of</strong> these prospective studies become available. Registries <strong>of</strong> high-riskpatients may include hereditary pancreatitis kindreds, families from various general cancersyndromes and those with a specific predisposition for pancreatic cancer. Unfortunately,such registries may well also include families that have multiple cases <strong>of</strong> pancreatic cancerdue to chance, unaffected members <strong>of</strong> the latter group having no elevated risk. TheEuropean Registry <strong>of</strong> Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC)recruits patients with at least two cases <strong>of</strong> pancreatic cancer or pancreatitis in first- orsecond-degree relatives. A family tree <strong>of</strong> at least three generations is produced. To avoid asmany random clusters as possible, only families which are consistent with autosomaldominant inheritance <strong>of</strong> either pancreatic cancer or pancreatitis are included as havingfamilial pancreatic cancer (FPC) or hereditary pancreatitis (HP). When the participantsconsent, EUROPAC also tests for mutations in PRSS1 for HP families and BRCA2 for FPCfamilies. If cases <strong>of</strong> melanoma are reported, the CDKN2A gene (coding for p16) is alsotested. Relatives <strong>of</strong> pancreatic cancer patients have an elevated risk <strong>of</strong> pancreatic cancerthemselves. In a study <strong>of</strong> 570 families where the proband had pancreatic cancer, 7 hadmultiple first- or second-degree relatives who had had the disease. This suggests that over 1percent <strong>of</strong> pancreatic cancer cases occur in high-risk families. Consensus recommendationsfor secondary screening <strong>of</strong> high-risk groups were proposed at the Fourth InternationalSymposium on Inherited Diseases <strong>of</strong> the Pancreas. It was concluded that secondaryscreening should only be carried out on a research basis and only in patients with HP,individuals from Peutz-Jeghers (PJS) kindreds or families with a history <strong>of</strong> pancreatic cancer.In the latter case the family history should include at least two first-degree relatives (or 3more distant relatives), unless the participant requesting screening has a mutation in either <strong>of</strong>the BRCA genes or CDKN2A (p16). The causative genetic mutation remains unknown in themajority <strong>of</strong> families, although BRCA2 has been detected in 19 percent <strong>of</strong> EUROPAC/FaPaCafamilial pancreatic cancer kindreds. Hereditary pancreatitis is consistent with autosomaldominance and in contrast to FPC, most but not all <strong>of</strong> the responsible mutations have beenidentified in PRSS1 . Cancer risk to 75 years has been variously calculated as 35 to 54percent. The risk <strong>of</strong> a pancreatic cancer in those affected by HP in the EUROPAC populationis 4-5 times less than in FPC families. The risks <strong>of</strong> surgery are ameliorated as any resectionwould be <strong>of</strong> diseased pancreatic tissue, with affected individuals likely to already haveendocrine and exocrine pancreatic failure. PJS is characterised by autosomal dominantinheritance <strong>of</strong> hamartomatous polyposis. It is described as conferring a 132-fold increasedrisk <strong>of</strong> pancreatic cancer. In many cases those affected by this syndrome have mutations inthe STK11 gene, but it is worth noting that mutations in this gene do not appear in FPCkindreds. Familial atypical multiple mole melanoma (FAMMM) is characterised by multipleatypical (dysplastic) naevi and malignant melanoma. An association between FAMMM andpancreatic cancer is well established, but seems to be limited to a subset <strong>of</strong> families whichhave been defined on this basis as suffering from FAMMMpancreatic carcinoma syndrome.Mutations in the tumour suppressor CDKN2A are associated with FAMMM and have beendescribed in families with multiple cases <strong>of</strong> pancreatic cancer but only in families which alsohave a high incidence <strong>of</strong> melanoma. Breast ovarian cancer syndrome is <strong>of</strong>ten associatedwith mutations in BRCA2 or BRCA1 genes and BRCA2 is associated with some FPCfamilies. BRCA1 has not been linked to FPC and only confers a slight increase in pancreaticcancer risk (between 1.3- and 4.1-fold increase). However, it cannot be excluded that, in amanner similar to BRCA2, it may confer a much greater risk in the rare families that alreadyinclude a case <strong>of</strong> pancreatic cancer. If 100,000 individuals were screened with a modalitythat had 98 percent specificity there would be 2,000 false positives and only 10 possible livessaved by early detection (even assuming 100 % sensitivity). The pre-test incidence <strong>of</strong> cancerwould have to be at least 2 percent in order for a screening programme with this level <strong>of</strong>specificity to potentially benefit more people than it harmed. Only the high-risk groupsdescribed above <strong>of</strong>fer the possibility <strong>of</strong> this level <strong>of</strong> incidence in a reasonable screening

window. Later generations tend to have an earlier onset <strong>of</strong> cancer; thus maximum risk is atapproximately the age <strong>of</strong> onset in affected siblings and is somewhat lower than the age <strong>of</strong>onset in affected parents. None <strong>of</strong> screening programmes in action today assume anysignificant positive predictive value for any <strong>of</strong> the blood tests used, but the results may informclinical decisions based on imaging. EUS meets many <strong>of</strong> the criteria as the ideal imagingmodality in screening, but there are limitations. EUS is not good at distinguishing betweenbenign lesions and cancers. In a small study (n=85) aimed at distinguishing between chronicpancreatitis and pancreatic cancer, positive predictive value was only 60 percent based onimaging alone. Initial results have been published by the Johns Hopkins and Washingtongroups. From a total cohort <strong>of</strong> 75 patients, 15 had abnormalities on EUS and ERCP, all <strong>of</strong>whom had surgery (12 total and 3 distal pancreatectomies). The three that had distalpancreatectomy remain under surveillance. Histology results revealed PanIN-3 lesions in 10individuals and the remaining 5 specimens contained PanIN-2. Although no cancers weredetected in the resected participants, 1 individual has developed an unresectable pancreaticmalignancy whilst under imaging surveillance. Screening for early pancreatic cancer remainsdifficult and has yet to be proven to be effective. The detection <strong>of</strong> early tumours will not onlyconfirm the validity <strong>of</strong> the successful screening modality but will reveal more about the earlystages <strong>of</strong> pancreatic cancer development [356].Lynch syndromeLynch syndrome is an inherited cause <strong>of</strong> colorectal cancer caused by mutations <strong>of</strong> DNAmismatch repair (MMR) genes. A number <strong>of</strong> extracolonic tumors have been associated withthe disorder, including pancreatic cancer; however, the risk <strong>of</strong> pancreatic cancer in Lynchsyndrome is uncertain and not quantified. To estimate pancreatic cancer risk in families withgermline MMR gene mutations cancer histories <strong>of</strong> probands and their relatives wereevaluated in MMR gene mutation carriers in two US familial cancer registries. Familiesenrolled before the study start date (June 2008) were eligible. Age-specific cumulative risksand hazard ratio estimates <strong>of</strong> pancreatic cancer risk were calculated and compared with thegeneral population using modified segregation analysis, with correction for ascertainment.Age-specific cumulative risks and hazard ratio estimates <strong>of</strong> pancreatic cancer risk werecalculated. Data on 6342 individuals from 147 families with MMR gene mutations wereanalyzed. Thirty-one families (21 %) reported at least 1 case <strong>of</strong> pancreatic cancer. Fortysevenpancreatic cancers were reported (21 men and 26 women), with no gender-relateddifference in age <strong>of</strong> diagnosis (52 vs 57 years for men and women, respectively). Thecumulative risk <strong>of</strong> pancreatic cancer in these families with gene mutations was 1.3 percent(95 % confidence interval 0.31 % to 2.32 %) up to age 50 years and 3.7 percent (95 %confidence interval 1.5 % to 5.9 %) up to age 70 years, which represents an 8.6-fold increase(95 % confidence interval 4.7 to 15.7) compared with the general population. It wasconcluded that among 147 families with germline MMR gene mutations, the risk <strong>of</strong> pancreaticcancer was increased compared with the US population [357].Clinical aspects <strong>of</strong> Lynch syndromeHereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2-3 percent<strong>of</strong> all colorectal cancers. Lynch syndrome is also associated with a high risk <strong>of</strong> extracoloniccancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinarytract, brain, and skin cancer. It was now discussed the risks, surveillance tests, andguidelines for the management <strong>of</strong> extracolonic tumours associated with Lynch syndrome. Forall types <strong>of</strong> extracolonic cancer, evidence supporting surveillance is scarce. A benefit <strong>of</strong>surveillance is evident only for endometrial cancer, where transvaginal ultrasound andendometrial sampling detect tumours in early stages. Surveillance is generally recommendedfor urinary tract and gastric cancer, especially in families with more than one member withthese types <strong>of</strong> cancer. For the other types <strong>of</strong> cancer, surveillance is typically notrecommended. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be

considered for women with Lynch syndrome who are past childbearing age, especially duringsurgery for colorectal cancer. No data show efficacy <strong>of</strong> chemopreventive drugs in reducingthe risk <strong>of</strong> extracolonic cancers for patients with Lynch syndrome [358].Molecular biologyAs with many human malignancies, pancreatic cancer is a complex genetic disorder. Severalthousand disease-associated alterations on the DNA, mRNA, miRNA and protein levels havebeen reported to date. Some <strong>of</strong> these alterations, including a number <strong>of</strong> gatekeepermutations, which are <strong>of</strong> pre-eminent importance for the onset and progression <strong>of</strong> the disease,have been extensively studied in primary tissues, in vitro experiments and transgenic mousemodels. For the vast majority <strong>of</strong> alterations, however, data about the functional significanceare lacking. The situation is complicated by the fact that no certainty exists concerning theidentity <strong>of</strong> the cells that originally undergo malignant transformation nor about the precisenature and fate <strong>of</strong> premalignant lesions that are observed in pancreatic tissues [359].Most cases <strong>of</strong> pancreatic cancer are diagnosed at an advanced stage when the disease isbeyond surgical intervention. Molecular studies during the past decade have contributedgreatly to our understanding <strong>of</strong> this disease. Various germ-line and somatic mutationsassociated with pancreatic cancers have been characterized, along with abnormal variationsin the gene expression patterns. A thorough characterization <strong>of</strong> molecular alterations such asgenetic and epigenetic changes, alterations in the expression <strong>of</strong> genes and changes inproteins, and posttranslational modifications in pancreatic cancer could lead to a betterunderstanding <strong>of</strong> its pathogenesis. The available data from pancreatic cancer suggests thatthere are a large number <strong>of</strong> molecular alterations at genomic, epigenetic, transcriptomic, andproteomic levels. It is now possible to initiate a systems approach to studying pancreaticcancer especially in light <strong>of</strong> newer initiatives to dissect the pancreatic cancer genome [360].MethodologyGenomic analysis using tissue samples is an essential approach in cancer genetics.However, technical and biological limits exist in this approach. Microsatellite instability (MSI)is frequently observed in human tumors. MSI assays are now prevalent and regarded ascommonplace. However, several technical problems have been left unsolved in theconventional assay technique. Indeed, the reported frequencies <strong>of</strong> MSI differ widely in eachmalignancy. An example is pancreatic cancer. Using a unique fluorescent technique, it wasfound that MSI is extremely infrequent in this malignancy, despite the relatively highfrequencies in some reports. In a series <strong>of</strong> simulations, we have demonstrated that theextremely low frequency was derived neither from less sensitive assays nor from a scarcity<strong>of</strong> cancer cells in tissue samples. Furthermore, analyzing laser-capture microdissection(LCM)-processed cell populations <strong>of</strong> a microsatellite-unstable colorectal cancer cell line,HCT116, it was shown that MSI can be detected only when comparing two cell populationsthat have grown independently to a sufficiently large size. When MSI is not detected inanalyses using tissue samples, LCM is not advisable. It was concluded that microsatellitesequence alterations are not detectable in human pancreatic cancer [361].ACLAMALCAM (activated leucocyte cell adhesion molecule, synonym CD166) is a cell adhesionmolecule, which belongs to the Ig superfamily. Disruption <strong>of</strong> the ALCAM-mediatedadhesiveness by proteolytic sheddases such as ADAM17 has been suggested to have arelevant impact on tumor invasion. Although the expression <strong>of</strong> ALCAM is a valuableprognostic and predictive marker in several types <strong>of</strong> epithelial tumors, its role as a prognostic

marker in pancreatic cancer has not yet been reported. In one study, paraffin-embeddedsamples <strong>of</strong> 97 patients with pancreatic cancer undergoing potentially curative resection wereimmunostained against ALCAM, ADAM17 and CK19. It could be show that in normalpancreatic tissue, ALCAM is predominantly expressed at the cellular membrane, whereas inpancreatic tumor cells, it is mainly localised in the cytoplasm. In addition, univariate andmultivariate analyses show that increased expression <strong>of</strong> ALCAM is an adverse prognosticfactor for recurrence-free and overall survival. Overexpression <strong>of</strong> ADAM17 in pancreaticcancer, however, failed to be a significant prognostic marker and was not coexpressed withALCAM. The findings support the hypothesis that the disruption <strong>of</strong> ALCAM-mediatedadhesiveness is a relevant step in pancreatic cancer progression. Moreover, ALCAMoverexpression is a relevant independent prognostic marker for poor survival and early tumorrelapse in pancreatic cancer [362].Actinin-4Actinin-4 is an actin-bundling protein that probably has a tumor-promoting potential in severalsolid tumors. The present study analyzed the expression <strong>of</strong> actinin-4 in the pancreas, inlocalized and metastasized pancreatic ductal adenocarcinoma, and the correlation withclinical outcome. Pancreatic ductal adenocarcinoma tissue from 38 patients, 15 lymph nodeand 10 liver metastases, normal pancreas, and 4 pancreatic cancer cell lines, wereexamined by immunohistochemistry, and actinin-4 expression was quantified byimmun<strong>of</strong>luorescence analysis. In the normal pancreas, actinin-4 was most prominentlyexpressed in ductal cells. In the cancers, tumor cells exhibited strong but differentialcytoplasmic immunoreactivity for actinin-4. A multivariate analysis revealed actinin-4immunoreactivity, advanced age, and undifferentiated grade as significant prognostic factorsassociated with worse survival after resection <strong>of</strong> the pancreatic cancer. Cells metastasized tolymph nodes or to the liver exhibited no significant increase <strong>of</strong> actinin-4 compared with theprimary tumors. A nuclear staining was observed neither in any <strong>of</strong> the cancer samples nor inthe 4 cell lines. In cancer cells, actinin-4 localized to dynamic actin structures and toinvadopodia. It was concluded that actinin-4 expression levels significantly correlate withworse survival after resection <strong>of</strong> pancreatic cancer. Although actinin-4 has been reported topromote lymph node metastases, there was no enhanced expression in cancer metastases[363].ADAMTSADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) is a family <strong>of</strong>proteins characterized by the presence <strong>of</strong> a metalloproteinase domain linked to a variety <strong>of</strong>specialized ancillary domains. The ADAMTS9 gene (ADAM metallopeptidase withthrombospondin type 1 motif, 9); has been characterized as a novel tumor suppressor genein and epigenetically silenced in association with lymph node metastases in nasopharyngealcarcinoma. It was reported high-resolution melting analysis used to detect the methylationlevels <strong>of</strong> ADAMTS9 gene in 100 gastric cancers, 100 colorectal cancers, 70 pancreaticcancers, and an equal number <strong>of</strong> adjacent normal tissues. The frequency <strong>of</strong> ADAMTS9methylation in all three types <strong>of</strong> cancers was significantly higher than in normal tissues.Consistent with previous reports, expression levels <strong>of</strong> ADAMTS9 were inversely correlatedwith methylation levels. There was no significant association between ADAMTS9 methylationstatus and tumor-node-metastasis staging in all three types <strong>of</strong> cancers. In summary,application <strong>of</strong> high-resolution melting analysis to large numbers <strong>of</strong> clinical samples is a rapidand high-throughput way to investigate the epigenetic status <strong>of</strong> ADAMTS9. The study wasnovel in evaluating the prevalence <strong>of</strong> ADAMTS9 methylation based on a large number <strong>of</strong>tumor samples and showing that epigenetic regulation <strong>of</strong> ADAMTS9 was associated withcarcinogenesis [364].

Annexin A5Protein misfolding is a central mechanism for the development <strong>of</strong> neurodegenerativediseases and type 2 diabetes mellitus. The accumulation <strong>of</strong> misfolded alpha-synucleinprotein inclusions in the Lewy bodies <strong>of</strong> Parkinson's disease is thought to play a key role inpathogenesis and disease progression. Similarly, the misfolding <strong>of</strong> the beta-cell hormonehuman islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in theinduction <strong>of</strong> beta-cell apoptosis in the context <strong>of</strong> type 2 diabetes. In one study, it was shownthat annexin A5 plays a role in interacting with and reducing the toxicity <strong>of</strong> the amyloidogenicproteins, h-IAPP and alpha-synuclein. It was found that annexin A5 is coexpressed in humanbeta-cells and that exogenous annexin A5 reduces the level <strong>of</strong> h-IAPP-induced apoptosis inhuman islets by approximately 50 protein and in rodent beta-cells by approximately 90protein. Experiments with transgenic expression <strong>of</strong> alpha-synuclein in Caenorhabditiselegans show that annexin A5 reduces alpha-synuclein inclusions in vivo. Using thi<strong>of</strong>lavin Tfluorescence, electron microscopy, and electron paramagnetic resonance, it was providedevidence that substoichiometric amounts <strong>of</strong> annexin A5 inhibit h-IAPP and alpha-synucleinmisfolding and fibril formation. It was concluded that annexin A5 might act as a molecularsafeguard against the formation <strong>of</strong> toxic amyloid aggregates [365].Basement membrane proteinsThe pathogenesis <strong>of</strong> pancreatic carcinoma is driven by the tumor cells ability to migratecausing invasion and metastases. The correlation between the aberrant expression <strong>of</strong>basement membrane proteins and the process <strong>of</strong> tumor invasion and metastasis has notbeen fully determined. In one study, the influence <strong>of</strong> laminin, fibronectin, and collagen type IVon migratory activity <strong>of</strong> 5 different cell lines has been investigated at the level <strong>of</strong> a singletumor cell using 3-dimensional time-lapse microscopy. All investigated cell lines have showna high baseline migration. The addition <strong>of</strong> laminin, fibronectin, and collagen type IV tocollagen type I matrix has significantly increased tumor cell migration. Tumor cell migrationwas strongly inhibited after treating the tumor cells with anti-beta1 monoclonal antibodies. Anabundant and continuous expression <strong>of</strong> laminin, fibronectin, and collagen type IV was foundon the basement membrane <strong>of</strong> perineurium, which sharply promoted tumor cell invasion. Theauthors concluded that continuous presentation <strong>of</strong> the basement membrane proteins byperineurium contributes to the affinity <strong>of</strong> pancreatic cancer cells for the perineural tumorinvasion. Blockade <strong>of</strong> integrins could represent a possible approach to control the basementmembrane-guided tumor spread [366].BCRA1Available studies allow to estimate that genetic factors play a role in 5-10 percent <strong>of</strong> patientswith pancreatic cancer. Beside other carcinomas, pancreatic cancer occurs in hereditaryneoplastic syndromes associated with gene mutations, including CDKN2A, CHEK2, BRCA2.It has also been suggested that BRCA1 mutation is involved given the fact that BRCA1mutation carriers are at increased risk for pancreatic cancer. However, a role <strong>of</strong> this mutationis not fully understood. Eighty-eight pancreatic cancer patients (56 males and 35 females)and 3784 carriers <strong>of</strong> BRCA1 mutation from 1637 families were enrolled in the study. Almost65 percent <strong>of</strong> pancreatic cancer patients were cigarette smokers. Genotyping for constitutiveBRCA1 gene mutation was performed in all patients with pancreatic cancer. ASA-PCR andPCR-RFLP methods were used to detect BRCA1 (5382insC, C61G, 4153delA) mutations.The frequency <strong>of</strong> pancreatic cancer in families <strong>of</strong> BRCA1 mutation carriers was evaluated.No carriers <strong>of</strong> BRCA1 mutation were identified in patients with pancreatic cancer. Only in 11families (0.7 %) with BRCA1 mutation carriers, pancreatic cancer was diagnosed. The resultssuggest that there is no relationship between BRCA1 mutation and pancreatic cancerdevelopment in Polish population [367].

B7 ligand familyB7-H3 is a new member <strong>of</strong> the B7 ligand family and regulates T-cell responses in variousconditions. However, the role <strong>of</strong> B7-H3 in tumour immunity is largely unknown. The purpose<strong>of</strong> one study was to evaluate the clinical significance <strong>of</strong> B7-H3 expression in humanpancreatic cancer and the therapeutic potential for cancer immunotherapy. It wasinvestigated B7-H3 expression in 59 patients with pancreatic cancer byimmunohistochemistry and real-time PCR. Tumour-related B7-H3 expression was abundantin most human pancreatic cancer tissues and was significantly higher compared with that innon-cancer tissue or normal pancreas. Moreover, its expression was significantly moreintense in cases with lymph node metastasis and advanced pathological stage. B7-H3blockade promoted CD8(+) T-cell infiltration into the tumour and induced a substantial antitumoureffect on murine pancreatic cancer. In addition, the combination <strong>of</strong> gemcitabine withB7-H3 blockade showed a synergistic anti-tumour effect without overt toxicity [368].CiliogenesisPrimary cilia have been proposed to participate in the modulation <strong>of</strong> growth factor signalingpathways. In one study, it was determined that ciliogenesis is suppressed in both pancreaticcancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreaticductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when notactively proliferating. Cilia were also absent from mouse PanIN cells in three different mousemodels <strong>of</strong> PDAC driven by an endogenous oncogenic Kras allele. Inhibition <strong>of</strong> Kras effectorpathways restored ciliogenesis in a mouse pancreatic cancer cell line, raising the possibilitythat ciliogenesis may be actively repressed by oncogenic Kras. By contrast, normal duct,islet, and centroacinar cells retained primary cilia in both human and mouse pancreata. Thus,arrested ciliogenesis is a cardinal feature <strong>of</strong> PDAC and its precursor PanIN lesions, does notrequire ongoing proliferation, and could potentially be targeted pharmacologically [369].COX-2Overexpression <strong>of</strong> cyclooxygenase-2 (COX-2) is implicated in cancer development. Onestudy examined the functional relevance <strong>of</strong> genetic polymorphisms in the COX-2 promoterand evaluated their associations with susceptibility to pancreatic cancer. Genotypes andhaplotypes <strong>of</strong> COX-2 -765G/C, -1195G/A, and -1290A/G were analyzed in 393 pancreaticcancer patients and 786 controls. The -1195AA or -765GC genotype carriers had a 1.34-fold(95 % confidence intervall 1.12 to 1.60) or 1.63-fold (95 % confidence intervall 1.25 to 2.10)excess risk for developing pancreatic cancer. These two variants showed a cooperativeeffect in context <strong>of</strong> haplotype, with the odds ratios for the A(-1195)-C(-765)- containinghaplotypes being significantly greater than those for the G(-1195)-G(-765)-containinghaplotypes. The -765C allele and smoking displayed a multiplicative joint effect, with an oddsratio <strong>of</strong> 3.72 (95 % confidence intervall 1.70to 8.14) for heavy smokers carrying the -765GCgenotype. Biochemical assays suggest that the -765GC change creates a binding site fornucleophosmin (NPM) and phosphorylated NPM (p-NPM), which acts as a transcriptionalinhibitor. Cigarette smoke remarkably increased COX-2 promoter activity, and this effect wasmore pronounced for the -765C allele compared with the -765G allele. Cigarette smokereduced nuclear p-NPM levels, which was reversely associated with COX-2 expression. Itwas thus found that functional COX-2 polymorphisms are associated with susceptibility topancreatic cancer and tobacco smoke specifically increases -765C promoter activity, whichmight be mediated by p-NPM [370].

CTNNB1To use fluorescence in situ hybridization (FISH) to visualize genetic abnormalities ininterphase cell nuclei (interphase FISH) <strong>of</strong> acinar cell carcinoma, ductal adenocarcinoma,and islet cell carcinoma <strong>of</strong> the pancreas interphase FISH was used to study paraffinembeddedpreparations <strong>of</strong> tissue obtained from 18 patients listed in the Mayo ClinicBiospecimen Resource for Pancreas Research with a confirmed diagnosis <strong>of</strong> acinar cellcarcinoma, ductal adenocarcinoma, islet cell carcinoma, or pancreas without evidence <strong>of</strong>neoplasia. FISH probes were used for chromosome loci <strong>of</strong> APC, BRCA2, CTNNB1, EGFR,ERBB2, CDKN2A, TP53, TYMP, and TYMS. These FISH probes were used with controlprobes to distinguish among various kinds <strong>of</strong> chromosome abnormalities <strong>of</strong> number andstructure. FISH abnormalities were observed in 12 (80 %) <strong>of</strong> 15 patients with pancreaticcancer: 5 <strong>of</strong> 5 patients with acinar cell carcinoma, 5 <strong>of</strong> 5 patients with ductaladenocarcinoma, and 2 (40 %) <strong>of</strong> 5 patients with islet cell carcinoma. All 3 specimens <strong>of</strong>pancreatic tissue without neoplasia had normal FISH results. Gains <strong>of</strong> CTNNB1 due totrisomy 3 occurred in each tumor with acinar cell carcinoma but in none <strong>of</strong> the other tumorsin this study. FISH abnormalities <strong>of</strong> all other cancer genes studied were observed in all forms<strong>of</strong> pancreatic tumors in this investigation. The authors concluded that FISH abnormalities <strong>of</strong>CTNNB1 due to trisomy 3 were observed only in acinar cell carcinoma. FISH abnormalities<strong>of</strong> genes implicated in familial cancer, tumor progression, and the 5-fluorouracil pathwaywere common but were not associated with specific types <strong>of</strong> pancreatic cancer [371].CytokinesChemokines and their receptors are involved in tumourigenicity and clinicopathologicalsignificance <strong>of</strong> chemokines receptor expression in pancreatic adenocarcinoma is not fullyunderstood. This study was conducted to determine patients' outcome according to theexpressions <strong>of</strong> CXCR4, CXCR7 and HIF-1alpha after resection <strong>of</strong> pancreatic cancer.Immunohistochemistry for CXCR4, CXCR7 and HIF-1alpha expressions as well as cellproliferative index (Ki-67) was conducted in 71 resected (R0) cancers and their 48 relatedlymph nodes using tissue microarray. CXCR4 and CXCR7 expressions were positivelycorrelated to HIF-1alpha suggesting a potential role <strong>of</strong> HIF-1alpha in CXCR4 and CXCR7transcription activation. Patients with CXCR4(high) tumour expression had significantlyshorter overall survival than those with low expression (median survival: 10 vs 43 months), ahigher risk <strong>of</strong> lymph node metastases and liver recurrence. In multivariate analysis, highCXCR4 expression, lymph node metastases and poorly differentiated tumour areindependent negative prognosis factors. In a combining analysis, patients withCXCR4(low)/CXCR7(low) tumour had a significantly shorter disease-free survival and overallsurvival than patients with a CXCR7(high)/CXCR4(high) tumour. CXCR4 in resectedpancreatic cancer may represent a valuable prognostic factor as well as an attractive targetfor therapeutic purpose [372].Cytokine polymorphismMany cytokine polymorphisms have been studied for associations with susceptibility tobreast, gastric, liver, lung, prostate, and ovarian cancer without conclusive results. Thecytokine network, indeed, is characterized by complex interactions, and the final biologicaleffect <strong>of</strong> a single genetic variation depends on the balance among different molecularsignals. As is well known, Th1/Th2 cytokine unbalanced production might predispose todifferent pathologies, cancer included. In general, a prolonged type 1 inflammatory responsemight allow that cells accumulating enough "genetic hits" are promoted to neoplastictransformation. On the other hand, IL-13-producing cells through the IL-13/IL-4 receptoralpha(R-alpha) pathway might facilitate escape from tumor immunosurveillance. Now it wasreported data on the evaluation <strong>of</strong> the influence <strong>of</strong> some type 2 and type 1 cytokine genetic

polymorphisms as risk factors for pancreatic cancer. There was no overall associationbetween pancreatic cancer risk and single cytokine SNPs. On the other hand, in evaluatingthe influence <strong>of</strong> combined cytokine genotypes it was found that the combined IL-10-1082GAheterozygous and IL-4 Ralpha-1902AA homozygous genotype is underrepresented in thepancreatic cancer subject group. As is well known, the IL-10-1082GA genotype is associatedwith an intermediate production <strong>of</strong> this regulatory cytokine, whereas the IL-10-1902AAgenotype <strong>of</strong> the IL-4Ralpha gene is associated with a reduced efficiency in signaltransduction when the receptor is engaged by IL-13 or IL-4. These results strongly suggestthat a genetic background associated to a mild downregulation <strong>of</strong> type 1 and type 2inflammatory signals might be protective against pancreatic cancer [373].DoxycyclinsTetracyclines such as doxycycline are reported to possess cytotoxic activity againstmammalian tumor cells, but the mechanism <strong>of</strong> their effects on cell proliferation remainsunclear. The antitumor effect <strong>of</strong> doxycycline was therefore investigated in human pancreaticcancer cell line, PANC-1. It was also investigated the effect <strong>of</strong> doxycycline on expression <strong>of</strong> apotent proangiogenic factor, interleukin (IL)-8. In excess <strong>of</strong> 20 microg/ml, cytotoxic effects <strong>of</strong>doxycycline were accompanied by G 1 -S cell cycle arrest and DNA fragmentation in PANC-1cells. Doxycycline consistently activated transcription <strong>of</strong> p53, p21 and Fas/FasL-cascaderelatedgenes, while reducing the expression <strong>of</strong> Bcl-xL and Mcl-1. Doxycycline (5 microg/ml)below the cytotoxic level suppressed endogenous and paclitaxel-induced IL-8 expression. Inthe mouse xenograft model, doxycycline treatment was shown to suppress tumor growth by80 percent. It was thus concluded that doxycycline exerts its antitumor effect by activatingproapoptotic genes, inhibiting IL-8 expression, and suppressing antiapoptotic genes [374].Epidermal growth factor receptorNovel therapeutic agents targeting the epidermal growth factor receptor (EGFR) haveimproved outcomes for a subgroup <strong>of</strong> patients with colorectal, lung, head and neck, andpancreatic cancers. In these tumors, the EGFR activation turns on at least five differentsignaling pathways (RAS/mitogen-activated protein kinase, phospholipase C,phosphatidylinositol 3-kinase/AKT, signal transducer and activator <strong>of</strong> transcription, andSRC/FAK pathways), which are intimately interconnected, and frequent mutations involvingeither the receptor itself or downstream effectors have been found. Up to now, it seems thatalterations at the EGFR level have major importance in EGFR tyrosine kinase inhibitorresponse, whereas modifications <strong>of</strong> downstream effectors could lead to treatment resistance.Furthermore, the understanding <strong>of</strong> the mechanism <strong>of</strong> the EGFR network activation providesnew hypotheses on potential new anticancer drugs that may be effektive [375].Epithelial-mesenchymal transitionExpression <strong>of</strong> transcription factors that mediate epithelial-mesenchymal transition (EMT),such as Twist and Slug, is correlated with poor prognosis in many tumor types. SelectedEMT markers were studied in a series <strong>of</strong> pancreatic ductal adenocarcinomas and benignpancreatic tissues to determine whether expression levels correlated with diagnosis,histologic grade, or patient outcome. Immunohistochemical stains for Twist, Slug, and N-cadherin were performed using a tissue microarray containing 68 pancreatic cancers and 38samples <strong>of</strong> normal pancreas or chronic pancreatitis tissues. Twist and Slug were identified inboth the nucleus and cytoplasm <strong>of</strong> benign pancreatic ductal epithelium, chronic pancreatitis,and pancreatic cancer. Compared with normal ductal epithelium, nuclear levels <strong>of</strong> Twist aredecreased in cancer tissue. None <strong>of</strong> the other EMT markers showed significant differences instaining indices among the diagnostic groups. There were no correlations between EMTmarker expression and histologic grade. Epithelial-mesenchymal transition marker

expression was not associated with N-cadherin expression, patient outcome, or duration <strong>of</strong>survival. It was concluded that decreased expression <strong>of</strong> nuclear Twist is observed inmalignant pancreatic epithelium. However, use <strong>of</strong> Twist as a diagnostic marker is precludedbecause decreased expression is also seen in chronic pancreatitis. None <strong>of</strong> the markersstudied were predictive <strong>of</strong> patient outcome [376].FibrinogenAlthough changes <strong>of</strong> plasma fibrinogen have been documented in limited pancreaticmalignant tumors, a relationship between plasma fibrinogen and pancreatic cancer in alarge-scale clinical study has not been shown. Therefore, preoperative plasma levels <strong>of</strong>fibrinogen were retrospectively analyzed in 133 pancreatic cancer and 38 pancreatic benigntumor patients. Plasma fibrinogen in pancreatic cancer patients was significantly higher thanthose with benign pancreatic tumor. The percentage <strong>of</strong> hyperfibrinogenemia (>4.20 g/L) inpancreatic cancer was 41 percent, and no positive results were obtained in benignpancreatic disease. Plasma fibrinogen levels were increased in pancreatic cancer withadvanced tumor stage. Accompanied with the progression <strong>of</strong> tumor stage, there was anincrease in the percentage <strong>of</strong> positivity <strong>of</strong> hyperfibrinogenemia in pancreatic cancer. Therewere significantly higher levels <strong>of</strong> plasma fibrinogen in the distant-metastasis group than inthe no-distant-metastasis group. Univariate and multivariate analysis revealed that highplasma fibrinogen levels (>4.20 g/L) were positively associated with distant metastasis <strong>of</strong>pancreatic cancer [377].Glycogen synthas kinase inhibitorRecent studies have demonstrated that glycogen synthase kinase 3beta (GSK-3beta) isoverexpressed in human colon and pancreatic carcinomas, contributing to cancer cellproliferation and survival. Here, we report the design, synthesis, and biological evaluation <strong>of</strong>benz<strong>of</strong>uran-3-yl-(indol-3-yl)maleimides, potent GSK-3beta inhibitors. Some <strong>of</strong> thesecompounds show picomolar inhibitory activity toward GSK-3beta and an enhanced selectivityagainst cyclin-dependent kinase 2 (CDK-2). Selected GSK-3beta inhibitors were tested in thepancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. It was determined that some <strong>of</strong>these compounds, namely compounds 5, 6, 11, 20, and 26, demonstrate antiproliferativeactivity against some or all <strong>of</strong> the pancreatic cancer cells at low micromolar to nanomolarconcentrations. Moreover, it was found that the treatment <strong>of</strong> pancreatic cancer cells withGSK-3beta inhibitors 5 and 26 resulted in suppression <strong>of</strong> GSK-3beta activity and a distinctdecrease <strong>of</strong> the X-linked inhibitor <strong>of</strong> apoptosis (XIAP) expression, leading to significantapoptosis. The present data suggest a possible role for GSK-3beta inhibitors in cancertherapy, in addition to their more prominent applications in CNS disorders [378].Hedgehog pathwayAberrant activation <strong>of</strong> the hedgehog pathway has been observed in multiple human cancers,including pancreatic cancer. For this reason, several small-molecule inhibitors <strong>of</strong> the pathwayhave been advanced to clinical trials to evaluate their efficacy in treating various solidcancers. It has also been suggested that pancreatic cancer is a particularly good candidatefor experimental treatment with hedgehog inhibitors. In the absence <strong>of</strong> ligands, such as sonichedgehog (SHH), the membrane receptor patched (PTCH) blocks the smoothened receptor(SMO), repressing its activity. The binding <strong>of</strong> the SHH ligand to the PTCH receptordiminishes its inhibitory effects on SMO, allowing signal transduction through the pathwaythat culminates in activation and nuclear translocation <strong>of</strong> GLI family zinc finger transcriptionfactors. These transcription factors turn on genes in the nucleus that promote cellularproliferation. Therapeutic blockade <strong>of</strong> the hedgehog pathway eliminates cancer stem cells,improves outcomes, and may effect a cure when combined with gemcitabine in a direct

xenograft model <strong>of</strong> pancreatic cancer. With respect to a test <strong>of</strong> therapeutic effect, it is clearfrom preclinical studies that hedgehog inhibitors should be examined in combination withgemcitabine, the current standard <strong>of</strong> care for treatment. It has been suggested that thosepatients with locally advanced pancreatic cancer are the most likely to benefit from atherapeutic approach that involves inhibition <strong>of</strong> the hedgehog pathway. This subgrouprepresents up to 30 percent <strong>of</strong> patients at the time <strong>of</strong> diagnosis, and these patient have atype <strong>of</strong> cancer that is characterized by stroma-rich hypovascular tumors that cannot beresected because <strong>of</strong> large-vessel involvement [379].HSP27A prior study suggested serum heat shock protein 27 (HSP27) as a potential marker forpancreatic carcinoma, but its accuracy in differentiating cancer from chronic pancreatitis wasnot evaluated. Pretreatment serums from 58 pancreatic carcinoma, 44 chronic pancreatitis,and 102 control subjects were collected. Serum HSP27 and carbohydrate antigen 19-9(CA19-9) levels were analyzed using an enzyme-linked immunosorbent assay andradioimmunoassay, respectively. Heat shock protein 27 levels were significantly higher incancer and pancreatitis compared with control, but no significant difference was notedbetween cancer and pancreatitis. By logistic regression, HSP27 was a significant predictor <strong>of</strong>differentiation between cancer and control but not between cancer and pancreatitis. At acut<strong>of</strong>f <strong>of</strong> 1650 ng/L, the sensitivity and specificity for differentiating cancer from healthycontrol were 62 percent and 95 percent, respectively. Receiver operating characteristicanalyses showed a significantly greater area under curve for CA19-9 compared with HSP27in differentiating between cancer and control. It was thus concluded that serum HSP27 isincreased in both chronic pancreatitis and pancreatic carcinoma but it should not berecommended as a diagnostic marker for pancreatic carcinoma [380].HuRGemcitabine has been the standard <strong>of</strong> care for pancreatic cancer for a decade but is onlyeffective in some patients. As a prodrug, gemcitabine is activated by different proteinkinases. The deoxycytidine kinase (dCK) is the first step <strong>of</strong> intracellular activation. TStudieson the Hu antigen R (HuR), a stress response protein, on dCK expression and the correlationbetween HuR expression levels and pancreatic cancer outcome demonstrates that dCKprotein concentration levels were regulated by HuR and that a high cytoplasmic HuR levelwas associated with a sevenfold decreased risk <strong>of</strong> mortality after resection <strong>of</strong> pancreaticadenocarcinoma and gemcitabine therapy [381].IGF-1 receptorThe insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling system hasprovoked considerable interest over recent years as a novel therapeutic target in cancer.There are in vitro and in vivo data in the published <strong>literature</strong> <strong>of</strong> the following compoundstargeting IGF-1R components using specific examples: growth hormone releasing hormoneantagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1Rantibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479,MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417,NVP-AEW541, NVP-ADW742, AG1024, potent quinolinyl-derived imidazo (1,5-a)pyrazinePQIP, picropodophyllin PPP, Nordihydroguaiaretic acid Insm-18/NDGA). Pancreatic canceris among the tumors that have been tested for response [382].IntegrinesFactors mediating the invasion <strong>of</strong> pancreatic cancer cells through the extracellular matrix

(ECM) are not fully understood. In this study, sub-populations <strong>of</strong> the human pancreaticcancer cell line, MiaPaCa-2 were established which displayed differences in invasion,adhesion, anoikis, anchorage-independent growth and integrin expression. The resultssuggest that altered expression <strong>of</strong> integrins interacting with different extracellular matrixesmay play a significant role in suppressing the aggressive invasive phenotype. Analysis <strong>of</strong>these clonal populations <strong>of</strong> MiaPaCa-2 provides a model for investigations into the invasiveproperties <strong>of</strong> pancreatic carcinoma [383].Interleukin-13 receptorWhereas interleukin-13 receptor alpha2 chain (IL-13Ralpha2) is overexpressed in a variety <strong>of</strong>human solid cancers including pancreatic cancer, it was investigated its significance incancer invasion and metastasis. It was used two pancreatic cancer cell lines, IL-13Ralpha2-negative HPAF-II and IL-13Ralpha2-positive HS766T, and generated IL-13Ralpha2 stablytransfected HPAF-II as well as IL-13Ralpha2 RNA interference knocked-down HS766T cells.Ability <strong>of</strong> invasion and signal transduction was compared between IL-13Ralpha2-negativeand IL-13Ralpha2-positive cells and tumor metastasis was assessed in murine model forhuman pancreatic cancer with orthotopic implantation <strong>of</strong> tumors. IL-13 treatment enhancedcell invasion in IL-13Ralpha2-positive cancer cell lines but not in IL-13Ralpha2-negative celllines. Furthermore, gene transfer <strong>of</strong> IL-13Ralpha2 in negative cell lines enhanced invasion,whereas its silencing downmodulated invasion <strong>of</strong> pancreatic cell lines in a Matrigel invasionassay. In vivo study revealed that IL-13Ralpha2-positive cancer metastasized to lymphnodes, liver, and peritoneum at a significantly higher rate compared with IL-13Ralpha2-negative tumors. The expression <strong>of</strong> IL-13Ralpha2 in metastatic lesions was found to beincreased compared with primary tumors, and mice with IL-13Ralpha2-positive cancerdisplayed cachexia and poor prognosis. Invasion and metastasis also correlated withincreased matrix metalloproteinase protease activity in these cells. Mechanistically, IL-13activated extracellular signal-regulated kinase 1/2 and activator protein-1 nuclear factors inIL-13Ralpha2-positive pancreatic cancer cell lines but not in IL-13Ralpha2-negative cell lines.Taken together, the results show for the first time that IL-13 can signal through IL-13Ralpha2in pancreatic cancer cells and IL-13Ralpha2 may serve as a prognostic biomarker <strong>of</strong> invasionand metastasis in pancreatic cancer [384].K-rasTo investigate the cellular origin(s) <strong>of</strong> pancreatic ductal adenocarcinoma, it was determinedthe effect <strong>of</strong> pancreatic cancer-relevant gene mutations in distinct cell types <strong>of</strong> the adultpancreas. It was shown that a subpopulation <strong>of</strong> Pdx1-expressing cells is susceptible tooncogenic K-Ras-induced transformation without tissue injury, whereas insulin-expressingendocrine cells are completely refractory to transformation under these conditions. However,chronic pancreatic injury can alter their endocrine fate and allow them to serve as the cell <strong>of</strong>origin for exocrine neoplasia. These results suggest that one mechanism by whichinflammation and/or tissue damage can promote neoplasia is by altering the fate <strong>of</strong>differentiated cells that are normally refractory to oncogenic stimulation [385].KRAS is mutated in more than 90 percent <strong>of</strong> pancreatic cancer patients, and oncogenicKRAS contributes to pancreatic cancer tumorigenesis and progression. In one report, usingan oncogenic KRASV12-based pancreatic cancer cell model, it was developed a chemicalgenetic screen to identify small chemical inhibitors that selectively target pancreatic cancercells with gain-<strong>of</strong>-function KRAS mutation. After screening ~3,200 compounds, it wasidentified one compound that showed selective synthetic lethality against the KRASV12transformed human pancreatic ductal epithelial cell over its isogenic parental cell line. Theseselective KRASV12-synthetic lethal compounds may serve as leads for subsequentdevelopment <strong>of</strong> clinically-effective treatments for pancreatic cancer [386].

MatriptaseMatriptase, also known as MT-SP1, is a type II transmembrane serine protease stronglyimplicated in both the development and progression <strong>of</strong> a variety <strong>of</strong> epithelial cancers.Evidence comes from studies <strong>of</strong> its expression in human cancers and from mouse models <strong>of</strong>spontaneous cancer. Matriptase is considered to be a major activator <strong>of</strong> two key stimulators<strong>of</strong> invasive growth, namely hepatocyte growth factor/scatter factor and urokinase-typeplasminogen activator. The aim <strong>of</strong> one study was to examine the role <strong>of</strong> matriptase inpancreatic ductal adenocarcinoma by expression analysis and functional assays in vitro.Immunohistochemical analysis <strong>of</strong> matriptase performed on microtissue arrays and largesamples <strong>of</strong> 55 pancreatic ductal adenocarcinomas and on 31 samples <strong>of</strong> normal pancreaticducts revealed that although matriptase expression differed greatly in both malignant andnormal ductal pancreatic tissue, matriptase scores were significantly elevated in pancreaticductal adenocarcinoma compared to normal pancreatic ducts. To evaluate the role <strong>of</strong>matriptase during development <strong>of</strong> pancreatic cancer, we studied the effects <strong>of</strong> newlydesigned matriptase inhibitors on the processing <strong>of</strong> the zymogen <strong>of</strong> urokinase-typeplasminogen activator in the human adenocarcinoma cell lines AsPC-1 and BxPC-3. In bothcell lines, at 1 microM, all matriptase inhibitors completely prevented zymogen activation. Atlower inhibitor concentrations, the degree <strong>of</strong> inhibition <strong>of</strong> zymogen processing correlated withthe affinities <strong>of</strong> the inhibitors towards matriptase indicating that this is a specific result <strong>of</strong>matriptase inhibition. Furthermore, matriptase inhibitors reduced the phosphorylation <strong>of</strong> theHGF receptor/cMet and the overall cellular invasiveness <strong>of</strong> the human pancreaticadenocarcinoma cell line AsPC-1. The findings demonstrate for the first time that matriptasemay be involved in the progression <strong>of</strong> pancreatic ductal adenocarcinoma and that matriptaseinhibition may contribute to preventing the progression <strong>of</strong> this disease [387].Mitochondrial DNAThe majority <strong>of</strong> cancer cells harbor homoplasmic somatic mutations in the mitochondrialgenome. It was now shown that mutations in mitochondrial DNA (mtDNA) are responsible foranticancer drug tolerance. It was constructed several trans-mitochondrial hybrids (cybrids)with mtDNA derived from human pancreas cancer cell lines CFPAC-1 and CAPAN-2 as wellas from healthy individuals. These cybrids contained the different mitochondrial genomeswith the common nuclear background. It was compared the mutant and wild-type cybrids forresistance against an apoptosis-inducing reagent and anticancer drugs by exposing thecybrids to staurosporine, 5-fluorouracil, and cisplatin in vitro, and found that all mutantcybrids were more resistant to the apoptosis-inducing and anticancer drugs than wild-typecybrids. Next, it was transplanted mutant and wild-type cybrids into nude mice to generatetumors. Tumors derived from mutant cybrids were more resistant than those from wild-typecybrids in suppressing tumor growth and inducing massive apoptosis when 5-fluorouracil andcisplatin were administered. To confirm the tolerance <strong>of</strong> mutant cybrids to anticancer drugs, itwas transplanted a mixture <strong>of</strong> mutant and wild-type cybrids at a 1:1 ratio into nude mice andexamined the effect by the drugs on the drift <strong>of</strong> the ratio <strong>of</strong> mutant and wild-type mtDNA. Themutant mtDNA showed better survival, indicating that mutant cybrids were more resistant tothe anticancer drugs [388].NF-kappaBTranscription factor nuclear factor-kappaB (NF-kappaB) is constitutively activated in mostpancreatic cancer tissues and cell lines but not in normal pancreas nor in immortalized ornontumorigenic human pancreatic ductal epithelial cells. Inhibition <strong>of</strong> constitutive NF-kappaBactivation in pancreatic cancer cell lines suppresses tumorigenesis and tumor metastasis.Recently, we identified autocrine secretion <strong>of</strong> proinflammatory cytokine interleukin (IL)-1alphaas the mechanism <strong>of</strong> constitutive NF-kappaB activation in metastatic pancreatic cancer cell

lines. However, the role <strong>of</strong> IL-1alpha in determining the metastatic potential <strong>of</strong> pancreatictumor remains to be further investigated. In one study, it was stably expressed IL-1alpha inthe nonmetastatic, IL-1alpha-negative MiaPaCa-2 cell lines. Our results showed that thesecretion <strong>of</strong> IL-1alpha in MiaPaCa-2 cells constitutively activated NF-kappaB and increasedthe expression <strong>of</strong> NF-kappaB downstream genes involved in the different steps <strong>of</strong> themetastatic cascade, such as urokinase-type plasminogen activator, vascular endothelialgrowth factor, and IL-8. MiaPaCa-2/IL-1alpha cells showed an enhanced cell invasion in vitrocompared with parental MiaPaCa-2 cells and induced liver metastasis in an orthotopicmouse model. The metastatic phenotype induced by IL-1alpha was inhibited by theexpression <strong>of</strong> phosphorylation-defective IkappaB (IkappaB S32, 36A), which blocked NFkappaBactivation. Consistently, silencing the expression <strong>of</strong> IL-1alpha by short hairpin RNAin the highly metastatic L3.6pl pancreatic cancer cells completely suppressed their metastaticspread. In summary, these findings showed that IL-1alpha plays key roles in pancreaticcancer metastatic behavior through the constitutive activation <strong>of</strong> NF-kappaB [389].OsteopontinPancreatic ductal adenocarcinoma is a lethal disease with etiological association withcigarette smoking. Nicotine, an important component <strong>of</strong> cigarettes, exists at highconcentrations in the bloodstream <strong>of</strong> smokers. Osteopontin is a secreted phosphoprotein thatconfers on cancer cells a migratory phenotype and activates signaling pathways that inducecell survival, proliferation, invasion, and metastasis. Here, it was investigated the potentialmolecular basis <strong>of</strong> nicotine's role in pancreatic cancer through studying its effect onosteopontin. Nicotine significantly increased osteopontin mRNA and protein secretion inpancreatic cancer cells through activation <strong>of</strong> the osteopontin gene promoter. The osteopontinmRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist,mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotinemediatedinduction <strong>of</strong> osteopontin, suggesting that mitogen activated protein kinase signalingmechanism is involved. Nicotine activated the phosphorylation <strong>of</strong> ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition <strong>of</strong> ERK1/2 activation reduced the nicotine-inducedosteopontin synthesis. Rats exposed to cigarette smoke showed a dose-dependent increasein pancreatic OPN that paralleled the rise <strong>of</strong> pancreatic and plasma nicotine levels. Analysis<strong>of</strong> cancer tissue from invasive pancreatic cancer patients, the majority <strong>of</strong> whom weresmokers, showed the presence <strong>of</strong> significant amounts <strong>of</strong> osteopontin in the malignant ductsand the surrounding pancreatic acini. The data suggest that nicotine may contribute topancreatic cancer pathogenesis through upregulation <strong>of</strong> osteopontin. They provide the firstinsight into a nicotine-initiated signal transduction pathway that regulates osteopontin as apossible tumorigenic mechanism in pancreatic cancer [390].p21/p27p21 (WAF1/Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members <strong>of</strong> the Cip/Kip family <strong>of</strong>cyclin-dependent kinase inhibitors, which can induce cell cycle arrest and serve as tumorsuppressors. It was hypothesized that genetic variants in p21 and p27 may modify individualsusceptibility to pancreatic cancer. To test this hypothesis, it was evaluated the associations<strong>of</strong> the Ser31Arg polymorphism in p21 and the Gly109Val polymorphism in p27, and theircombinations, with pancreatic cancer risk in a case-control study <strong>of</strong> 509 pathologicallyconfirmed pancreatic adenocarcinoma patients and 462 age- and sex-matched cancer-freecontrols in non-Hispanic whites. It was found that the heterozygous and homozygous variantgenotypes combined in a dominant model <strong>of</strong> the p21 polymorphism were associated withincreased risk <strong>of</strong> pancreatic cancer compared with the homozygous wild type (adjusted oddsratio 1.70; 95 % confidence interval 1.13 to 2.55). This increased risk was more pronouncedin carriers with the p27 homozygous wild type (adjusted odds ratio 2.20; 95 % confidenceinterval 1.32 to 3.68) and in nonsmokers (adjusted odds ratio 2.16; 95 % confidence interval

1.14 to 4.10), although the p27 polymorphism alone was not associated with pancreaticcancer risk. These results indicate that the p21 polymorphism may contribute to susceptibilityto pancreatic cancer, particularly among p27 homozygous wild-type carriers and nonsmokers[391].p53With the aim <strong>of</strong> improving early detection <strong>of</strong> pancreatic carcinoma, it was attempted to makecorrelations among positive immunohistochemical detection <strong>of</strong> p53 expression, mutations inthe p53 gene, and detailed histologic features <strong>of</strong> pancreatic carcinoma. Seven cases <strong>of</strong>invasive pancreatic ductal carcinoma demonstrating p53 overexpression were analyzed.Serial 4- and 20-microm sections from paraffin blocks were used for immunodetection <strong>of</strong> p53protein and microdissection, respectively. It was used direct sequencing <strong>of</strong> polymerase chainreaction at 101 p53-positive and 10 p53-negative sites to sequence exons 5 to 8 <strong>of</strong> p53 andthen analyzed these results in concert with detailed histologic features. Regardless <strong>of</strong> thedegree <strong>of</strong> p53 overexpression, it was detected p53 point mutations in all p53-positive lesions,including 22 noninvasive sites, 17 invasive areas, and 1 lymph node metastasis. Nosignificant correlations were measured between specific p53 mutations and histologicfeatures. Within individual tumors, the same p53 mutation was generally, but not always,detected in different areas in invasive and noninvasive lesions. The results demonstrate thatp53 mutation is an early genetic event affecting a diversity <strong>of</strong> molecular pathways inpancreatic carcinogenesis and indicates a possibility <strong>of</strong> early diagnosis <strong>of</strong> pancreaticcarcinoma by detecting a few p53-positive cells obtained from the pancreatic fluid [392].Pain and nerve growth factorPerineural invasion is one <strong>of</strong> the most common routes <strong>of</strong> invasion in pancreatic cancer andthe exact mechanism is still not clear. The aim <strong>of</strong> one study was to investigate the effect <strong>of</strong>nerve growth factor (NGF) and tyrosine kinase receptor A (TrkA) on perineural invasion andto clarify the possible mechanism <strong>of</strong> perineural invasion in pancreatic cancer. Expressions <strong>of</strong>NGF/TrkA were examined in 51 human primary pancreatic cancer usingimmunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR).Immunohistochemical analysis indicated that the presence and kind <strong>of</strong> perineural invasionare prognostic parameters. Tumors with high NGF expression exhibited significantly morefrequent presence <strong>of</strong> perineural invasion. NGF expression was significantly correlated withmetastasis <strong>of</strong> lymph nodes and involvement <strong>of</strong> surgical margins. TrkA expression wassignificantly correlated with degree <strong>of</strong> perineural invasion. Negative correlations were foundbetween expression <strong>of</strong> NGF/TrkA and Ki-67. As shown by RT-PCR, mRNA levels <strong>of</strong>NGF/TrkA with perineural invasion were significantly higher than that without perineuralinvasion. It was concluded that in pancreatic cancer, overexpression <strong>of</strong> NGF may contributeto perineural invasion by prompting the hyperplasia <strong>of</strong> nerves, restraining the apoptosis <strong>of</strong>tumor cells and specifically combining NGF and TrkA [393].PPARGThe Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma (PPARG)gene has been associated with diabetes and several cancers. A pilot study tested for theassociation between Pro12Ala and pancreatic cancer risk in a high-risk sample <strong>of</strong> smokers.A nested case-control study was conducted in 83 incident cases <strong>of</strong> pancreatic cancer and166 matched controls originally recruited into a cohort chemoprevention study <strong>of</strong> lung cancer.Associations between Pro12Ala and pancreatic cancer risk were measured using conditionallogistic regression. Carriers <strong>of</strong> the G allele (Ala) <strong>of</strong> the Pro12Ala variant had a borderlineincreased relative risk <strong>of</strong> pancreatic cancer compared with homozygous carriers <strong>of</strong> the Callele (Pro), with an odds ratio <strong>of</strong> 1.79 (95 % confidence interval 0.96-3.33). Among subjects

andomized to high-dose vitamin A, the odds ratio was 2.80 versus 1.20 in the placebogroup. A haplotype including Pro12Ala was also significantly associated with pancreaticcancer risk in all subjects and in subjects randomized to vitamin A. The analysis presentsevidence that PPARG may be associated with pancreatic cancer risk [394].Plasminogen activatorThe serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) areknown to be involved in the invasion and metastasis <strong>of</strong> many solid tumors. In one study, itwas analyzed the role <strong>of</strong> the uPAR/uPA system in both the development and progression <strong>of</strong>pancreatic cancer in invasive ductal adenocarcinomas <strong>of</strong> the pancreas and theirpremalignant precursors (PanIN lesions) in 50 patients with long-term clinical follow-up. Itwas found overexpression <strong>of</strong> the uPAR in 48 <strong>of</strong> 50 invasive carcinomas as well as in a largeproportion <strong>of</strong> high-grade PanIN lesions by immunohistochemistry and in situ hybridization.Fluorescence in situ hybridization analysis showed both high- and low-level amplification <strong>of</strong>the uPAR gene in approximately 50 percent <strong>of</strong> cases with strictly identical patterns betweeninvasive cancers and their accompanying precursor lesions. These results suggest thatpancreatic cancer may develop from PanIN lesions along an alternative rather than asequential molecular pathway. The detection <strong>of</strong> the gene amplification <strong>of</strong> uPAR was a highlysignificant, adverse prognostic parameter because it likely renders the tumors more sensitiveto uPA and its proproliferative and anti-apoptotic signals. It was concluded that the activation<strong>of</strong> the uPAR/uPA system is an early event in the development <strong>of</strong> PDA and that uPAR geneamplifications identify a subgroup <strong>of</strong> particularly aggressive tumors, making the uPAR/uPAsystem a critical and highly promising target for therapeutic interventions [395].REG4Preoperative chemoradiotherapy is one <strong>of</strong> the key strategies for the improvement <strong>of</strong> survivalin pancreatic cancer; however, no method to predict the response has yet been established.The aim <strong>of</strong> one study was to prospectively evaluate the predictive value <strong>of</strong> REG4, a newmember <strong>of</strong> the regenerating (REG) islet-derived family <strong>of</strong> proteins. Stably REG4-expressingcells were established from a pancreatic cancer cell line and exposed in vitro to gamma-rayor gemcitabine to investigate the relevance <strong>of</strong> REG4 to the resistance to chemotherapy orradiotherapy. In 23 patients with resectable pancreatic cancer, the serum concentration <strong>of</strong>REG4 was measured before preoperative chemoradiotherapy, and the histologic responsewas evaluated after the surgery. A 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide assay and fluorescence activated cell scanning (FACS) revealed that REG4-overexpressing cells were resistant to [gamma]-radiation but showed a modest resistance togemcitabine. The patients with a higher REG4 level, but not carcinoembryonic antigen or CA-19-9, showed an unfavorable histologic response to chemoradiotherapy. The patientsshowing a higher REG4 level experienced local recurrence postoperatively [396].RosiglitazoneEvaluate the effect <strong>of</strong> fen<strong>of</strong>ibrate, bezafibrate, and rosiglitazone on nonalcoholic fattypancreatic disease and islet peroxisome proliferator-activated receptor-alpha (PPAR-alpha)and PPAR-beta immunostain in mice fed high-fat high-sucrose (HFHS) diet. Two-month-oldmale mice were fed standard chow (n=10) or HFHS chow (n=40) for 6 weeks. Afterward,HFHS mice were grouped by treatment: untreated HFHS and HFHS treated withrosiglitazone (HFHS-Ro), fen<strong>of</strong>ibrate (HFHS-Fe), or bezafibrate (HFHS-Bz). Medicationswere administered for 5 weeks. After treatment, the pancreas was removed and analyzed bymorphometry, stereology, and immunohistochemistry. Results: The HFHS-fed mice showedaltered fasting glucose (+33 %) and insulin (+138 %); increased body (+20 %) and pancreas(+28 %) masses, pancreatic fat (+700 %), islet hypertrophy (+38 %); and decreased GLUT2

immunostain (-60 %). Rosiglitazone reduced fasting glucose and insulin but induced weightgain. Fibrates impeded weight gain, but only bezafibrate prevented islet hypertrophy. TheGLUT2 stain was improved in all treatments, and there were no alterations in PPAR-alpha.There were morphological signs <strong>of</strong> pancreatitis with fen<strong>of</strong>ibrate, although there were noalterations in amylase and lipase. Rosiglitazone exacerbated pancreatic fat infiltration (+75 %vs HFHS group), and bezafibrate increased PPAR-beta expression in pancreatic islets. Theauthors concluded that rosiglitazone is shown for the first time to exacerbate pancreatic fatinfiltration; therefore, precaution has to be taken when rosiglitazone is prescribed to obesepatients [397].Somatostatin receptor subtype 2The somatostatin receptor subtype 2 (sst2) behaves as a tumor suppressor when expressedand stimulated by its ligand somatostatin in pancreatic cancer. It was reveal a mechanismunderlying oncosuppressive action <strong>of</strong> sst2, whereby this inhibitory receptor upregulates theexpression <strong>of</strong> the secreted angioinhibitory factor thrombospondin-1 (TSP-1), asdemonstrated in exocrine BxPC-3 and endocrine BON pancreatic cancer cells. The sst2-dependent upregulation <strong>of</strong> TSP-1 occurs through the inhibition <strong>of</strong> the PI3K pathway. Itdepends on transcriptional and translational events, involving a previously undescribed IRESin the 5'-UTR <strong>of</strong> TSP-1 mRNA. Chick chorioallantoic membrane was used as an in vivomodel to demonstrate that TSP-1 is a critical effector <strong>of</strong> the inhibitory role <strong>of</strong> sst2 on theneoangiogenesis and oncogenesis induced by pancreatic cancer cells. TSP-1 reduced invitro tubulogenesis <strong>of</strong> endothelial cells when grown in conditioned medium from pancreaticcancer cells expressing sst2, as compared to those expressing the control vector. TSP-1inhibited tumor cell-induced neoangiogenesis by directly sequestering the proangiogenicfactor VEGF, and inactivating the angiogenesis initiated by VEGFR2 phosphorylation inendothelial cells. Using human pancreatic tissue-microarrays, the expression <strong>of</strong> both sst2and TSP-1 was shown to be correlated during the pancreatic neoplastic program. Bothproteins are nearly undetectable in normal exocrine pancreas and in most invasive cancerlesions, but their expression is strikingly upregulated in most preinvasive cancer-adjacentlesions. The upregulation <strong>of</strong> both sst2 and TSP-1 tumor suppressors may function as anearly negative feedback to restrain pancreatic carcinogenesis [398].SphingolipidsDefeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains achallenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improvingtumor chemosensitivity has recently emerged as a promising strategy. The fine balancebetween intracellular levels <strong>of</strong> the prosurvival sphingosine-1-phosphate (S1P) and theproapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control thismetabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed inmany cancers, favors survival through S1P production, and inhibitors <strong>of</strong> SphK1 are used inongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to variouschemotherapeutic drugs. It was reported that the cellular ceramide/S1P ratio is a criticalbiosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level <strong>of</strong> theceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsicpancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing theceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or smallinterfering RNA-based approaches to up-regulate intracellular ceramide levels or reduceSphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasingthe ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance inthese cells [399].

Synuclein-gammaPerineural invasion is associated with the high incidence <strong>of</strong> local recurrence and a dismalprognosis in pancreatic cancer. It was previously reported a novel perineural invasion modeland distinguished high- and low-perineural invasion groups in pancreatic cancer cell lines. Toidentify key biological markers involved in perineural invasion, differentially expressedmolecules were investigated by proteomics and transcriptomics. Synuclein-gamma emergedas the only up-regulated molecule in high-perineural invasion group by both analyses. Theclinical significance and the biological property <strong>of</strong> synuclein-gamma were examined in 62resected cases <strong>of</strong> pancreatic cancer and mouse models. Synuclein-gamma overexpressionwas observed in 38 (61 %) cases and correlated significantly with major invasive parameters,including perineural invasion and lymph node metastasis. Multivariate analyses revealedsynuclein-gamma overexpression as the only independent predictor <strong>of</strong> diminished overallsurvival and the strongest negative indicator <strong>of</strong> disease-free survival. In mouse perineuralinvasion and orthotopic transplantation models, stable synuclein-gamma suppression byshort hairpin RNA significantly reduced the incidence <strong>of</strong> perineural invasion and liver/lymphnode metastasis compared with the control. This study provides in vivo evidence thatsynuclein-gamma is closely involved in perineural invasion/distant metastasis and is asignificant prognostic factor in pancreatic cancer. Synuclein-gamma may serve as apromising molecular target <strong>of</strong> early diagnosis and anticancer therapy [400].Tyrosine kinasesThe tyrosine kinase (TK) gene family, which encodes important regulators <strong>of</strong> various signaltransduction pathways, is one <strong>of</strong> the most frequently altered gene families in human cancer.To clarify the somatic mutation pr<strong>of</strong>ile <strong>of</strong> TKs in pancreatic cancer, it was performed asystematic screening <strong>of</strong> mutations in the kinase domains <strong>of</strong> all human TK genes (636 exons<strong>of</strong> 90 genes in total) in 11 pancreatic cancer cell lines and 29 microdissected primary tumors.It was identified 15 nonsynonymous alterations that included 9 DNA alterations in cell linesand 6 somatic mutations in primary tumors. In particular, it was identified the previouslyreported pathogenic mutation <strong>of</strong> NTRK3 in a KRAS/BRAF wild-type tumor and 2 somaticmutations in the Src family <strong>of</strong> kinases (YES1 and LYN) that would be expected to causestructural changes [401].Urokinase-type plasminogen activatorThe serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) areknown to be involved in the invasion and metastasis <strong>of</strong> many solid tumors. In one study, itwas analyzed the role <strong>of</strong> the uPAR/uPA system in both the development and progression <strong>of</strong>pancreatic cancer in invasive ductal adenocarcinomas <strong>of</strong> the pancreas and theirpremalignant precursors (PanIN lesions) in 50 patients with long-term clinical follow-up. Itwas found overexpression <strong>of</strong> the uPAR in 48 <strong>of</strong> 50 invasive carcinomas as well as in a largeproportion <strong>of</strong> high-grade PanIN lesions by immunohistochemistry and in situ hybridization.Fluorescence in situ hybridization analysis showed both high- and low-level amplification <strong>of</strong>the uPAR gene in approximately 50 percent <strong>of</strong> cases with strictly identical patterns betweeninvasive cancers and their accompanying precursor lesions. These results suggest thatpancreatic cancer may develop from PanIN lesions along an alternative rather than asequential molecular pathway. The detection <strong>of</strong> the gene amplification <strong>of</strong> uPAR was a highlysignificant, adverse prognostic parameter because it likely renders the tumors more sensitiveto uPA and its proproliferative and anti-apoptotic signals. It was concluded that the activation<strong>of</strong> the uPAR/uPA system is an early event in the development <strong>of</strong> PDA and that uPAR geneamplifications identify a subgroup <strong>of</strong> particularly aggressive tumors [402].Pancreatic ductal adenocarcinoma expresses high levels <strong>of</strong> urokinase-type plasminogen

activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor (PAI)-2, which mayplay an important role in progression <strong>of</strong> pancreatic adenocarcinoma. The overexpression <strong>of</strong>uPAR predicted short survival in PDAC patients. In one study, two different PDAC cell lineswere used to examine the effect <strong>of</strong> small interfering (si) RNAs to uPAR, uPA and PAI-2 onproliferation, apoptosis, migration and MAP kinase activation. In both pancreatic cancer celllines, siRNA to uPAR significantly inhibited cell proliferation and migration and stimulatedapoptosis, to a greater extent than uPA siRNA. When either PDAC cell line was treated withuPAR siRNA, the level <strong>of</strong> phosphorylated ERK (p-ERK) decreased substantially, whereasphosphorylated p38 (p-p38) increased when compared to non-silencing control, uPA siRNAor PAI-2 siRNA treatment. This resulted in enhancement <strong>of</strong> the p-p38/p-ERK ratio whichfavors cancer cell arrest. Interestingly, uPAR protein expression was suppressed by p-ERKinhibition and stimulated with p-p38 inhibition, suggesting the presence <strong>of</strong> a positivefeedback loop between uPAR and ERK. In summary, the data indicate that, <strong>of</strong> the uPAsystem, uPAR exerts the strongest effects on pancreatic cancer cells, by acting through theERK signaling pathway via a positive feedback loop. Disruption <strong>of</strong> this loop with uPAR siRNAor inhibitor <strong>of</strong> p-ERK, inhibits PDAC proliferation and migration and promotes apoptosis[403].Vitamin DEcological studies support the hypothesis that there is an association between vitamin D andpancreatic cancer mortality, but observational studies are somewhat conflicting. It wascontributed further data to this issue by analyzing the differences in pancreatic cancermortality across the eastern states <strong>of</strong> Australia and investigating if there is a role <strong>of</strong> vitaminD-effective ultraviolet radiation (DUVR), which is related to latitude. Mortality data from 1968to 2005 were sourced from the Australian General Record <strong>of</strong> Incidence and Mortality books.Mortality from pancreatic cancer was 10 percent higher in southern states than inQueensland, with those in Victoria recording the highest mortality risk (relative risk, 1.13; 95% confidence interval, 1.09 to 1.17). It was found a highly significant association betweenDUVR and pancreatic cancer mortality, with an estimated 1.5 percent decrease in the riskper 10 kJ/m 2 increase in yearly DUVR. These data show an association between latitude,DUVR, and pancreatic cancer mortality. Although this study cannot be used to infer causality,it supports the need for further investigations <strong>of</strong> a possible role <strong>of</strong> vitamin D in pancreaticcancer etiology [404].ProteomicsThe purpose <strong>of</strong> one <strong>review</strong> was to describe progress in the application <strong>of</strong> proteomicapproaches to advance The understanding <strong>of</strong> the biology <strong>of</strong> pancreatic cancer as well ascontribute potential protein biomarkers for this disease. It was <strong>review</strong>ed proteomic studiesrelating to pancreatic cancer that have been published in the past 12 months. It wasdescribed novel techniques for the simplification <strong>of</strong> complex protein samples, focusingparticularly on emerging methods for reducing the complexity <strong>of</strong> blood. Both the range <strong>of</strong>proteomic-based approaches and their sensitivities for the detection <strong>of</strong> low-abundanceproteins has increased. This provides promise that further research will yield insight intopancreatic cancer, including valuable information on proteins that may ultimately serve asbiomarkers for pancreatic cancer [405].Proteomics from lymph node metastasesThe aim <strong>of</strong> one study was to observe different protein pr<strong>of</strong>iles in pancreatic cancer with andwithout lymph node metastasis (LNM), and search for novel LNM-associated proteins, whichwould help to understand the metastatic mechanisms and provide targets for therapeutic

interventions. Cancer nests were manually miscrodissected from 8 LNM and 7 non-LNMpancreatic cancer tissues, and the protein extracts were then separated by difference gelelectrophoresis (DIGE) and identified by MALDI-TOF-TOF. Four differently regulatedproteins, ezrin, radixin, moesin, and c14orf166, were selected for further validation byWestern blot and immunohistochemistry. In DIGE analysis, it was identified 18 up-regulatedproteins and 15 down-regulated proteins in LNM pancreatic cancer nests compared withnon-LNM ones. Western blot and immunohistochemical analyses confirmed that radixin,moesin and c14orf166, but not ezrin, had significantly higher expression levels in LNMpancreatic cancers than in non-LNM controls. In conclusion, the specific protein pr<strong>of</strong>ilesfound in this study might provide new insights into the mechanism <strong>of</strong> lymph node metastasis.For the first time, c14orf166 was identified asa novel metastasis-associated protein, and theroles <strong>of</strong> radixin, moesin and c14orf166 in cancer metastasis deserve further investigations[406].Familial pancreatic cancerApproximately 5-10 percent <strong>of</strong> individuals with pancreatic cancer report a history <strong>of</strong>pancreatic cancer in a close family member. In addition, several known genetic syndromes,such as familial breast cancer (BRCA2), the Peutz-Jeghers syndrome, and the familialatypical multiple mole melanoma syndrome, have been shown to be associated with anincreased risk <strong>of</strong> pancreatic cancer. The known genes associated with these conditions canexplain only a portion <strong>of</strong> the clustering <strong>of</strong> pancreatic cancer in families, and research toidentify additional susceptibility genes is ongoing. Even in the absence <strong>of</strong> predictive genetictesting, the collection <strong>of</strong> a careful, detailed family history is an important step in themanagement <strong>of</strong> all patients with pancreatic cancer. While most pancreatic cancers that arisein patients with a family history are ductal adenocarcinomas, certain subtypes <strong>of</strong> pancreaticcancer have been associated with familial syndromes. Therefore, the histologic appearance<strong>of</strong> the pancreatic cancer itself, and/or the presence and appearance <strong>of</strong> precancerouschanges in the pancreas, may increase the clinical index <strong>of</strong> suspicion for a genetic syndrome[407].It has been reported that germline mutations in the palladin gene cause the familialaggregation <strong>of</strong> pancreatic cancer (in Seattle), but the evidence is weak and controversial. Itwas sequenced the coding regions <strong>of</strong> palladin gene in 48 individuals with familial pancreaticcancer. It was not found any deleterious mutations and find no evidence to implicatemutations in palladin gene as a cause <strong>of</strong> familial pancreatic cancer [408].Histologic precursorsPancreatic intraepithelial neoplasia (PanIN) is a precursor to invasive ductal adenocarcinoma<strong>of</strong> the pancreas. Observations made in genetically engineered mouse models suggest thatthe acinar/centroacinar compartment can give rise to ductal neoplasia. To integrate findingsin mice and men, it was examined human acinar cells, acinar-ductal metaplasia (ADM)lesions, and PanINs for KRAS2 gene mutations. Surgically resected pancreata werescreened for foci <strong>of</strong> ADM with or without an associated PanIN lesion. Stromal cells, acinarcells, ADMs, and PanINs were separately isolated using laser capture microdissection.KRAS2 status was analyzed using genomic DNA isolated from the microdissected tissue.Twelve <strong>of</strong> these 31 foci <strong>of</strong> ADM occurred in isolation, whereas 19 were in the same lobulesas a PanIN lesion. All 31 microdissected foci <strong>of</strong> acinar cells were KRAS2 gene wild-type, aswere all 12 isolated ADM lesions lacking an associated PanIN. KRAS2 gene mutations werepresent in 14 <strong>of</strong> 19 (74 %) PanIN lesions and in 12 <strong>of</strong> the 19 (63 %) foci <strong>of</strong> ADM associatedwith these PanINs. All ADM lesions with a KRAS2 gene mutation harbored the identical

KRAS2 gene mutation found in their associated PanIN lesions. Ductal neoplasms <strong>of</strong> thehuman pancreas, as defined by KRAS2 gene mutations, do not appear to arise from acinarcells. Isolated AMD lesions are genetically distinct from those associated with PanINs, andthe latter may represent retrograde extension <strong>of</strong> the neoplastic PanIN cells or less likely areprecursors to PanIN [409].Experimental pancreatic cancerIn an effort to provide useful models for preclinical evaluation <strong>of</strong> new experimentaltherapeutics, it has been developed orthotopic mouse models <strong>of</strong> pancreatic cancer. Theutility <strong>of</strong> these models for pre-clinical testing is dependent upon quantitative, noninvasivemethods for monitoring in vivo tumor progression in real time. Toward this goal, it wasperformed whole-body fluorescence imaging and ultrasound imaging to evaluate and tocompare these noninvasive imaging modalities for assessing tumor burden and tumorprogression in an orthotopic mouse model <strong>of</strong> pancreatic cancer. Now whole-bodyfluorescence imaging and ultrasound imaging in the mice both allowed for the visualizationand measurement <strong>of</strong> orthotopic pancreatic tumor implants in vivo. The imaging sessionswere well-tolerated by the mice and yielded data which correlated well in the quantitativeassessment <strong>of</strong> tumor burden. Whole-body fluorescence and two-dimensional ultrasoundimaging showed a strong correlation for measurement <strong>of</strong> tumor size over a range <strong>of</strong> tumorsizes. The findings suggest a complementary role for fluorescence imaging and ultrasoundimaging in assessing tumor burden and tumor progression in orthotopic mouse models <strong>of</strong>human cancer [410].Early pancreatic cancerTumor cell migration along the periphery <strong>of</strong> blood vessels to remote sites has been termedextravascular migratory metastasis, which is distinct from direct gross tumor infiltration <strong>of</strong>blood vessels and from intravascular dissemination. A case report was presented whereEUS examination was performed with targeted fine-needle aspiration (FNA) <strong>of</strong> previouslyunrecognized perivascular cuffing by computed tomography, which established the presence<strong>of</strong> celiac axis malignant perivascular cuffing in the setting <strong>of</strong> a T1 pancreatic cancer [411].StagingA retrospective study was performed in 87 patients who underwent surgical resection forpancreatic cancer. Preoperative levels <strong>of</strong> tumor markers such as carbohydrate antigen 19-9(CA19-9) and duke pancreatic monoclonal antigen type 2 (DUPAN-2) were estimated andanalyzed in relation to disease-specific survival (DSS). The CA19-9 level did not correlatewith the DUPAN-2 level. Prognosis correlated with CA19-9 levels, and patients with 185U/mL or lower CA19-9 level showed significantly better disease-specific survival thanpatients with 186-U/mL or higher CA19-9 level. Patients with 151-800-U/mL DUPAN-2 levelshowed significantly worse DSS than patients with 801- U/mL or higher DUPAN-2 level, sothe prognosis was reversely related to the DUPAN-2 level. Patients with increased levels <strong>of</strong>both CA19-9 and DUPAN-2 showed significantly worse disease-specific survival than thepatients without elevated levels. The independent predictors <strong>of</strong> poor DSS (hazards ratio, 95% confidence interval) were the following: non-well-differentiated adenocarcinoma, invasion<strong>of</strong> the portal vein, and increased levels <strong>of</strong> both CA19-9 and DUPAN-2 [412].Recent years have brought important developments in preoperative imaging and use <strong>of</strong>laparoscopic staging <strong>of</strong> patients with pancreatic adenocarcinoma. There are few data about

the optimal combination <strong>of</strong> preoperative studies to accurately identify resectable patients.Therefore, it was conducted a statewide <strong>review</strong> <strong>of</strong> all patients with surgically managedpancreatic cancer from 1996 to 2003 using data from the Oregon State Cancer Registry,augmented with clinical information from primary medical record <strong>review</strong>. It was documentedthe use <strong>of</strong> all staging modalities, including CT, endoscopic ultrasonography, andlaparoscopy. Primary outcomes included resection with curative intent. The associationbetween staging modalities, clinical features, and resection was measured using amultivariate logistic regression model. There were 298 patients from 24 hospitals who metthe eligibility criteria. Patients were staged using a combination <strong>of</strong> CT (98 %), laparoscopy(29 %), and endoscopic ultrasonography (32 %). The overall proportion <strong>of</strong> patients who wentto surgical exploration and were resected was 87 percent. Of patients undergoing diagnosticlaparoscopy, metastatic disease that precluded resection was discovered in 24 (28 %). Forpatients who underwent diagnostic laparoscopy and were not resected, vascular invasionwas the most common determinant <strong>of</strong> unresectability (57 %). In multivariate analysis,preoperative weight loss and surgeon decision to use laparoscopy predicted unresectabilityat laparotomy. This population-based study demonstrates that surgeons appear to uselaparoscopy in a subset <strong>of</strong> patients at high risk for metastatic disease. The combination <strong>of</strong>current staging techniques is associated with a high proportion <strong>of</strong> resectability for patientstaken to surgical exploration. With current imaging modalities, selective application <strong>of</strong>laparoscopy with a dual-phase CT scan as the cornerstone <strong>of</strong> staging is a sound clinicalapproach to evaluate pancreatic cancer patients for potential resectability [413].Prognostic factorsThe purpose <strong>of</strong> one study was to determine the operative indications for pancreatic cancerwith paraaortic lymph node metastases (node 16+). Between 1981 and 2007, 335 patientswith pancreatic cancer including 45 node 16) patients underwent extended radical surgery.Although there was no significant difference in survival between the node 16+ patients andthe unresectable cases, there were some long-term survivors among the node 16+ patients.Multivariate analysis <strong>of</strong> the node 16+ patients identified age (59 years or younger), tumorsize (>4 cm), and pathologically confirmed portal invasion (pPV+) as independent prognosticfactors. The survival <strong>of</strong> node 16+ patients without these factors was significantly better thanthe unresectable cases. The survival <strong>of</strong> patients with only 1 metastatic paraaortic lymph nodealso was significantly better than the unresectable cases, and tended to be better than thosewith more than 2 metastatic nodes. It was concluded that node 16 + pancreatic cancerpatients with age 60 years or older, tumor size 4 cm or less, and pPV- may benefit fromresection [414].Pancreatic cancer diagnosing and stagingAlgorithmTo develop an algorithmic approach to the diagnosis <strong>of</strong> pancreatic neoplasms that simplifiestheir pathologic evaluation it was <strong>review</strong>ed <strong>literature</strong> related to the classification <strong>of</strong> pancreaticneoplasms on the basis <strong>of</strong> their gross, histologic, and immunohistochemical features. Byusing a series <strong>of</strong> dichotomous decisions, the differential diagnosis <strong>of</strong> a pancreatic neoplasmcan be narrowed, and in cases <strong>of</strong> the more common neoplasms, accurate classification canbe achieved [415].Tumor markersAggressive growth and metastases <strong>of</strong> pancreatic cancer are the result <strong>of</strong> basement

membrane degradation that may be attributed to the action <strong>of</strong> matrix metalloproteinase-9(MMP-9). The aim <strong>of</strong> one study was to determine the diagnostic and prognostic significance<strong>of</strong> the measurements <strong>of</strong> serum MMP-9 and tissue inhibitor <strong>of</strong> metalloproteinase-1 (TIMP-1) inpatients with pancreatic cancer. The study involved 78 patients with pancreatic cancer, 45with chronic pancreatitis, and 70 healthy subjects. It was assayed the serum concentrations<strong>of</strong> MMP-9, TIMP-1, and classic tumor markers (carbohydrate antigen 19-9 and CEA) anddefined the prognostic value and the diagnostic criteria for all the proteins tested. In thepatients with pancreatic cancer, the serum levels <strong>of</strong> MMP-9, TIMP-1, and the tumor markerswere higher as compared with those in the patients with chronic pancreatitis and the healthysubjects. The diagnostic sensitivity and the area under the receiver operating characteristiccurve for TIMP-1 were higher than for MMP-9 and the tumor markers. The elevatedpreoperative concentration <strong>of</strong> MMP-9 was a significant independent prognostic factor for thepatients' survival. The authors concluded that the findings indicated a potential clinicalsignificance <strong>of</strong> serum TIMP-1 and MMP-9 measurements in the diagnosis and prognosis <strong>of</strong>patients with pancreatic cancer, respectively [416].Contrast-enhanced ultrasonographyUltrasound is <strong>of</strong>ten the first examination performed in patients with suspicion <strong>of</strong> pancreaticdisease. The introduction <strong>of</strong> contrast-enhanced ultrasonography (CEUS) has led to greatdevelopments in the diagnostic capabilities <strong>of</strong> ultrasound. Dynamic observation <strong>of</strong> anenhancement allows a highly sensitive evaluation <strong>of</strong> any perfusion <strong>of</strong> the abdominal organs.Study <strong>of</strong> the pancreas is a new and promising application <strong>of</strong> CEUS, and can be used tocharacterize pancreatic lesions visible with conventional ultrasonography (US). One article<strong>review</strong>s the clinical and surgical applications <strong>of</strong> CEUS in different pancreatic diseases and intheir management [417].Contrast-enhanced ultrasound is a relatively new technique, currently used for liver tumorsdiagnosis. Newer contrast agents are composed <strong>of</strong> stabilized micro-bubbles capable <strong>of</strong>traversing the capillary circulation. Lately, the method has also been used in the assessment<strong>of</strong> pancreatic disorders. Pulse inversion harmonic imaging allows the assessment <strong>of</strong> thehypervascularised masses as neuroendocrine tumors, <strong>of</strong> the hypoperfused masses asadenocarcinomas and <strong>of</strong> the necrotic areas in acute pancreatitis. Also, this imaging methodallows a better assessment <strong>of</strong> the pancreatic tumor resectability and the identification <strong>of</strong>septa inside the cystic lesion. Contrast-enhanced ultrasound might represent a valuableadditional imaging method to contrast CT for selected cases [418].Endoscopic ultrasonographyThe main objective in the management <strong>of</strong> pancreatic cancer is to perform an early diagnosisand a correct staging <strong>of</strong> the disease. Endoscopic ultrasonography (EUS) appears to be anessential tool for the diagnosis and staging <strong>of</strong> pancreatic cancer. EUS diagnostic accuracyfor detecting pancreatic tumors ranges from 85 to 100 percent, clearly superior to otherimaging techniques. EUS accuracy for the local staging <strong>of</strong> pancreatic cancer ranges from 70to 90 percent, superior or equivalent to other imaging modalities. EUS-guided fine-needleaspiration allows a cyto-histological diagnosis in nearly 90 percent <strong>of</strong> cases, with a very lowcomplication rate. At present, the formal indications for EUS-guided fine-needle aspirationare the necessity <strong>of</strong> palliative treatment or whenever the possibility <strong>of</strong> neoadjuvant treatmentis present. It could be also indicated to differentiate pancreatic adenocarcinoma from otherpancreatic conditions, like lymphoma, metastasis, autoimmune pancreatitis or chronicpancreatitis [419].Endoscopic ultrasound (EUS) has become well established as a diagnostic modality ingastrointestinal cancer staging. It <strong>of</strong>fers high-resolution imaging and fine-needle biopsy,

which is essential in tumor and nodal staging <strong>of</strong> gastrointestinal cancers. In the recentdecade, however, many therapeutic applications <strong>of</strong> EUS have become possible. Currently,interventional EUS endoscopy involves celiac plexus neurolysis, pseudocyst drainage, andintratumoral fine-needle injection therapy for inoperable pancreatic malignancy. Emergingtechniques include the accurate endoscopic delivery <strong>of</strong> radioactive beads to localize tumortherapy as well as other therapies, such as radi<strong>of</strong>requency ablation or cryotherapy.Diagnostic and therapeutic access to the biliary tree and pancreatic duct is increasingly beingused successfully in failed endoscopic retrograde cholangiopancreatography (ERCP)procedures. A <strong>review</strong> discusses these procedures and several evolving future applications,including vascular access and EUS-guided enteral anastomosis [420].The role <strong>of</strong> EUS to evaluate subtle radiographic abnormalities <strong>of</strong> the pancreas is not welldefined. To assess the yield <strong>of</strong> EUS + FNA for focal or diffuse pancreaticenlargement/fullness seen on abdominal CT scan in the absence <strong>of</strong> discrete mass lesions aretrospective database <strong>review</strong> <strong>of</strong> 691 pancreatic EUS exams were <strong>review</strong>ed. Sixty-nine metinclusion criteria <strong>of</strong> having been performed for focal enlargement or fullness <strong>of</strong> the pancreas.Known chronic pancreatitis, pancreatic calcifications, acute pancreatitis, discrete mass onimaging, pancreatic duct dilation (greater than 4 mm) and obstructive jaundice wereexcluded. FNA was performed in 19/69 (28 %) with 4 new diagnoses <strong>of</strong> pancreaticadenocarcinoma, one metastatic renal cell carcinoma, one metastatic colon cancer, onechronic pancreatitis and 12 benign results. Eight patients had discrete mass lesions on EUS;two were cystic. All malignant diagnoses had a discrete solid mass on EUS. It was concludedthat pancreatic enlargement/fullness is <strong>of</strong>ten a benign finding related to anatomic variation,but was related to malignancy in 9 percent <strong>of</strong> these patients (6/69). EUS should be stronglyconsidered as the next step in the evaluation <strong>of</strong> patients with focal enlargement <strong>of</strong> thepancreas when clinical suspicion <strong>of</strong> malignancy exists [421].Hyperechogenic pancreas suggestive <strong>of</strong> fatty replacement is a common finding duringendoscopic ultrasound. Recent data have implicated pancreatic steatosis as a risk factor forpancreatitis and pancreatic malignancy. Hepatic steatosis has been linked to obesity,increased age, hypertriglyceridemia, hyperglycemia, and hyperinsulinemia. The objective <strong>of</strong>one study was to evaluate the effect <strong>of</strong> body mass index (BMI), hepatic steatosis, and othermetabolic risk factors on HP seen on EUS. Patients with hyperechogenic pancreas wereidentified by a <strong>review</strong> <strong>of</strong> a structured EUS database. The degree <strong>of</strong> echogenicity was judgedrelative to the liver (or spleen if the liver is hyperechogenic) at a similar depth. Variousdemographic and metabolic risk factors were assessed. Chronic pancreatitis was excludedbased on normal findings on prior imaging studies. Each case was age matched and sexmatched to 1 control with a normal pancreas on EUS. By multivariate logistic regressionanalysis, BMI, hepatic steatosis, and alcohol use in excess <strong>of</strong> 14 g/wk were highly associatedwith the presence <strong>of</strong> hyperechogenic pancreas compared with controls. Hepatic steatosiswas the strongest predictor with an odds ratio <strong>of</strong> nearly 14-fold [422].Endoscopic ultrasound-guided fine-needle aspiration biopsiEndoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an effective method forproviding tissue diagnosis, but problems occur when lesions are small or the cytologicaldiagnosis is indeterminate. To prospectively evaluate the utility <strong>of</strong> EUS-FNA in patients withsmall solid pancreatic lesions and those with initial indeterminate or negative cytologicaldiagnosis a total <strong>of</strong> 119 EUS-FNA procedures on 46 patients (mean age 56 years) for 47small solid pancreatic lesions (range 7-30 mm, mean 17 mm in diameter) were studied.FNAs were performed in the presence <strong>of</strong> a cytopathologist. If cytological diagnoses wereindeterminate, EUS-FNA was repeated within 3 weeks. Diagnoses were confirmedhistologically or by follow-up (clinical and imaging: EUS + FNA and CT). On average, 3.7passes were performed. It was not observed any complications. Initial cytological findingswere: malignant 17 (36 %), benign 21 (45 %), and indeterminate 9 (19 %). Eight (78 %) <strong>of</strong>

the indeterminate findings were confirmed to be malignant on repeated procedures. Adiagnosis <strong>of</strong> pancreatic cancer was subsequently confirmed in 1 patient who had a benigncytological finding. Nineteen patients underwent surgery. Histology confirmed a neoplasm inall cases. Sensitivity, specificity, positive predictive value, negative predictive value anddiagnostic accuracy were 68, 100, 100, 73 and 83 percent, respectively. After repeated EUS-FNAs <strong>of</strong> indeterminate findings sensitivity, negative predictive value and diagnostic accuracyrose to 92, 77 and 96 perent, respectively [423].Patients presenting with suspected pancreatic neoplasm based on a focal pancreatic lesionon computed tomographic (CT) scan/magnetic resonance image (MRI) but withoutobstructive jaundice were evaluated by endoscopic ultrasound-guided fine needle aspiration(EUS-FNA) in a retrospective analysis <strong>of</strong> a prospective database. Patients were excluded ifthey had obstructive jaundice or the lesion appeared cystic on CT/MRI. In the 213 studypatients, a focal pancreatic lesion was identified in 173 patients by EUS. The final diagnosisincluded adenocarcinoma (n=89), neuroendocrine tumor (n=14), solid pseudopapillary tumor(n=2), metastases (n=4), mucinous cystadenocarcinoma (n=1), benign cyst (n=19),pseudocyst (n=9), abscess (n=4), chronic pancreatitis (n=32), and normal pancreas (n=39).Endoscopic ultrasound-guided FNA had an accuracy <strong>of</strong> 98 percent for diagnosing malignantneoplasm, with 97 percent sensitivity, 99 percent specificity, 96 percent negative predictivevalue, and 99 percent positive predictive value. The authors concluded that endoscopicultrasound-guided FNA is highly accurate for diagnosing malignancy in patients with a focalpancreatic lesion on CT scan/MRI but without obstructive jaundice. Endoscopic ultrasoundguidedFNA can potentially be used as a definitive diagnostic test in the management <strong>of</strong>these patients [424].It was prospectively evaluated the diagnostic accuracy and major complications <strong>of</strong> EUSguidedfine needle aspiration (EUS-FNA) in a newly developed EUS program. All procedureswere performed by a single endosonographer in the presence <strong>of</strong> a cytopathologist.Reference standard for classification <strong>of</strong> final disease included: surgical resection, death fromdisease progression and repeat radiologic and/or clinical follow-up. Major complications weredefined as oversedation, and those that resulted in a physician or emergency departmentvisits, hospitalization, or death. 540 patients (median age 63 years) underwent EUS-FNAs <strong>of</strong>656 lesions: lymph nodes (n=248), solid pancreatic masses (n=229), cystic pancreaticmasses (n=57), mural lesions (n=41), bile duct/gallbladder (n=28), liver (n= 17),mediastinum/lung (n=17), adrenal (n=15), spleen (n=3) and kidney (n=1). Solid pancreaticmasses and bile duct/gallbladder lesions were more likely to have suspicious/atypicalcytology when compared to other lesions (9 vs 5 %) and required significantly more passesto achieve a tissue diagnosis. The overall sensitivity, specificity, PPV, NPV and accuracy <strong>of</strong>EUS-FNA was 92, 97, 98, 88 and 94 percent, respectively. Six patients (1 %) experienced amajor complication. One patient died shortly after the procedure due to preexistingpulmonary embolus (0.18 %) [425].Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) can characterize anddiagnose pancreatic lesions as malignant, but cannot definitively rule out the presence <strong>of</strong>malignancy. To determine the long-term outcome and provide follow-up guidance for patientswith negative EUS-FNA diagnosis <strong>of</strong> suspected pancreatic lesions based on imagingpredictors a retrospective <strong>review</strong> <strong>of</strong> patients undergoing EUS-FNA for suspected pancreaticlesions, but with negative or nondiagnostic FNA results was conducted. Seventeen <strong>of</strong> 55patients (31 %) with negative/nondiagnostic FNA were subsequently diagnosed withpancreatic malignancy. The risk <strong>of</strong> cancer was significantly higher for patients who hadassociated lymph nodes on EUS and vascular involvement on EUS. The mean time todiagnosis in the group with falsenegative EUS-FNA diagnosis was 66 days. The truenegativeEUS-FNA patients were followed for a mean <strong>of</strong> 403 days after negative EUS-FNAresults without the development <strong>of</strong> malignancy. It was concluded that for patients undergoingEUS-FNA for a suspected pancreatic lesion, a negative or nondiagnostic FNA does not

provide conclusive evidence for the absence <strong>of</strong> cancer. Patients for whom vascular invasionand lymphadenopathy are detected on EUS are more likely to have a true malignant lesionand should be followed closely. When a patient has been monitored for six months or morewith no cancer being diagnosed, there appears to be much less chance that a pancreaticmalignancy is present [426].It was also described an acute hemorrhage with retroperitoneal hematoma after endoscopicultrasound-guided fine-needle aspiration <strong>of</strong> an intraductal papillary mucinous neoplasm <strong>of</strong> thepancreas [427].Endoscopic ultrasound-guided trucut biopsyEndoscopic ultrasound-guided trucut biopsy (EUS-TCB) technique has the advantage <strong>of</strong>obtaining tissue for histological examination rather than for cytology alone. However, thediagnostic yield may depend on factors related to both technical aspects and the lesionssampled. Safety <strong>of</strong> EUS-TCB is yet to be established in a large number <strong>of</strong> procedures. Theaim <strong>of</strong> one study was to determine factors predicting a positive diagnostic yield, and safetyfor EUS-TCB in a large tertiary referral center-based service. All patients were referred forEUS-guided tissue sampling as a part <strong>of</strong> their diagnostic workup. Linear-arrayechoendoscope (GF-2000-OL5, KeyMed) with a 19-gauge trucut needle (Quick-Core,Wilson-Cook) was used by two operators to obtain tissue samples. In total, 247 patients (143men) aged 57-73 (median 66) had EUS-TCB performed. Lesions sampled were in thepancreas (113), esophagogastric wall (34), and extra-pancreatic areas (100) (lymph nodes:52). The maximum diameter <strong>of</strong> the lesion/wall thickness ranged from 0.6 to 5.4 cm (median3). One to five passes were made (median 3) to obtain tissue cores 2-18 mm (median 10) inlength. The procedure failed in 6 percent <strong>of</strong> cases. The overall diagnostic accuracy was 75percent. The overall complication rate was 2 percent (bronchopneumonia, minor hemoptysis,minor hematemesis, mucosal tear, retropharyngeal abscess) with no procedure-relateddeaths. Site <strong>of</strong> lesion (pancreatic vs extra-pancreatic), site <strong>of</strong> biopsy (stomach vs duodenumvs esophagus), and number <strong>of</strong> passes (2) were signifikant predictors <strong>of</strong> a positivediagnostic yield in univariate analysis. However, only the site <strong>of</strong> biopsy and number <strong>of</strong>passes were independent predictors in multinominal logistic regression. It was concludedthat the diagnostic yield <strong>of</strong> EUS-TCB is higher when lesion is approached through thestomach and better when more than two passes were made. In this large series, thecomplication rate <strong>of</strong> 2 percent associated with EUS-TCB was similar to that reported withEUS-fine needle aspiration technique [428].Computed tomographyFatty infiltration <strong>of</strong> the pancreas is generally a diffuse process; however, it may be unevenlydistributed in the pancreas. Focal fatty infiltration <strong>of</strong> the pancreas is usually most prominentin the anterior aspect <strong>of</strong> the head <strong>of</strong> the pancreas and seen as a region <strong>of</strong> decreasedattenuation on computed tomography and may simulate pancreatic neoplasm. It may bediscussed and illustrated the various features <strong>of</strong> focal fatty infiltration <strong>of</strong> the pancreas onmultidetector row helical computed tomography with multiplanar reformation images andshow how this imaging modality helps to differentiate between focal fatty infiltration <strong>of</strong> thepancreas and actual pancreatic tumors [429].Fatty infiltration <strong>of</strong> the pancreas is generally a diffuse process; however, it may be unevenlydistributed in the pancreas. Focal fatty infiltration <strong>of</strong> the pancreas is usually most prominentin the anterior aspect <strong>of</strong> the head <strong>of</strong> the pancreas and seen as a region <strong>of</strong> decreasedattenuation on computed tomography and may simulate pancreatic neoplasm. It wasdiscussed and illustrated the various features <strong>of</strong> focal fatty infiltration <strong>of</strong> the pancreas onmultidetector row helical computed tomography with multiplanar reformation images and

show how this imaging modality helps to differentiate between focal fatty infiltration <strong>of</strong> thepancreas and actual pancreatic tumors [430].EUS versus CTTo compare the performances <strong>of</strong> EUS to helical CT in the diagnosis and staging <strong>of</strong>pancreatic adenocarcinoma 42 consecutive patients (mean age 63 years; 25 men) who hadsurgical exploration and histologically proved pancreatic cancer were retrospectivelyincluded. All the patients underwent with endoscopic ultrasonography (EUS) and helicalcomputed tomography (CT). Data analysis compared helical CT, EUS with the surgical datawith or without histological study in diagnosis, staging and resectability <strong>of</strong> pancreatic cancer.Surgical findings were used as gold standard. For positive diagnosis EUS was moresensitive 100 percent (95 % confidence interval 93 to 100) than helical CT 88 percent (77 to95). However, helical CT was more specific 89 percent (64 to 98) than EUS 83 percent (58 to96) for small tumors whose diameter is below 2.5 cm in witch EUS was more sensitive intheir detection (100 % vs 83 %). In evaluating venous involvement EUS was significantlymore sensitive than helical CT (96 % vs 50 %), while CT was significantly more specific (81% vs 75 %). Regarding lymph nodes invasion, the two imaging technique had the samesensibility (56 %) with better specificity for helical CT (83 % vs 75 %). The accuracy <strong>of</strong> EUSin identifying the T and N stages were 80 and 67 percent, respectively, while helical CT havean accuracy <strong>of</strong> 50 and 71 percent, respectively. EUS and helical CT correctly identified allresectable tumors while EUS was more accurate than helical CT in detecting non resectabletumors 94 percent versus 69 percent. It was concluded that EUS remains superior to helicalCT in positive diagnosis <strong>of</strong> pancreatic adenocarcinoma especially for small tumors and als<strong>of</strong>or the diagnosis <strong>of</strong> venous invasion and in identifying non resectable tumors. The twotechniques have the same accuracy in the detection <strong>of</strong> lymph node involvement [431].For evaluation <strong>of</strong> cytotoxic treatmentResponse Evaluation Criteria in Solid Tumors (RECIST) guidelines assume spherical shape<strong>of</strong> tumors. Morphology <strong>of</strong> pancreatic adenocarcinoma (PAC) on multidetector row computedtomography was investigated to evaluate the applicability <strong>of</strong> RECIST guidelines. Studypopulation comprised 16 patients with histologically confirmed localized PAC enrolled in aphase II clinical trial <strong>of</strong> chemoradiation. Pancreatic adenocarcinomas were segmented onbaseline and follow-up multidetector row computed tomography with commercially availables<strong>of</strong>tware. Tumor volumes (mL), RECIST diameter (mm), volume equivalent sphere diameter(VESD, mm), maximum 3-dimensional diameter (M3DD, mm), and elongation value wereobtained. RECIST diameter, VESD and M3DD <strong>of</strong> the tumors at baseline and follow-up werecompared to determine differences. Elongation values were analyzed. Mean volume,RECIST diameter, VESD, M3DD, and elongation for baseline versus follow-up studies were23.12 mL versus 19.43 mL, 41.86 mm versus 39.35 mm, 33.14 mm versus 32.1 mm, 51.76mm versus 51.73 mm, and 0.67 versus 0.76, respectively. There was a significant differenceat baseline and follow-up between RECIST diameter, VESD, and M3DD. The results suggestthat pancreatic cancers are not spherical in shape. Evaluation <strong>of</strong> PAC treatment responsebased on RECIST guidelines may not be accurate [432].A prospective study to determine the value <strong>of</strong> multidetector CT (MD-CT) in assessing thecourse <strong>of</strong> nonresectable pancreatic carcinoma during therapy was performed in 26 patientswith nonresectable pancreatic carcinoma underwent MD-CT before and after therapy. Theexaminations were evaluated with regard to tumor size and vascular invasion using aninvasion score (IS) by 2 radiologists independently. Diagnosis was confirmed surgically, bybiopsy or clinical course. Sensitivity for the assessment <strong>of</strong> irresectability was 100 percent.Following therapy, 54 percent <strong>of</strong> all the tumors were smaller (14/26), 42 percent hadincreased in volume (11/26), and one tumor remained stable (1/26). The IS (veins) duringfollow-up changed in 26 patients (portal vein: 5 higher, 4 lower; superior mesenteric vein: 12higher, 5 lower). The IS (arteries) changed in 13 patients (celiac trunk: 3 higher; hepaticartery: 4 higher, 3 lower; superior mesenteric artery: 2 higher, 1 lower). It was concluded that

MD-CT is suitable for evaluating tumor spread during therapy for nonresectable pancreaticcarcinoma. The IS is useful for assessing the impact on the veins and arteries, i.e. degree <strong>of</strong>change in vessel invasion [433].After neoadjuvant treatmentTo evaluate the effect <strong>of</strong> neoadjuvant combined chemotherapy and radiation therapy (CCRT)on preoperative accuracy <strong>of</strong> multidetector computed tomography (CT) for resectability andtumor staging in patients with pancreatic head cancer from 2002 to 2007,38 patients withpancreatic head adenocarcinoma underwent multidetector CT before surgery. Of these, 12patients received neoadjuvant CCRT. The accuracy in determining resectability was 83percent (10 <strong>of</strong> 12) in patients who had received neoadjuvant CCRT and 81 percent (21 <strong>of</strong> 26)in patients who had not. Of 32 patients who underwent pancreaticoduodenectomy,histopathologic tumor staging was reported for T1 (n=2), T2 (n=1), and T3 (n=9) lesions inpatents with neoadjuvant CCRT (n=12), and for T3 in all patients without neoadjuvant CCRT(n=20). T-staging accuracy was 67 percent (eight <strong>of</strong> 12) with neoadjuvant CCRT and 95percent (19 <strong>of</strong> 20) without it, which is a significant difference. This means that neoadjuvantCCRT reduces the accuracy <strong>of</strong> tumor restaging after treatment <strong>of</strong> pancreatic head cancer,but this effect is not so great as to affect the determination <strong>of</strong> resectability [434].PET-CTThe purpose <strong>of</strong> one study was to evaluate the diagnostic usefulness <strong>of</strong> PET/CT forpancreatic malignancy. It was retrospectively analyzed medical records <strong>of</strong> 115 patients withpathologically diagnosed pancreatic cancer between 2003 to 2008 who underwentabdominal CT and PET/CT examination before histological confirmation. CT and PET/CTimages were <strong>review</strong>ed in single-blinded status and diagnostic ability on primary pancreaticlesion, regional lymph node metastasis, and distant metastasis was evaluated. Ninety-ninepatients (86 %) had malignant diseases including 91 cases <strong>of</strong> adenocarcinoma, and 16patients (14 %) benign diseases. Only CA 19-9 value and SUV were significantly differentbetween PET/CT positive and negative groups. Sensitivity, specificity and positive predictivevalues (PPV) <strong>of</strong> both modality for pancreatic lesion were same (94 %, 62 %, and 95 %,respectively), and negative predictive values (NPV) were 67 percent on CT and 57 percenton PET/CT. PET/CT correctly diagnosed 8 cases (7 %) <strong>of</strong> falsely diagnosed pancreaticlesion on CT. Nine cases (16 %) <strong>of</strong> misdiagnosed lymph node metastasis on CT werecorrectly diagnosed on PET/CT. But, there was no significant difference in the diagnosis <strong>of</strong>regional lymph node metastasis. Three out <strong>of</strong> 29 cases <strong>of</strong> distant metastasis, except 2 cases<strong>of</strong> supraclavicular lymph node metastasis, were additionally diagnosed by PET/CT. But,overall sensitivity <strong>of</strong> distant metastasis was significantly higher in CT (83 % vs 69 %).Although PET/CT provided additional correct diagnoses in many cases, it showed fairdiagnostic power for primary pancreatic lesion and lymph node metastasis, and lowersensitivity for distant metastasis. Therefore, PET/CT should be used as an supplementarymodality <strong>of</strong> CT in diagnosing pancreatic malignancy [435].Magnetic resonance imaging (MRI)To compare diffusion-weighted imaging (DWI) findings and the apparent diffusion coefficient(ADC) values <strong>of</strong> pancreatic cancer, mass-forming focal pancreatitis (FP), and the normalpancreas DWI (b = 0 and 600 seconds/mm 2 ) findings <strong>of</strong> 14 patients with mass-forming FPproven by histopathology and or clinical follow-up, 10 patients with histopathologically-provenpancreatic cancer, and 14 subjects with normal pancreatic exocrine function and normalimaging findings were retrospectively evaluated. ADC values <strong>of</strong> the masses, the remainingpancreas, and the normal pancreas were measured. On b = 600 seconds/mm 2 DWI, massformingFP was visually indistinguishable from the remaining pancreas whereas pancreaticcancer was hyperintense relative to the remaining pancreas. The mean ADC value <strong>of</strong>

pancreatic cancer was significantly lower than the remaining pancreas, mass-forming FP andpancreatic gland in the control group. There was no significant difference <strong>of</strong> ADC valuesbetween the mass-forming focal pancreatitis and the remaining pancreas. It was concludedthat differences on DWI may help to differentiate pancreatic cancer, mass-forming fokalpancreatitis, and normal pancreas from each other [436].To determine whether the degree <strong>of</strong> enhancement <strong>of</strong> pancreatic adenocarcinoma visualizedon arterial phase gadolinium-enhanced magnetic resonance imaging (MRI) correlates withthe histopathological tumor grade 39 patients with pancreatic adenocarcinoma had MRIwithin 14 days before tumor resection. Gadolinium-chelate-enhanced 3-dimensional gradientecho images were acquired including the arterial phase. Tumor imaging patterns on thearterial phase images were classified for low, moderate, or high degree <strong>of</strong> enhancement andcompared against conventional histological grading. Based on histological grading, therewere 12 poorly differentiated, 2 poorly to moderately differentiated, 22 moderatelydifferentiated, and 3 well-differentiated adenocarcinomas. There was agreement between theMRI arterial enhancement pattern and histological grading in 30 <strong>of</strong> 39 cases. The mean size<strong>of</strong> tumors grouped by enhancement pattern or grade was not significantly different betweengroups. Although minor discordance was found in 9 <strong>of</strong> the 39 cases, statistical analysisshowed agreement between the degree <strong>of</strong> arterial enhancement on MRI and histologicaltumor differentiation [437].The purpose <strong>of</strong> one study was to investigate whether, at dynamic MRI <strong>of</strong> the upperabdominal organs, contrast enhancement with gadoxetic acid, a hepatobiliary contrast agent,is comparable with that achieved with an extracellular contrast agent. Dynamic gadoxeticacid-enhanced MRI <strong>of</strong> the pancreas, spleen, kidney, liver, and abdominal aorta wasperformed on 50 patients; dynamic gadobutrol-enhanced MRI was performed on a controlgroup <strong>of</strong> 50 patients; and the images were compared. Dynamic imaging with a T1-weightedvolumetric interpolated breath-hold examination gradient-echo sequence (TR/TE, 3.35/1.35;flip angle, 12 degrees) was performed before and 20 (arterial phase), 55 (portal venousphase), and 90 (hepatic venous phase) seconds after bolus injection <strong>of</strong> gadoxetic acid (0.25mmol/mL) or gadobutrol (1.0 mmol/mL). Signal-to-noise ratios and enhancement indexeswere calculated for each organ and time. All MR images in both groups were <strong>of</strong> diagnosticquality. During the early dynamic phases, significantly lower mean enhancement indexeswere found in the gadoxetic acid group than in the gadobutrol group in the pancreas, spleen,renal cortex, and liver. In the abdominal aorta, the mean enhancement index was greaterafter bolus injection <strong>of</strong> gadoxetic acid. It was concluded that early dynamic MRI <strong>of</strong> the upperabdominal organs, especially the spleen, pancreas, and kidney, benefits from the highergadolinium concentration <strong>of</strong> gadobutrol than in the organ-specific contrast agent gadoxeticacid. Higher protein binding resulting in increased relaxivity <strong>of</strong> gadoxetic acid compensatesfor the low gadolinium concentration in the abdominal aorta [438].Perfusion-weighted magnetic resonance imaging can detect the changes <strong>of</strong> signal intensityin tumors. It was evaluated the prognostic value <strong>of</strong> perfusion-weighted MRI in 27 consecutivepatients with advanced pancreatic cancer. The American Joint Committee on Cancer (AJCC)stages <strong>of</strong> patients were as follows (8, stage III; 19, stage IV). Imaging acquisition wascontinually repeated with echo planar sequence every 2 seconds for 2 minutes after a bolusinjection <strong>of</strong> gadolinium. All cases showed transient decreases signal intensity (SR, 7-56 %).These patients were classified into 2 groups at cut<strong>of</strong>f median SR <strong>of</strong> 22 percent. The high SRgroup significantly correlated with the higher stage and the presence <strong>of</strong> lymph nodemetastasis. The high SR group had significantly shorter overall survival [439].Our current understanding <strong>of</strong> intrafraction pancreatic tumor motion due to respiration islimited. In one study, it was characterized pancreatic tumor motion and evaluated theapplication <strong>of</strong> several radiotherapy motion management strategies. Seventeen patients withunresectable pancreatic cancer were enrolled in a prospective internal <strong>review</strong> board-

approved study and imaged during shallow free-breathing using cine MRI on a 3T scanner.Tumor borders were agreed on by a radiation oncologist and an abdominal MRI radiologist.Tumor motion and correlation with the potential surrogates <strong>of</strong> the diaphragm and abdominalwall were assessed. These data were also used to evaluate planning target volume marginconstruction, respiratory gating, and four-dimensional treatment planning for pancreatictumors. Tumor borders moved much more than expected. To provide 99 percent geometriccoverage, margins <strong>of</strong> 20 mm inferiorly, 10 mm anteriorly, 7 mm superiorly, and 4 mmposteriorly are required. Tumor position correlated poorly with diaphragm and abdominal wallposition, with patient-level Pearson correlation coefficients <strong>of</strong> -0.18-0.43. Sensitivity andspecificity <strong>of</strong> gating with these surrogates was also poor, at 53-68 percent, with overall error<strong>of</strong> 35-38 percent, suggesting that the tumor may be underdosed and normal tissuesoverdosed. Motion <strong>of</strong> pancreatic tumor borders is highly variable between patients and largerthan expected. There is substantial deformation with breathing, and tumor border positiondoes not correlate well with abdominal wall or diaphragmatic position. Current motionmanagement strategies may not account fully for tumor motion and should be used withcaution [440].MRCPTo determine the diagnostic accuracy <strong>of</strong> combined magnetic resonance cholangiopancreatography(MRCP) and computed tomography (CT) for preoperative diagnosis <strong>of</strong>Mirizzi syndrome 52 patients with surgically proven Mirizzi syndrome (n=13) and cholecystitiswithout evidence for Mirizzi syndrome (n=39) underwent both MRCP using single-shot turbospin echo and 3-dimensional turbo spin echo sequences and CT. Two blinded observersindependently and retrospectively <strong>review</strong>ed the combination <strong>of</strong> MRCP and CT images andCT images alone. The overall sensitivity, specificity, positive and negative predictive values,and accuracy <strong>of</strong> the combination <strong>of</strong> MRCP and CT were 96, 94, 84, 99, and 94 percent,respectively. Corresponding values <strong>of</strong> CT were 42, 99, 93, 84, and 85 percent, respectively.The sensitivity, negative predictive value, and accuracy <strong>of</strong> combined protocol weresignificantly higher than those <strong>of</strong> CT alone. It was concluded that the combination <strong>of</strong> MRCPand CT is useful for preoperative diagnosis <strong>of</strong> Mirizzi syndrome [441].ElastographIt was investigated the feasibility <strong>of</strong> using real-time tissue elastography (EG) withtranscutaneous ultrasonography (EG-US) for pancreatic diseases. A preliminary study(phase I) and a prospective (phase II) study were conducted. Phase I: subjects were 10volunteers, 5 with cancer, 2 with endocrine tumor, 5 with chronic pancreatitis, 14 withintraductal papillary-mucinous neoplasm. To determine the characteristic EG images(diagnostic criteria for phase II), B-mode images were compared with EG images andhistopathologic findings. Phase II: 53 consecutive patients were enrolled. The visualizationrate by EG-US in lesions visualized by B mode was assessed, and the correct diagnosis rateby B mode alone (B diagnosis) or in combination with EG-US was evaluated. Phase Ishowed normal parenchyma with a homogeneous color. In cancer, EG-US showed amarkedly hard area with s<strong>of</strong>t spots inside. Endocrine tumor was uniform and s<strong>of</strong>t comparableto parenchyma. Chronic pancreatitis showed a mixture <strong>of</strong> various colors. In phase II it wasidentified 77 percent (41/53) <strong>of</strong> the lesions and observed 60 percent <strong>of</strong> the (15/25) <strong>of</strong> thecancers, 3/3 <strong>of</strong> the endocrine tumor, and 92 percent (23/25) <strong>of</strong> the cases <strong>of</strong> chronicpancreatitis cases on EG-US. The B-diagnosis rates ranged from about 70 to 80 percent.The diagnosis rates <strong>of</strong> the combination were more than 90 percent <strong>of</strong> lesions <strong>of</strong> each type[442].To evaluate the ability <strong>of</strong> endoscopic ultrasound elastography to distinguish benign frommalignant pancreatic masses and lymph nodes a multicenter study was conducted andincluded 222 patients who underwent EUS examination with assessment <strong>of</strong> a pancreatic

mass (n=121) or lymph node (n=101). The classification as benign or malignant, based onthe real time elastography pattern, was compared with the classification based on the B-mode EUS images and with the final diagnosis obtained by EUS-guided fine needleaspiration (EUS-FNA) and/or by surgical pathology. An interobserver study was performed.The sensitivity and specificity <strong>of</strong> EUS elastography to differentiate benign from malignantpancreatic lesions are 92 and 80 percent, respectively, compared to 92 percent and 69percent, respectively, for the conventional B-mode images. The sensitivity and specificity <strong>of</strong>EUS elastography to differentiate benign from malignant lymph nodes was 92 percent and 83percent, respectively, compared to 79 percent and 50 percent, respectively, for the B-modeimages. The kappa coefficient was 0.785 for the pancreatic masses and 0.657 for the lymphnodes. EUS elastography is superior compared to conventional B-mode imaging andappears to be able to distinguish benign from malignant pancreatic masses and lymph nodeswith a high sensitivity, specificity and accuracy. It might be reserved as a second lineexamination to help characterise pancreatic masses after negative EUS-FNA and mightincrease the yield <strong>of</strong> EUS-FNA for lymph nodes [443].MetabolomicsObesity is a worldwide epidemic and a significant risk factor for pancreatic diseases includingpancreatitis and pancreatic cancer; the mechanisms underlying this association areunknown. Metabolomics is a powerful new analytical approach for describing themetabolome (compliment <strong>of</strong> small molecules) <strong>of</strong> cells, tissue or bi<strong>of</strong>luids at any given time.The aim was now to analyze pancreatic fat content in lean and congenitally obese miceusing both metabolomic analysis and conventional chromatography. The pancreatic fatcontent <strong>of</strong> 12 lean (C57BL/6J), 12 obese leptin-deficient (Lep ob ) and 12 obesehyperleptinemic (Lep db ) mice was evaluated by metabolomic analysis, thin-layer and gaschromatography. Pancreata <strong>of</strong> congenitally obese mice had significantly more totalpancreatic fat, triglycerides and free fatty acids, but significantly less phospholipids andcholesterol than those <strong>of</strong> lean mice. Metabolomic analysis showed excellent correlation withthin-layer and gas chromatography in measuring total fat, triglycerides and phospholipids.Differences in pancreatic fat content and character may have important implications whenconsidering the local pancreatic proinflammatory milieu in obesity. Metabolomic analysis is avalid, powerful tool with which to further define the mechanisms by which fat impactspancreatic disease [444].Optical markersPancreatic cancer screening has been hampered by the high rate <strong>of</strong> complicationsassociated with interrogating the pancreas. The closest non-invasively accessible mucosaavailable for pancreatic cancer screening is the periampullary duodenal tissue. An earlierreport has shown the potential <strong>of</strong> using optical markers to interrogate this tissue for thepresence <strong>of</strong> pancreatic cancer. In one study, it was reported a larger data set <strong>of</strong> lowcoherenceenhanced backscattering (LEBS) and elastic light scattering fingerprinting (ELF)optical markers from the periampullary duodenal mucosa. Optical measurements from biopsysamples were acquired from a total <strong>of</strong> 203 patients with varying clinical classificationincluding healthy controls, a family history <strong>of</strong> pancreatic cancer, pancreatitis, mucinous cysticprecursor lesions, pancreatic cancer, and other pancreatic malignancies. Evaluation <strong>of</strong> theperformance <strong>of</strong> an independent testing set for discriminating healthy control patients frompancreatic cancer patients showed a 95 percent sensitivity, 71 percent specificity, and 85percent area under the receiver operator characteristic (AUROC) curve. Importantly, thisperformance was uncompromised for detecting potentially curable stages <strong>of</strong> the disease.Additionally, optical markers in higher risk populations such as family history and pancreatitishad values between those <strong>of</strong> healthy control and pancreatic cancer patients, thus allowing forfuture investigations <strong>of</strong> screening from these high risk groups [445].

Quantum dotsIt was reported the successful use <strong>of</strong> non-cadmium-based quantum dots (QDs) as highlyefficient and nontoxic optical probes for imaging live pancreatic cancer cells. Indiumphosphide (core)-zinc sulfide (shell), or InP/ZnS, QDs with high quality and brightluminescence were prepared by a hot colloidal synthesis method in nonaqueous media. Thesurfaces <strong>of</strong> these QDs were then functionalized with mercaptosuccinic acid to make themhighly dispersible in aqueous media. Further bioconjugation with pancreatic cancer specificmonoclonal antibodies, such as anticlaudin 4 and antiprostate stem cell antigen (anti-PSCA),to the functionalized InP/ZnS QDs, allowed specific in vitro targeting <strong>of</strong> pancreatic cancer celllines (both immortalized and low passage ones). The receptor-mediated delivery <strong>of</strong> thebioconjugates was further confirmed by the observation <strong>of</strong> poor in vitro targeting innonpancreatic cancer based cell lines which are negative for the claudin-4-receptor. Theseobservations suggest the immense potential <strong>of</strong> InP/ZnS QDs as non-cadmium-based safeand efficient optical imaging nanoprobes in diagnostic imaging, particularly for early detection<strong>of</strong> cancer [446].Differential diagnosisBronchogenic carcinomaHyperamylasemia in patients with bronchogenic carcinoma has been reported rarely. Onereport described a case <strong>of</strong> lung adenocarcinoma coexisting with hyperamylasemia in a 67-year-old man. Abdominal computed tomograhy and ultrasonography demonstrated a normalpancreas. A mutational analysis <strong>of</strong> the EGFR gene indicated an in-frame deletion at exon 19.He underwent treatment with gefitinib. Chest radiography follow-up showed a partialresponse and the amylase level also decreased to normal [447].Hydatide cystPrimary hydatid disease <strong>of</strong> the pancreas is very rare. It was reported a 33-year-old femalewho was admitted to the hospital with abdominal discomfort due to the pancreatic mass. Adiagnosis <strong>of</strong> a pancreatic cystic mass was established through abdominal ultrasonographyand computed tomography scan. Hydatid disease as well as a cystic neoplasm <strong>of</strong> thepancreas was both thought in the differential diagnosis. Distal pancreatectomy withsplenectomy was performed. The histopathologic evaluation <strong>of</strong> the specimen revealed ahydatid cyst affecting the tail <strong>of</strong> the pancreas. Hydatid disease should be considered in thedifferential diagnosis <strong>of</strong> all cystic masses <strong>of</strong> the pancreas, especially in endemic regions[448].GISTDiagnosis by endoscopic ultrasound <strong>of</strong> a large aberrant pancreas mimicking malignantgastrointestinal stromal tumor <strong>of</strong> the stomach was described in a case report [449].Chronic pancreatitisDistinguishing chronic pancreatitis from pancreatic ductal adenocarcinoma (PDAC) is a wellknownchallenge, at both the clinical and the morphologic level. Findings that are specific toPDAC are the presence <strong>of</strong> duct structures in perineural and vascular spaces and ("naked")ducts in fatty tissue. However, these findings are only observed in specimens containingextrapancreatic tissue. The features that are suggestive <strong>of</strong> PDAC in specimens from thepancreas include haphazard distribution <strong>of</strong> ductlike structures (i.e. loss <strong>of</strong> a lobular pattern),

markedly irregular ductal contours, ruptured ducts, nuclear enlargement, pleomorphism andhyperchromatism, and mitotic figures. Immunohistologic markers that are helpful arecarcinoembryonic antigen, MUC1, p53, and Ki-67/ MIB1. There are a few features that arediagnostic and a number that are suggestive <strong>of</strong> PDAC. Therefore, a combination <strong>of</strong> severalfeatures may be required to clearly distinguish chronic pancreatitis from invasive PDAC[450].PseudotumorA variety <strong>of</strong> nonneoplastic conditions may form pancreatic masses that mimic carcinoma.Approximately 5-10 percent <strong>of</strong> pancreatectomies performed with the clinical diagnosis <strong>of</strong>pancreatic cancer prove on microscopic evaluation to be pseudotumors. To illustrate theclinical and pathologic characteristics <strong>of</strong> the 2 most frequent pseudotumoral inflammatoryconditions, autoimmune pancreatitis and paraduodenal pancreatitis, and describe the criteriathat may be useful in the differential diagnosis versus pancreatic carcinoma recent <strong>literature</strong>and the authors' experience with the clinical and pathologic characteristics <strong>of</strong> autoimmunepancreatitis and paraduodenal pancreatitis were <strong>review</strong>ed. The knowledge <strong>of</strong> the clinical,radiologic, and pathologic findings in both autoimmune pancreatitis and paraduodenalpancreatitis is crucial in making the correct preoperative diagnosis. Autoimmune pancreatitis,which occurs in isolated or syndromic forms, is characterized by a distinctivefibroinflammatory process that can either be limited to the pancreas or extend to the biliarytree. Its correct preoperative identification on biopsy material with ancillaryimmunohistochemical detection <strong>of</strong> dense immunoglobulin G4-positive plasma cell infiltrationis possible and crucial to prevent major surgery and to treat these patients with steroidtherapy. Paraduodenal pancreatitis is a special form <strong>of</strong> chronic pancreatitis that affects youngmales with a history <strong>of</strong> alcohol abuse and predominantly involves the duodenal wall in theregion <strong>of</strong> the minor papilla. Pathogenetically, the anatomical and/or functional obstruction <strong>of</strong>the papilla minor, resulting from an incomplete involution <strong>of</strong> the intraduodenal dorsalpancreas, associated with alcohol abuse represents the key factor [451].Special symptoms and signsHemosuccus pancreaticusThe major symptoms <strong>of</strong> cancer <strong>of</strong> the pancreas, even those <strong>of</strong> the head, are insidious weightloss, abdominal pains, back pain, anorexia, nausea, vomiting and generalized malaise.Jaundice is present in about 90 percent <strong>of</strong> the patients with cancer <strong>of</strong> the head and 10-40percent <strong>of</strong> those with cancer <strong>of</strong> body and tail. Massive haemorrhage is an uncommonpresentation. Most causes <strong>of</strong> gastrointestinal haemorrhage respond to conservativetreatment. Haemosuccus pancreaticus is a care cause <strong>of</strong> gastrointestinal hemorrhage andcan prove difficult to diagnose. It was presented two with upper gastrointestinal bleeding.Both patients were found to have pancreatic caranoma with bleding into the pancreatic ducts.I was concluded that haemosuccus pancreaticus may present as one <strong>of</strong> the early symptoms<strong>of</strong> carcinoma <strong>of</strong> the pancreas in young patients in our environment [452].Venous tromboembolismSeveral recent studies have shown that the incidence <strong>of</strong> venous thromboembolism is highestin patients who present with metastatic cancer, particularly cancers associated with a highone-year mortality rate, such as pancreatic cancer. The incidence rate <strong>of</strong> VTE is highest inthe first few months after the diagnosis <strong>of</strong> cancer, and it decreases over time thereafter. Formost cancers, it is not clear to what extent undergoing major surgery adds to the alreadyhigh risk <strong>of</strong> VTE associated with the presence <strong>of</strong> the cancer. However, patients with glioma

clearly have a very high incidence <strong>of</strong> VTE soon after they undergo any invasiveneurosurgical procedure. Active chemotherapy, the use <strong>of</strong> erythropoetin agents, and the use<strong>of</strong> certain anti-cancer therapies such as thalidomide, high-dose steroids, and anti-angiogenictherapy also increase the risk <strong>of</strong> thrombosis. Similar to patients without cancer, the risk <strong>of</strong>venous thromboembolism is higher in patients with coexisting chronic medical illnesses.Development <strong>of</strong> VTE is clearly associated with decreased survival and this effect is greateramong patients initially diagnosed with local or regional stage cancer compared to patientswith metastatic cancer [453].Venous thrombosis with and without pulmonary embolism is a frequent complication <strong>of</strong>malignancies and second among the causes <strong>of</strong> death in tumor patients. Its incidence isreported to be 10 to 15 percent. Since for methodological reasons, this rate can be assumedto be too low and to disregard asymptomatic venous thrombosis, a combined retrospectiveand prospective study was performed to examine the actual frequency <strong>of</strong> venous thrombosisin tumor patients. The histories <strong>of</strong> 409 patients with different tumors, consecutively enrolledin the order <strong>of</strong> their altogether 426 inpatient treatments, were checked in retrospect for thefrequency <strong>of</strong> venous thrombosis and pulmonary embolism. Subsequently, 97 tumorinpatients were systematically screened, by means <strong>of</strong> duplex sonography and/orvenography, for venous thromboses in the veins <strong>of</strong> the pelvis and both legs. In theretrospective analysis, where no systematic screening for thromboses was performed andonly symptomatic thrombosis was recorded, venous thrombosis was found in 6.6 percent <strong>of</strong>all tumor patients, whereas in the prospective examination with systematic duplexsonography and / or venography <strong>of</strong> all patients, the percentage was 33 percent. In theprospective study, 31 percent <strong>of</strong> venous thromboses were symptomatic and 69 percentasymptomatic. In 39 percent <strong>of</strong> the cases in the retrospective analysis and 25 percent in theprospective analysis, venous thrombosis occurred during chemotherapy, surgery or radiationtherapy. Venous thrombosis was most <strong>of</strong>ten seen in metastasizing tumors and in colorectalcarcinoma (40 %), haematological system diseases (29 %), gastric cancer (30 %), bronchial,pancreas and ovarian carcinoma (29 %), and carcinoma <strong>of</strong> the prostate (17 %). It wasconcluded that regular screening for thrombosis is indicated even in asymptomatic tumorpatients because asymptomatic venous thrombosis is frequent, can lead to pulmonaryembolism and has to be treated like symptomatic venous thrombosis. This is particularly truefor metastasization during chemotherapy, surgical interventions, or radiation [454].Cancer is the most important acquired but <strong>of</strong>ten overlooked risk factor for the development <strong>of</strong>venous thromboembolism (VTE). Tumors can express procoagulant proteins, for example,and tumor masses may compromise venous blood flow by extrinsic compression <strong>of</strong> adjacentvessels. Cancers can also induce the production <strong>of</strong> inflammatory cytokines that indirectlycontribute to the development <strong>of</strong> hypercoagulability and the risk <strong>of</strong> thromboembolism.Additional risk factors for VTE experienced by patients with cancer include immobilization,because <strong>of</strong> cancer or its treatment, and the potential presence <strong>of</strong> thrombophilic geneticfactors. Many common therapeutic modalities also increase VTE risk, including surgery,chemotherapy agents, adjuvant hormonal manipulation, the use <strong>of</strong> angiogenesis inhibitors,and the presence <strong>of</strong> central venous access devices. The risk <strong>of</strong> VTE seems to be greaterwith certain tumor types, such as cancers <strong>of</strong> the pancreas, kidney, or brain. The value <strong>of</strong>extensive screening <strong>of</strong> patients with the first episode <strong>of</strong> idiopathic thromboembolism for thepresence <strong>of</strong> an occult malignancy remains debatable at this time. VTE continues to pose asubstantial risk to patients with cancer because <strong>of</strong> a variety <strong>of</strong> tumor-, host-, and therapyrelatedfactors [455].Venous thromboembolism (VTE) is a well-recognized and relatively frequent complication <strong>of</strong>malignancy, whereas tumor thrombosis is a rare complication <strong>of</strong> solid cancers. The correctdiagnosis <strong>of</strong> tumor thrombosis and its differentiation from VTE can alter patient managementand prevent unnecessary long-term anticoagulation treatment. To evaluate the contribution<strong>of</strong> 18 F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography to the

diagnosis <strong>of</strong> tumor thrombosis and its differentiation from VTE PET/CT scans from 11patients with suspected tumor thrombosis were retrospectively evaluated. Suspicion arosefrom positive PET/CT in eight cases or from findings on contrast-enhanced CT in threepatients. Criteria for positivity <strong>of</strong> PET/CT included increased focal or linear uptake <strong>of</strong> 18 F-FDGin the involved vessel. Findings were categorized as PET/CT positive, or PET/CT negativeand compared to contrast-enhanced or ultrasound Doppler, pathology where available, andclinical follow-up. Eight occult tumor thromboses were identified by PET/CT-positive scans.Underlying pathologies included pancreatic, colorectal, renal cell, and head-neck squamouscell carcinoma, as well as lymphoma (4 patients). Three thrombotic lesions on contrastenhancedCT were PET/ CT negative, due to VTE (2 patients) and leiomyomatosis.Accuracy <strong>of</strong> PET/CT to differentiate between tumor thrombosis and benign VTE was 100percent in this small study. It was concluded that contrast-enhanced CT defines the extent <strong>of</strong>thrombotic lesions, while the functional information from PET/CT characterizes the lesions. Itappears that PET/CT may be helpful in the diagnosis <strong>of</strong> occult tumor thrombosis and itsdifferentiation from venous tromboembolism [456].ObesityClinical and basic studies have shown obesity to be associated with an increased incidenceand progression <strong>of</strong> pancreatic cancer. The precise role that pancreatic fat plays in thisprocess has remained undefined. It was tested the hypothesis that pancreatic steatosiswould be associated with increased dissemination and reduced survival in patients withresected pancreatic cancer. A case-control analysis was conducted in patients who hadundergone resection for pancreatic adenocarcinoma. Twenty lymph node-positive patientsand 20 node-negative patients were matched for age (59 vs 63 years), gender (70 % male vs60 % male), body mass index (24.5 vs 25.6), medical comorbidities (hypertension, diabetes,hyperlipidemia), tumor size (2.8 vs 2.6 cm), and resection status (R0 80 % vs 85 %).Pancreatic neck margins were <strong>review</strong>ed in a blinded fashion by two trained investigators.Pancreatic fat (number <strong>of</strong> cells/5 high power field) and degree <strong>of</strong> fibrosis (0 to 4+) wererecorded. Node-positive patients had significantly more fat cells in the pancreas comparedwith node-negative patients. Node-positive patients also demonstrated decreased fibrosiscompared with node-negative patients. Mean survival was reduced in node-positive patients(19 + 3 vs 31 + 5 months). These data show that increased pancreatic fat promotesdissemination and lethality <strong>of</strong> pancreatic cancer. It was therefore conclude that pancreaticsteatosis alters the tumor microenvironment, enhances tumor spread, and contributes to theearly demise <strong>of</strong> patients with pancreatic adenocarcinoma [457].Between 2000 and 2007, 262 patients underwent pancreatoduodenectomy, <strong>of</strong> whom 240had complete data, including body mass index (BMI) for analysis. Data on BMI, preoperativeparameters, operative details, and postoperative course were collected. Patients werecategorized as obese (BMI > 30), overweight (BMI > 25 and < 30), or normal weight (BMI

patients for operation and when counseling patients about operative risk, but they do notpreclude obese individuals from undergoing definitive pancreatic operations [458].To examine the influence <strong>of</strong> obesity, as measured by body mass index (BMI) onclinicopathologic factors and survival after pancreatectomy to treat adenocarcinoma aretrospective <strong>review</strong> and statistical analysis using prospectively collected data wasperformed. Two hundred eighty-five consecutive patients with data available for BMIcalculation who underwent potentially curative pancreas resection to treat adenocarcinomafrom 1999 to 2006. It was identified a subset <strong>of</strong> obese patients (BMI >35) who were at 12-foldrisk <strong>of</strong> lymph node metastasis compared with nonobese patients (BMI < 35). The estimateddisease-free and overall survival rates were decreased in the obese patients, and the risk <strong>of</strong>cancer recurrence and death after pancreatectomy was nearly twice that in nonobesepatients. It was concluded that obese patients with a BMI <strong>of</strong> more than 35 are more likely tohave node-positive pancreatic cancer and decreased survival after surgical resection. Datasuggest that the negative influence <strong>of</strong> BMI <strong>of</strong> more than 35 on cancer-related end points isunrelated to the potential complexity <strong>of</strong> performing major oncologic surgery in obese patients[459].Diabetes in pancreatic cancerIn Korea, the prevalence <strong>of</strong> pancreatic cancer (PC) in general population has been reportedas 7 in 100,000. However, that in diabetes mellitus (DM) has not been elucidated yet. Onestudy was designed to estimate the prevalence <strong>of</strong> PC among diabetes mellitus patients, andcharacterize and compare the patients with diabetes mellitus with and without PC. 5,082patients (4,890 diabetes mellitus without PC, 78 PC with diabetes mellitus, and 114 PCwithout diabetes mellitus) were enrolled during a period <strong>of</strong> 4 years between 2004 and 2008.The prevalence <strong>of</strong> PC in diabetes mellitus patients was 1.6 percent and that <strong>of</strong> diabetesmellitus in PC patients was 41 percent. No significant differences in the clinicalcharacteristics except HbAIc and ALP were observed between PC patients with diabetesmellitus and without diabetes mellitus. Among 78 PC patients with diabetes mellitus, diabetesmellitus was diagnosed in 19 (29 %) and 29 (37 %) patients concomitantly or within 2 yearsprior to the diagnosis <strong>of</strong> PC, respectively. Among the cases with recent onset diabetesmellitus (less than 2 years duration), the disease duration <strong>of</strong> diabetes mellitus before thediagnosis <strong>of</strong> PC was less than 1 year in 14 patients (18 %) and 1 to 2 years in 15 patients(19 %). Diabetes mellitus patients with PC were found to have significantly higher ALT, totalbilirubin, and ALP levels than in diabetes mellitus patients without PC. It was concluded thatthe prevalence <strong>of</strong> pancreatic cancer in diabetes mellitus patients was 1.6 percent and washigher than in the general population. Recent onset diabetes mellitus was frequent in PCpatients (less than 2 years duration) [460].Coeliac axis stenosisPatients with celiac axis stenosis are asymptomatic due to the rich collateral blood supplythrough superior mesenteric artery. However, ligating and dividing gastroduodenal arteryduring pancreatoduodenectomy can cause ischemic threat especially to liver, less frequentlystomach and spleen, or failure <strong>of</strong> anastomoses. It was presented a case <strong>of</strong> 27-year-oldfemale who underwent duodenopancreatectomy for pseudopapillary tumor <strong>of</strong> the head <strong>of</strong>pancreas. Celiac axis stenosis was found peroperatively and proven during angiography.Although an attempt <strong>of</strong> endovascular dilatation <strong>of</strong> celiac axis was unsuccessful, blood supplyto the liver was sufficient and therefore it was not performed any other intervention toimprove blood flow to the liver. Postoperative course was uneventful. Celiac axis stenosiscan be caused by tumor infiltration or lymphadenopathy in malignant disease,atherosclerosis or compression <strong>of</strong> the median arcuate ligament. The stenosis can be

managed by endovascular treatment or arterial reconstruction. In conclusion the authorspropose a management algorithm to prevent the consequences <strong>of</strong> celiac axis stenosis [461].Preoperative biliary drainageIt was examined the effect <strong>of</strong> selective preoperative biliary drainage (BD) on perioperativeresuscitation, morbidity, and mortality in patients undergoing pancreaticoduodenectomy.Biliary drainage prior to pancreaticoduodenectomy remains controversial. Proponents arguethat it facilitates referral to high-volume tertiary centers, while detractors maintain that itincreases surgical morbidity and mortality. It was performed a retrospective analysis <strong>of</strong>single-institution tumor registry database. From 2003 to 2008 90 patients underwentpancreaticoduodenectomy for periampullary mass lesions. Clinicopathologic data were<strong>review</strong>ed and analyzed among patients who did and did not receive biliary drainage for theirassociation with perioperative outcomes. Fifty-six patients (62 %) underwent BD, and 34 (38%) did not. Intraoperative bile cultures were positive for 1 or more species <strong>of</strong> microorganismsin 88 percent <strong>of</strong> stented patients (35 <strong>of</strong> 40). There were no significant differences in fluidrequirements, transfusion requirements, or surgery duration between patients who did anddid not undergo biliary drainage. Estimated blood loss was significantly increased in patientswho received biliary drainage (625 mL vs 525 mL in patients who did not undergo BD), whilereoperation was significantly more common in nonstented patients (4 % vs 15 % in patientswho did not undergo BD). Intensive care unit stay, overall length <strong>of</strong> stay, pancreaticleak/abscess/fistula, infectious complications, postoperative percutaneous drainage, hospitalreadmission, and 30- and 90-day mortality were not significantly different between the twogroups. Although preoperative biliary stents may complicate the intraoperative managementand lessen the postoperative complications <strong>of</strong> patients undergoing pancreatic resection, onlyestimated blood loss and reoperation were significantly different in this cohort. Currently,selective preoperative BD appears appropriate in the multidisciplinary management <strong>of</strong>patients with periampullary lesions [462].In one study it was evaluated whether preoperative biliary drainage should be routinelyperformed in patients with jaundice. The 342 patients undergoing pancreaticoduodenectomybetween 2004 and 2008 were analyzed. Of these patients, 303 without biliary drainage weredivided into 4 groups: (1) no jaundice, (2) mild jaundice, (3) moderate jaundice, and (4)severe jaundice. Postoperative complications were stratified by severity according to themodified Clavien classification. It was found that patients with jaundice had a higherincidence in subsequent complications than those with no jaundice. The complications werestratified by severity. Compared with those in group 1, patients in groups 2, 3, and 4 hadsignificantly more complications just in grade 2 (16 %, 23 %, 28 %, and 40 %, respectively),but not other more severe grades including 3a, 3b, 4a, 4b, and 5; all <strong>of</strong> the complications inthis grade could be conservatively treated and cured without requiring surgical, endoscopic,or radiological intervention. The incidences <strong>of</strong> infection and overall complications were higherin patients with drainage than those without, but neither difference was statisticallysignificant. Preoperative drainage should not routinely be performed in patients with jaundicescheduled for pancreaticoduodenectomy, and immediate surgery is preferable [463].ExperimentalOne work presented a novel approach to producing manganese (Mn)-doped quantum dots(Mnd-QDs) emitting in the near-infrared (NIR). Surface functionalization <strong>of</strong> Mnd-QDs withlysine makes them stably disperse in aqueous media and able to conjugate with targetingmolecules. The nanoparticles were structurally and compositionally characterized andmaintained a high photoluminescence quantum yield and displayed paramagnetism in water.The receptor-mediated delivery <strong>of</strong> bioconjugated Mnd-QDs into pancreatic cancer cells was

demonstrated using the confocal microscopy technique. Cytotoxicity <strong>of</strong> Mnd-QDs on live cellshas been evaluated. The NIR-emitting characteristic <strong>of</strong> the QDs has been exploited toacquire whole animal body imaging with high contrast signals. In addition, histological andblood analysis <strong>of</strong> mice have revealed that no long-term toxic effects arise from MnD-QDs.These studies suggest multimodal Mnd-QDs have the potentials as probes for earlypancreatic cancer imaging and detection [464].To determine the clinical utility <strong>of</strong> nuclear morphometry by confocal laser scanningmicroscopy for the diagnosis <strong>of</strong> malignant biliary strictures 51 patients with bile duct strictureswho underwent ERCP were studied. Based on the initial workup, 6 patients were diagnosedwith benign strictures, and 12 patients had malignant strictures, while in the remaining 33cases the diagnoses were inconsistent, due mainly to inadequate samples. Smears fromERCP brushings were stained for DNA with propidium iodide. Nuclear morphometry wasassessed on images acquired by a confocal laser scanning microscope. Three parametersnuclearvolume, nuclear shape and nuclear staining intensity-were calculated. Based onthese features, a distinctive nuclear morphometric pattern was attributed to the malignantnuclei, and its predictive value was assessed prospectively in the 33 undiagnosed cases.After an overall median follow-up period <strong>of</strong> 8 months, 19 patients were diagnosed withmalignant strictures, and 14 patients were considered to have benign strictures. With respectto the prediction <strong>of</strong> malignancy, the sensitivity <strong>of</strong> the described method was 78 percent, thespecificity was 63 percent, the positive predictive value was 64 percent, and the negativepredictive value was 80 percent. Nuclear morphometry may provide significant informationfor the diagnosis <strong>of</strong> malignant bile duct strictures when conventional cytology fails to [465].Pancreatic cancer cachexiaCachexia is a devastating process especially in pancreatic cancer patients and contributes totheir poor survival. It was attempted to clarify the pathological and molecular changes thatoccur in the liver during the development <strong>of</strong> cachexia. Using immunohistochemistry it wasinvestigated the infiltration <strong>of</strong> inflammatory mononuclear cells in liver biopsies <strong>of</strong> pancreaticcancer patients with or without cachexia, and the potential relevance <strong>of</strong> the cells for thenutritional and inflammatory status. Additionally, these findings were compared with thepatients' clinical parameters. It was found a significantly higher amount <strong>of</strong> CD68immunoreactive macrophages in liver cross sections <strong>of</strong> patients with pancreatic cancer andcachexia. The number <strong>of</strong> CD68-positive macrophages was significantly inversely correlatedwith the nutritional status. Additionally, in these CD68-positive areas a significant increase inIL-6 and IL-1 immunoreactive cells was localized. Moreover, it was found significantlyincreased areas <strong>of</strong> CD68-positive macrophages in liver biopsies <strong>of</strong> patients with a morededifferentiated (aggressive) grading <strong>of</strong> the tumor. In conclusion, these results suggest that acrucial interaction between the tumor, PBMCs, and the liver may play a central role in thedevelopment and regulation <strong>of</strong> cachexia. Furthermore, pancreatic cancer may be able toalter systemic organ function even without obvious metastatic disease [466].Ghrelin is a growth hormone-releasing acylated peptide found to be an appetite stimulantand low levels <strong>of</strong> it are detected in cachexia. The aim <strong>of</strong> one study was to investigate theplasma ghrelin levels in cancer patients with a low performance status and weight loss andcompare them with those <strong>of</strong> healthy individuals without weight loss. Thirty patients (medianage 65 years) with different malignancies, mainly pancreatic and gastric, and 27 healthyindividuals (median age 62 years) were examined. The gender <strong>of</strong> both groups was wellbalanced. Plasma ghrelin was measured by a radioimmunoassay kit that uses a polyclonalantibody which recognizes the C-terminal <strong>of</strong> ghrelin. There was a statistically significantdifference in the plasma ghrelin levels <strong>of</strong> the patients versus the controls, with the patientshaving much lower levels. The notable reduction <strong>of</strong> ghrelin levels might be due to the severity

and progression <strong>of</strong> the disease [467].Effect <strong>of</strong> age on outcomeBoth morbidity and mortality rates following pancreatic resection increase with advancedage. The reported mortality rates following pancreatic surgery arc underestimated in singleinstitutionstudies. There is a significant publication bias where only centers with good resultsreport their outcomes. The population-based data are critical to provide a more realistic view<strong>of</strong> mortality rates following pancreatic resection. It is essential in counseling elderly patientsthat they understand that mortality rates are increased, morbidity rates are increased, andthe effect <strong>of</strong> complications <strong>of</strong>ten leads to a prolonged convalescence. They will have a longerlength <strong>of</strong> stay and up to a 30 to 40 percent chance that they will not be able to go home butwill need to recover in an extended care facility following hospital discharge. Although themorbidity and mortality rates are increased for elderly patients, they are well within theacceptable range for major abdominal surgery when performed at experienced centers.Patients also need to be aware that surgical resection is the only curative option forpancreatic cancer. In reasonable risk elderly patients the benefit <strong>of</strong> surgical resection doesnot decrease with age and these patients can experience long-term survival and good quality<strong>of</strong> life. Once patients over 80 get beyond the 2-year survival mark without cancer recurrencetheir survival parallels that <strong>of</strong> their age-matched counterparts. One should also keep in mindthat the reported survival rates are mostly for pancreatic cancer, but patients with otherperiampullary cancers have improved long-term survival when compared with those withpancreatic cancer. Elderly patients also need to be aware <strong>of</strong> the fact that hospital volume andsurgeon experience significantly impact outcomes. The mortality rates following surgery inthe oldest patients, those over 80, are nearly twice as high at low-volume facilities comparedwith high-volume facilities. The overall mortality rate and the difference decrease withdecreasing age. This likely represents improved processes <strong>of</strong> care at experienced centersand better ability to manage the complications <strong>of</strong> pancreatic surgery, which occur morecommonly in elderly patients. It is important to educate both physicians and elderly patientsabout this difference. Currently, elderly patients are less likely to be resected at high-volumecenters than younger patients. The reasons for this are unclear but include lack <strong>of</strong>awareness <strong>of</strong> the importance <strong>of</strong> hospital volume and surgeon experience and reluctance <strong>of</strong>patients in this age group to travel long distances from home for their care. When <strong>review</strong>ingthe data, one must be aware that these studies (both population-based and single-institution)are retrospective and subject to significant selection bias. The elderly patients undergoingresection were dearly carefully chosen. There is still nihilism, however, toward aggressivecare in these patients, with fewer than 10 percent <strong>of</strong> patients over 80 with locoregionaldisease and no comorbidities being resected, whereas 40 percent <strong>of</strong> patients 66 to 70 in thesame category are resected. These data provide an excellent foundation to guide informeddecision-making in the elderly population with pancreatic and periampullary cancer. Patientsneed to know that surgical resection <strong>of</strong>fers the only hope for cure and that the benefit <strong>of</strong>surgical resection does not diminish with age. The diagnosis (pancreatic versus otherperiampullary cancers versus benign disease or premalignant lesions) needs to be taken intoaccount to balance fully the risks and benefits. Older patients need to be aware <strong>of</strong> theincreased morbidity, mortality, and prolonged convalescence they may experience. Theyalso need to be advised to have their surgery done by experienced surgeons at experiencedcenters where these complications can be best managed. Further studies are needed toguide patient selection. The effect <strong>of</strong> patient comorbidities, cognitive status, preoperativefunctional status, and frailty need to be more formally assessed to select patients, maximizesurgical resection in appropriate candidates, and improve short-term outcomes. Once bettercharacterized, specialized geriatric pathways may optimize surgical resection rates,streamline care, and improve outcomes in this challenging population. Age alone, however,should not be a contraindication to pancreatic resection in elderly patients with pancreatic

cancer [468].To evaluate pancreatic surgery as a model for high-acuity surgery in elderly patients forimmediate and long-term outcomes, predictors <strong>of</strong> adverse outcomes, and hospital costs.Four hundred twelve consecutive patients who underwent pancreatic resection from 2001,through 2008 for benign and malignant periampullary conditions. Clinical outcomes werecompared for elderly (> 75 years) and nonelderly patient cohorts. Quality assessmentanalyses were performed to show the differential impact <strong>of</strong> complications and resourceutilization between the groups. The elderly cohort constituted one-fifth <strong>of</strong> all patients.Benchmark standards <strong>of</strong> quality were achieved in this group, including low operative mortality(1 %). Despite higher patient acuity, clinical outcomes were comparable to those <strong>of</strong>nonelderly patients at a marginal cost increase (median, USD 2202 per case). Cost modelinganalysis showed further that minor and moderate complications were more frequent but nomore debilitating for elderly patients. Major complications, however, were far morethreatening to older patients. In these cases, duration <strong>of</strong> hospital stay doubled, and invasiveinterventions were more commonly deployed. It was concluded that quality standards forpancreatic resection in the elderly can – and should – mirror those for younger patients. Agerelatedcare, including geriatric consultation, supplemental enteral nutrition, and earlyrehabilitation placement planning, can be designed to mitigate the impact <strong>of</strong> complications inthe elderly and guarantee quality [469].Surgical techniquesPancreatojejunostomyTo evaluate the impact <strong>of</strong> the length <strong>of</strong> the isolated jejunal loop and the type <strong>of</strong>pancreaticojejunostomy on pancreatic leakage after pancreaticoduodenectomy 132consecutive patients who underwent a pancreaticoduodenectomy were studied according tothe length <strong>of</strong> the isolated jejunal loop (short loop, 20-25 cm vs long loop, 40-50 cm) and thetype <strong>of</strong> pancreaticojejunostomy (invagination vs duct to mucosa). The use <strong>of</strong> the longisolated jejunal loop was associated with a significantly lower pancreatic leakage ratecompared with the use <strong>of</strong> a short isolated jejunal loop (4.3 % vs 14.2 %). In addition, the use<strong>of</strong> duct-to-mucosa technique was associated with significantly lower incidence <strong>of</strong>postoperative pancreatic fistula compared with the invagination technique (4.2 % vs 14.5 %).Finally, patients with a short isolated jejunal loop compared with patients with a long loop hadincreased morbidity (50.7 % vs 27.5 %) and prolonged hospital stay (16 + 2 days vs 10 +/- 2days). Overall mortality rate was 1.5 percent. It was concluded that the use <strong>of</strong> a long isolatedjejunal loop and a duct-to-mucosa pancreaticojejunostomy is associated with decreasedpancreatic leakage rate after pancreaticoduodenectomy [470].Pancreatic fistula is one <strong>of</strong> the most common complications after pancreaticoduodenectomy.It was now tested the hypothesis that a duct to mucosa pancreaticojejunostomy wouldreduce the pancreatic fistula rate. Between 2006 and 2008, 197 patients at two institutionsunderwent pancreaticoduodenectomy by a total <strong>of</strong> 8 experienced pancreatic surgeons aspart <strong>of</strong> this prospective randomized trial. All patients were stratified by pancreatic texture andrandomized to either an invagination or a duct to mucosa pancreaticojejunal anastomosis.Recorded variables included pancreatic duct diameter, operative time, blood loss,complications, and pathology. Primary end point was fistula rate, as defined by theInternational Study Group on Pancreatic Fistula. Rate <strong>of</strong> pancreatic fistula rate for the entirecohort was 18 percent. There were 23 fistulas (24 %) in the duct to mucosa cohort and 12fistulas (12 %) in the invagination cohort, which was a statistically significant difference. Thegreatest risk factor for a fistula was pancreas texture: pancreatic fistulas developed in only 8patients (8 %) with hard glands, and in 27 patients (27 %) with a s<strong>of</strong>t gland. There were two

perioperative deaths (both in the duct to mucosa group), with the proximate causes <strong>of</strong> deathbeing pancreatic fistula, followed by bleeding and sepsis. This dual-institution prospectiverandomized trial reveals considerably fewer fistulas with invagination compared with duct tomucosa pancreaticojejunostomy after pancreaticoduodenectomy [471].To evaluate the impact <strong>of</strong> the length <strong>of</strong> the isolated jejunal loop and the type <strong>of</strong>pancreaticojejunostomy on pancreatic leakage after pancreaticoduodenectomy 132consecutive patients who underwent a pancreaticoduodenectomy were studied according tothe length <strong>of</strong> the isolated jejunal loop (short loop, 20-25 cm vs long loop, 40-50 cm) and thetype <strong>of</strong> pancreaticojejunostomy (invagination vs duct to mucosa). The use <strong>of</strong> the longisolated jejunal loop was associated with a significantly lower pancreatic leakage ratecompared with the use <strong>of</strong> a short isolated jejunal loop (4 % vs 14 %). In addition, the use <strong>of</strong>duct-to-mucosa technique was associated with significantly lower incidence <strong>of</strong> postoperativepancreatic fistula compared with the invagination technique (4 % vs 15 %). Finally, patientswith a short isolated jejunal loop compared with patients with a long loop had increasedmorbidity (51 % vs 28 %) and prolonged hospital stay (16 + 2 days vs 10 + 2 days). Overallmortality rate was 1.5 percent. It was concluded that the use <strong>of</strong> a long isolated jejunal loopand a duct-to-mucosa pancreaticojejunostomy is associated with decreased pancreaticleakage rate after pancreaticoduodenectomy [472].It was compared the different techniques for pancreatojejunostomy using the definitions <strong>of</strong>the International Study Group <strong>of</strong> Pancreatic Surgery for postoperative complications afterpancreaticoduodenectomy. Perioperative data <strong>of</strong> 119 patients that underwent pancreaticoduodenectomyby a single surgeon were retrospectively analyzed. Pancreaticojejunalanastomosis was performed using the dunking method (n=39), the duct-to-mucosaanastomosis method (n=40), and the duct-to-mucosa adaptation (n=40). The most frequentcomplication was postoperative pancreatic fistula (POPF; grades A, 21 %; B, 8 %; and C, 3%), postpancreatectomy hemorrhage (PPH; grades B, 7 % and C, 1 %), and delayed gastricemptying (DGE; grades A, 1 % and B, 6 %). No significant differences in POPF were foundbetween patients who underwent different types <strong>of</strong> pancreatic anastomoses. Only pancreaticductal adenocarcinoma and pancreatic texture were potentially related to fistulas. Patientswith or without fistulas grade A had shorter postoperative stays than patients with grade B orC fistulas, and similar findings were obtained for DGE and PPH. It was concluded that thesuccessful management <strong>of</strong> pancreatic anastomoses depends more on a meticulous surgicaltechnique and appropriate experience rather than on the type <strong>of</strong> technique. Furthermore, theInternational Study Group <strong>of</strong> Pancreatic Surgery definitions <strong>of</strong> postoperative pancreaticfistula, postpancreatectomy hemorrhage, and delayed gastric emptying seem objective anduniversally acceptable [473].Pancreaticoduodenectomy is the standard treatment for periampullary tumors. One <strong>of</strong> themajor causes <strong>of</strong> morbidity after pancreaticoduodenectomy is the failure <strong>of</strong> the healing at thepancreaticoenteric anastomosis. The aim <strong>of</strong> one study is to summarize the results <strong>of</strong> a newtechnique which is designed to decrease the panreticoje-junostomy anastomotic leakage.Consecutive patients whose pancreaticojejunostomy anastomosis after pancreaticoduodenectomywas performed by modified invagination method were evaluatedprospectively. Thirtyone patients were included in the study. Twenty complications hadoccurred in a total <strong>of</strong> 15 patients. There were no pancreaticojejunostomy anastomoticleakage and mortality in any <strong>of</strong> the patients. An ideal pancreaticojejunostomy anastomosisafter pancreaticoduodenectomy should be safe, simple and secure. This modifiedinvagination method seems to be promising when these parameters are taken in to account[474].The aim <strong>of</strong> one study was to compare postoperative morphological changes in remnantpancreas between pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG) after

pancreaticoduodenectomy (PD). The study subjects were 28 patients with PJ and 14 withPG. The diameter <strong>of</strong> the main pancreatic duct (MPD) and pancreatic parenchymal thickness2 years after PD were measured on computed tomography scans and compared betweenthe 2 groups. The preoperative and postoperative MPD diameter was 5.2 mm (SD, 2.4 mm)and 4.2 mm (SD, 2.0 mm) in the PJ group and 4.8 mm (SD, 3.2 mm) and 5.7 mm (SD, 1.8mm) in the PG group, respectively. In those patients with preoperatively normal-size MPD,MPD after surgery tended to become dilated relative to before surgery in the PJ group, andthe MPD measured postoperatively was significantly larger than preoperatively in the PGgroup. A significant atrophy <strong>of</strong> the pancreatic parenchyma was noted postoperatively in bothgroups, but these changes were significantly more severe in the PG group than the PJ group[475].Bioabsorbable staple line-reinforcementTo investigate the use <strong>of</strong> Seamguard, a bioabsorbable staple line-reinforcement product, toprevent pancreatic leak after distal pancreatectom a retrospective study examined 85consecutive patients undergoing distal pancreatectomy at an academic institution from 1997,to 2007. Indications for resection included trauma (11 patients), neoplasms (62 patients), andchronic pancreatitis (12 patients). Pancreatic leak was defined as drain output <strong>of</strong> 25 mL/d ormore 7 days postoperatively with a drain amylase level <strong>of</strong> 1000 U/L or more. Pancreatic leakoccurred in 10 <strong>of</strong> 38 patients (26 %) undergoing conventional resection with suture ligation <strong>of</strong>the pancreatic duct or nonreinforced stapled resection versus 2 <strong>of</strong> 47 patients (4 %)undergoing staple resection using Seamguard reinforcement. Multivariate analysis showedthat use <strong>of</strong> Seamguard with the stapler independently decreased the risk for pancreaticfistula after distal pancreatectomy (odds ratio, 0.07; 95 % confidence interval 0.01 to 0.43). Itwas concluded that the use <strong>of</strong> Seamguard is quickly becoming a common adjunct in distalpancreas resections. The study shows a lower incidence <strong>of</strong> pancreatic leak after distalpancreatectomy with the use <strong>of</strong> this staple line-reinforcing product [476].Pancreatic fistula is a major cause <strong>of</strong> morbidity after distal pancreatic resection. Whenresections are performed with linear stapling devices, the use <strong>of</strong> bioabsorbable staple linereinforcement has been suggested to decrease the rate <strong>of</strong> pancreatic fistula. The objective <strong>of</strong>one study was to investigate the incidence <strong>of</strong> pancreatic fistula when using the GoreSeamguard staple line reinforcement in stapled distal pancreatic resections. A retrospective<strong>review</strong> <strong>of</strong> 30 consecutive patients with stapled distal pancreatectomy was conducted. Abroad definition <strong>of</strong> pancreatic fistula was used. Clinicopathologic factors and outcomes werecompared between groups. Pancreatic fistula was diagnosed in 11 <strong>of</strong> 15 patients (73 %) andthree <strong>of</strong> 15 patients (20 %) in the Seamguard and non-Seamguard groups, respectively.Pancreatic parenchymal transection at the neck <strong>of</strong> the gland was associated with pancreaticfistula, whereas laparoscopic procedures, splenic preservation, or additional organ resectionwere not. On multivariate analysis, the association between Seamguard use and pancreaticfistula was significant. In conclusion, after introduction <strong>of</strong> the Gore Seamguard bioabsorbablestaple line reinforcement, it was experienced a significant increase in the rate <strong>of</strong> pancreaticfistula. This experience raises concern about the efficacy <strong>of</strong> this device in limiting pancreaticfistula after stapled distal pancreatic resection [477].Total pancreatectomyIn one study, it was reappraised the outcomes <strong>of</strong> total pancreatectomy, retrospectivelyanalyzing the safety <strong>of</strong> the procedures and factors associated with long-term survival. Thirtysixconsecutive patients underwent total pancreatectomy for pancreas disease.Postoperative morbidity was 39 percent (14/36) and severe complications were anastomoticleakage (n=3) and liver necrosis (n=1). In benign disease, 5-year survival was 50 percent,while 5-year survival in malignant disease was 22 percent. Postoperative glycosylated

hemoglobin A1c (HbA1c) level was 7.8 + 1.2 percent at 6 months and 7.8 + 1.5 percent at 12months after total pancreatectomy, respectively. It was concluded that total pancreatectomycan be safely performed and the treatment option for selectively limited pancreatic cancerand intraductal papillary mucinous neoplasm <strong>of</strong> the pancreas (IPMN), when the patientcondition permits and <strong>of</strong>fers a chance <strong>of</strong> cure, although careful long-term medical care andfollow-up are essential [478].With preserving stomach and spleenTotal pancreatectomy has been used to treat both benign and malignant diseases <strong>of</strong> thepancreas. The procedure <strong>of</strong> total pancreatectomy for invasive pancreatic cancer usuallyincludes distal gastrectomy and splenectomy to prevent ischemic changes due to decreasedblood supply. In one report, it was introduced a new technique <strong>of</strong> total pancreatectomy forinvasive pancreatic cancer preserving both the whole stomach and spleen. It was tried,initially to perform pylorus-preserving pancreatoduodenectomy (PPPD). Repeated frozensection examination <strong>of</strong> the pancreatic stumps, however, revealed persistent cancer infiltrationto the distal pancreas. Therefore, it was altered the planned PPPD to total pancreatectomypreserving the whole stomach and spleen with severing both the splenic artery and vein attheir origins. The postoperative course was uneventful. Enhanced CT following surgeryshowed sufficient blood supply to the whole stomach and spleen without any congestivechanges <strong>of</strong> blood flow. This method is considered safe and useful for patients with bothbenign and malignant disease <strong>of</strong> the pancreas [479].Portal vein reconstructionAggressive preoperative and intraoperative management may improve the resectability ratesand outcomes for locally advanced pancreatic adenocarcinoma with venous involvement.The efficacy and use <strong>of</strong> venous resection and especially arterial resection in themanagement <strong>of</strong> pancreatic adenocarcinoma remain, however, controversial. A retrospective<strong>review</strong> <strong>of</strong> 2 prospective databases <strong>of</strong> 593 consecutive pancreatic resections for pancreaticadenocarcinoma from 1999 through 2007 showed that 36 (6 %) underwent vascularresection at the time <strong>of</strong> pancreatectomy. Thirty-one <strong>of</strong> the 36 (88 %) underwent venousresection alone; 3 (8 %), combined arterial and venous resection; and 2 (6 %), arterialresection (superior mesenteric artery resection) alone. Patients included 18 men and 18women, with a median age <strong>of</strong> 62 (range, 42-82) years. The 90-day perioperative mortalityand morbidity rates were 0 and 35 percent, respectively, compared with 2 and 39 percent,respectively, for the group undergoing nonvascular pancreatic resection. Median survivalwas 18 (range, 8-42) months in the vascular resection group compared with 19 months in thenonvascular resection group. Multivariate analysis demonstrated node-positive disease,tumor location (other than head), and no adjuvant therapy as adverse prognostic variables.This means that in this combined experience, en bloc vascular resection consisting <strong>of</strong>venous resection alone, arterial resection alone, or combined vascular resection at the time<strong>of</strong> pancreatectomy for adenocarcinoma did not adversely affect postoperative mortality,morbidity, or overall survival. The need for vascular resection should not be acontraindication to surgical resection in the selected patient [480].Portal vein-superior mesenteric vein resection is frequently required after surgical resection<strong>of</strong> tumours <strong>of</strong> the pancreas head. Between 2000 and 2007, 28 patients had portal veinsuperiormesenteric vein resection and PVR during pancreaticoduodenectomy. Their clinicalreports were <strong>review</strong>ed retrospectively with specific attention to the methods <strong>of</strong> PVR andoutcomes. Ten patients had PVR with primary anastomosis, seven had PVR with autologousvein, one had a polytetrafluoroethylene (PTFE) patch, one did not have PVR and nine hadPVR with a PTFE interposition graft. There was no infection after PTFE grafting. Six patientshad PVR thrombosis after surgery: four after primary anastomosis, one after interpositionPTFE and one after vein repair. It was concluded that PTFE appeared to be an effective and

safe option as an interposition graft for portomesenteric venous reconstruction afterpancreaticoduodenectomy [481].Arterial reconstruction at pancreatic resectionThe arterial anatomy supplying the liver is highly variable. A replaced common hepatic arteryoriginating from superior mesenteric artery is a rare anomaly. It was presented the case <strong>of</strong> apatient with retropancreatic lymph nodes recurrence after laparoscopic cholecystectomy forpT2 gallbladder carcinoma, whose replaced common hepatic artery arose from the superiormesenteric artery. It was performed a Whipple operation en bloc with the replaced commonhepatic artery resection (enhanced by the tumour). The arterial reconstruction was needed(due to the severe decrease <strong>of</strong> the arterial flow after clamping the replaced common hepaticartery), using the splenic artery, without any serious complications [482].The authors report a case <strong>of</strong> operative injury <strong>of</strong> the hepatic artery during a total splenopancreasectomyprocedure for a mixed-type intraductal papillary mucinous neoplasm. Duringthe preparation <strong>of</strong> the structures <strong>of</strong> the hepatic pedicle, a "true" hepatic artery was notidentified, but only a small arterial vessel measuring about 2 mm in diameter, just in front <strong>of</strong>the portal vein, apparently emerging from the parenchyma <strong>of</strong> the pancreatic head. To obtaincomplete mobilisation <strong>of</strong> the duodeno-pancreatic block from the portal vein, it was necessaryto cut this small arterial vessel. In the postoperative period, the patient developed extensiveliver ischaemia, which was gradually resolved, but resulted in multiple stenosis <strong>of</strong> the intraandextra-hepatic biliary tree. At follow-up at three years, the patient was in fairly goodcondition, with a permanent percutaneous biliary drainage, but with no clinical or radiologicalsigns <strong>of</strong> local or distant disease. Although interruption <strong>of</strong> hepatic arterial flow is usually welltolerated, this is not always the case. It is important to predict in what circumstancescomplications are likely to occur. The main determinants that should guide the surgeon facedwith this problem are whether the portal circulation is normal, whether structures carryingcollateral blood supply have been interrupted, and whether some form <strong>of</strong> biliaryreconstruction is needed [483].Extended lymphadenectomySeveral factors argue for extended lymphadenectomy in surgery for pancreaticadenocarcinoma: 1) lymph node extension is an adverse prognostic factor; 2) some tumorrecurrences are only loco-regional suggesting that initial resection was insufficient; 3) someretrospective studies suggest that extension <strong>of</strong> lymphadenectomy improves post-resectionsurvival. Extended lymphadenectomy, including circumferential dissection <strong>of</strong> both the celiacaxis and the superior mesenteric artery and resection <strong>of</strong> para-aortic nodes, was evaluated by4 randomized trials; globally there was no survival benefit. Extended lymphadenectomyincreases, at least transiently, the risk <strong>of</strong> post-operative diarrhea. Its influence on the rate <strong>of</strong>loco-regional recurrences has not been evaluated. However, this technique should not bedefinitively and globally precluded since a more radical resection was associated with a trendtoward better long-term survival in the trial with the largest number <strong>of</strong> patients [484].CryosurgeryTo test the feasibility <strong>of</strong> cryosurgery for pancreatic carcinoma and to observe theconsequence <strong>of</strong> cryosurgery by two different techniques. Twelve healthy pigs underwentlaparotomy, during which, chop amputation <strong>of</strong> common bile duct and duodenum wereperformed, meanwhile other intra-abdominal organs with the pancreas were isolated. Twodifferent techniques <strong>of</strong> cryosurgery were performed on the pancreas. Group A (n=6)accepted the mild hypothermic cryosurgery with liquid nitrogen superficial refrigeration, andgroup B (n=6) were performed with the deep hypothermic cryosurgery at -170 o C with

LCS2000 cryogenic surgical system. All the animals' digestive tract was reconstructed withcholecystojejunostomy and gastroenterostomy, respectively. Acute necrotizing pancreatitisoccurred on all animals in group A, <strong>of</strong> which 5 <strong>of</strong> the 6 died within 1 week, whereas only 1 <strong>of</strong>the 6 reported a 4-week survival. All animals in group B survived during the observation, inwhich only a transient increment and a gradual correction <strong>of</strong> pancreatic amylase level wererecorded. Small pancreatic pseudocyst occurred in 1 case. It was concluded that mildhypothermic cryosurgery with liquid nitrogen superficial refrigeration might lead to pancreaticinjury and induce acute pancreatitis, yet deep hypothermic cryosurgery with adequate timeshowed a promising effect in destroying pancreatic tissue and preventing acute pancreatitis[485].Postoperative complicationsIt was aimed to compare different techniques using the definitions <strong>of</strong> the International StudyGroup <strong>of</strong> Pancreatic Surgery for postoperative complications after pancreaticoduodenectomy.The perioperative data <strong>of</strong> 119 patients that underwent pancreaticoduodenectomy bya single surgeon were retrospectively analyzed. Pancreaticojejunal anastomosis wasperformed using the dunking method (n=39), the duct-to-mucosa anastomosis method(n=40), and the duct-to-mucosa adaptation (n=40). The most frequent complication waspostoperative pancreatic fistula (POPF; grades A, 21 %; B, 8 %; and C, 3 %),postpancreatectomy hemorrhage (PPH; grades B, 7 % and C, 1 %), and delayed gastricemptying (DGE; grades A, 1 % and B, 6 %). No significant differences in POPF were foundbetween patients who underwent different types <strong>of</strong> pancreatic anastomoses. Only pancreaticductal adenocarcinoma and pancreatic texture were potentially related to POPF. Patientswith or without POPF grade A had significantly shorter postoperative stays than patients withgrade B or C POPF, and similar findings were obtained for DGE and PPH. It was concludedthat the successful management <strong>of</strong> pancreatic anastomoses depends more on a meticuloussurgical technique and appropriate experience rather than on the type <strong>of</strong> technique.Furthermore, the International Study Group <strong>of</strong> Pancreatic Surgery definitions <strong>of</strong> POPF, DGE,and PPH seem objective and universally acceptable [486].Surgical resultsAlthough a positive resection margin has been reported to be a strong prognostic factor afterresection for pancreatic cancer, several studies indicated that resection status did notindependently affect survival. The aim <strong>of</strong> one study was to examine the influence <strong>of</strong> resectionmargin status on survival after extended radical resection for pancreatic head cancer. Onehundred thirty-eight cases <strong>of</strong> pancreatoduodenectomy and 38 cases <strong>of</strong> pylorus-preservingpancreatoduodenectomy for invasive ductal carcinoma <strong>of</strong> the pancreas were retrospectivelyanalyzed. The resection margins were negative (R0) in 115 patients (65 %), microscopicallypositive (R1) in 38 patients (22 %), and grossly positive (R2) in 23 patients (13 %). Patientswith R1 resection survived significantly shorter (median survival time, MST, 9 months) thanR0 resection patients (MST, 15 months) but survived longer than R2 resection patients(MST, 6 months). By multivariate analysis, R2 resection, together with lymph nodemetastasis, portal venous system, and extrapancreatic nerve plexus invasions,independently affected the overall survival, but R1 resection was not significantly influential.It was concluded that R1 resection did not independently affect the survival [487].The authors analysed the results <strong>of</strong> 363 patients, who underwent surgery for pancreatic orperiampullary tumours. There were 175 operable and 188 inoperable cases. Thepreoperative data (age, gender, site <strong>of</strong> the tumour, characteristic clinical signs), as well assurgical methods are overviewed. A pancreatoduodenectomy was most frequently applied as

a curative surgery, while double-bypass was mainly performed for palliation. As far aspostoperative complications, especially the rate <strong>of</strong> pancreatic fistula, which is influenced bythe anastomotic method, were discussed. Reoperation and early postoperative mortality ratewas 5.7 percent and 4.5 percent in the operable cases, respectively. These numbers were1.6 percent and 6.9 percent among the inoperable cases [488].Long-term survivalAs surgeons, one may justifiably be proud <strong>of</strong> the significant role we have played in reducingboth the morbidity and mortality <strong>of</strong> pancreatoduodenectomy within the past 20 years. But, asJohn Howard once stated, the surgeon's role in curing pancreatic ductal adenocarcinoma islimited to "a margin-negative resection, accomplished with minimal postoperativecomplications." It is apparent that other intrinsic factors determine the likelihood <strong>of</strong> actualcure. Rather than being disappointed at the low rate <strong>of</strong> eradication <strong>of</strong> disease, surgeons cantake solace in being able to provide meaningful increases in the length <strong>of</strong> patient survival. Todetermine the actual eradication <strong>of</strong> disease rates for ductal adenocarcinoma <strong>of</strong> the pancreastreated by pancreatoduodenectomy, an extensive search <strong>of</strong> the <strong>literature</strong> was undertaken.Articles reporting actuarial survival rates were excluded, and only studies providing actualsurvival rates have been included in the analysis [489-498]. From the summarized data it canbe reach several important conclusions. First, actual 5-year survival after "curative"pancreatoduodenectomy for ductal adenocarcinoma <strong>of</strong> the pancreas is not common,occurring in only 1 in 10 patients undergoing resection for "cure." Nevertheless, the 10percent 5-year actual survival rate following pancreatoduodenectomy for ductaladenocarcinoma in this collected series is higher than many 5-year actual survival rates inprevious reports. This may be due to the large percentage <strong>of</strong> R0 resections included in thethe analysis. However, these results must also be tempered with the realization that 5-yearsurvivors <strong>of</strong> ductal adenocarcinoma <strong>of</strong> the pancreas can occur without resection and havebeen well documented [499]. Furthermore, to place these collective survival results in aneven broader perspective, the percentage <strong>of</strong> 5-year survivors would markedly diminish if thedenominator were to be changed from R0 resections to R1 resections, or if the denominatorincluded patients with adenocarcinoma <strong>of</strong> the body or tail <strong>of</strong> the gland. Another importantconclusion from the data is that 5-year surgical survivors continue to expire from recurrentpancreatic adenocarcinoma as they are followed for longer periods. By 10 years after"curative" resection, the number <strong>of</strong> survivors from the original surgical population haddecreased from 9.8 percent to 2.8 percent. Of course, not all <strong>of</strong> the deaths in the second 5-year observation period were due to recurrent pancreatic ductal adenocarcinoma, beenexpected to die after the 10-year mark, but deaths from recurrent adenocarcinoma <strong>of</strong> thepancreas have been known to occur more than 10 years after pancreatoduodenectomy [500,501]. Using a life-table analysis <strong>of</strong> age-matched healthy controls, Riall et al [502] haveestimated that, at some point in their course, 71 percent <strong>of</strong> 5-year surgical survivors will die<strong>of</strong> recurrent pancreatic ductal adenocarcinoma. Nevertheless, 20-year survivors afterpancreatoduodenectomy for documented ductal adenocarcinoma <strong>of</strong> the pancreas have beenreported. Almost certainly, some <strong>of</strong> these 10-year survivors either were living with recurrenceor would develop recurrence in the future. It seems clear that the answer to the question <strong>of</strong>the likelihood <strong>of</strong> eventual surgical "cure" is "not very likely.”The aim <strong>of</strong> one study was to determine the survival <strong>of</strong> patients with advanced, unresectablepancreatic cancer in relation to whether they underwent nonsurgical biopsy <strong>of</strong> their primarytumor. A total <strong>of</strong> 1481 patients with distant stage pancreatic cancer diagnosed between 1992and 2001 who underwent radiation treatment but not cancer-directed surgery were analyzed.The design is a retrospective cohort study from the Surveillance, Epidemiology, and EndResults program <strong>of</strong> the US National Cancer Institute. Of 1481 patients (median age, 66years) included in our analysis, 1406 (95 %) underwent nonsurgical biopsy (95 %) and 75 (5%) did not. There was no statistically significant difference in overall median survival

according to receipt <strong>of</strong> nonsurgical biopsy. A subgroup analysis <strong>of</strong> patients younger than 65years who did not undergo biopsy revealed a hazard ratio <strong>of</strong> 1.76 (95 % confidence interval,1.14 to 2.72); that is, there was a 76 percent higher hazard for death among younger patientswho did not undergo biopsy compared with those who did. It was concluded that nonsurgicalbiopsy did not seem to negatively impact survival among patients with advanced pancreaticcancer [503].Intrahepatic recurrent biliary tract stonesIntrahepatic biliary lithiasis is fairly rare in western countries. In a case described, liver stoneshad developed as a late consequence <strong>of</strong> biliary derivative surgery, which is well known tolead to this complication. However, this case is unusual because people who haveundergone radical surgery for cancer <strong>of</strong> the head <strong>of</strong> the pancreas seldom survive longenough for liver stones to develop. Treatment for this 65-year-old woman, previouslysubmitted to duodeno-cephalopancreatectomy, involved percutaneous balloon bilioplasty,with several passages in order to open the anastomosis. We then positioned two inner-outerbiliary drains, through which repeated lavages were done. Finally, the patient underwentlaser lithotripsy <strong>of</strong> the intrahepatic calculi and the fragments were cleared using a Dormiabasket. Repeated cholangiographic monitoring showed progressively fewer stones, until theintrahepatic biliary tree was finally completely clear 120 days after the initial diagnosis. At thelast follow-up, the patient was healthy, with normal blood values, considering her overallcondition [504].Body and tail tumorsIt was evaluated prognostic indicators for distal pancreatectomy with regional lymph nodedissection in pancreatic body or tail carcinoma. Between 1993 and 2008, 50 patients withductal carcinoma <strong>of</strong> the body or tail <strong>of</strong> the pancreas who underwent distal pancreatectomywith regional lymph node dissection were retrospectively analyzed. Clinicopathologicalfactors associated with patient survival were evaluated. No in-hospital deaths occurredamong the study patients. The overall 5-year survival rate was 19 percent, and mediansurvival was 23 months. Univariate analysis revealed that lymph node metastasis,intrapancreatic neural infiltration, peripancreatic nerve plexus infiltration, and tumordifferentiation affected patient survival significantly. Multivariate analysis validated lymphnode metastasis as an independent prognostic factor. Moreover, the lymph nodes attachedto the pancreas were the most frequent metastatic nodes, and the number <strong>of</strong> metastasis inthe lymph nodes attached to the pancreas was significantly associated with survival aftersurgical resection. It was concluded lymph node metastasis was a significant andindependent prognostic factor for the surgically resected pancreatic body or tail carcinoma.Furthermore, the lymph nodes attached to the pancreas were the most frequent metastaticnodes, and these lymph nodes were potential indicators predicting both tumor extension andsurvival after surgery for pancreatic body or tail carcinoma [505].Distal pancreatectomyPancreatic leak remains a major cause <strong>of</strong> postoperative morbidity in patients undergoingpancreatic resection. It was evaluated the incidence <strong>of</strong> and identify risk factors for thedevelopment <strong>of</strong> pancreatic leak in patients undergoing distal pancreatectomy (DP) at a singlehigh-volume institution. All patients who underwent primary open distal pancreatectomy(excluding completion pancreatectomy and debridement) between 1984 and 2006 wereidentified, and their medical records were <strong>review</strong>ed. In a cohort <strong>of</strong> 704 patients undergoingprimary DP, the indications for distal pancreatectomy were benign pancreatic neoplasm (34%), malignant pancreatic neoplasm (31 %), other neoplasm (15 %), chronic pancreatitis (14

%), pseudocyst (3 %), and trauma (3 %). The pancreatic remnant was sutured alone in 83percent, stapled alone in 5 percent, and both stapled and sutured in 9 percent <strong>of</strong> cases.Ligation <strong>of</strong> the pancreatic duct was performed in 22 percent <strong>of</strong> cases. Perioperative mortalitywas

pre-operative demographics, disease comorbidities, tumor size, length <strong>of</strong> operation, rates <strong>of</strong>postoperative mortality, postoperative morbidity, and pancreatic fistula. Patients undergoingLP were less likely to have ductal adenocarcinoma and had fewer lymph nodes harvested intheir resection but had a significantly shorter postoperative length <strong>of</strong> stay and significantlylower estimated blood loss than those undergoing ODP. It was concluded that laparoscopicdistal pancreatectomy is a safe, effective modality for managing premalignant neoplasms <strong>of</strong>the pancreatic body and tail, providing a morbidity rate comparable to that for ODP andsubstantially shorter length <strong>of</strong> stay. Laparoscopic distal pancreatectomy fails to provide alymphadenectomy comparable to open distal pancreatectomy. This may limit the applicability<strong>of</strong> laparoscopic distal pancreatectomy to the treatment <strong>of</strong> pancreatic adenocarcinoma [509].Despite the relatively slow start <strong>of</strong> laparoscopic pancreatectomy relative to otherlaparoscopic resections, an increasing number <strong>of</strong> these procedures are being performedaround the world. Operations that were once considered impossible to performlaparoscopically, such as pancreaticoduodenectomy and central pancreatectomy are gainingmomentum. Technology continues to improve, as does surgical experience and prowess.There are both enough experience and data (though retrospective) to confirm thatlaparoscopic distal pancreatectomy with or without spleen preservation appears to be a safetreatment for benign or noninvasive lesions <strong>of</strong> the pancreas. Based on the fact thatlaparoscopic distal pancreatectomy can be performed with similar or shorter operative times,blood loss, complication rates, and length <strong>of</strong> hospital stay than open distal pancreatectomy, itcan be recommended as the treatment <strong>of</strong> choice for benign and noninvasive lesions inexperienced hands when clinically indicated. It is very difficult to make clearrecommendations with regard to laparoscopic resection <strong>of</strong> malignant pancreatic tumors dueto the lack <strong>of</strong> conclusive data. As long as margins are negative and lymph node clearance iswithin accepted standards, laparoscopic distal pancreatectomy appears to have no untowardoncologic effects on outcome. Certainly more data, preferably in the manner <strong>of</strong> a randomizedclinical trial, are needed before additional recommendations can be made. Potential benefits<strong>of</strong> laparoscopic resection for cancer include the ability to inspect the abdomen and abort theprocedure with minimal damage if occult metastases are identified. This does not delay theonset <strong>of</strong> palliative chemotherapy, which would be the primary treatment in that circumstance.In fact, there is evidence to suggest that there is a greater likelihood <strong>of</strong> receiving systemictherapy if a laparotomy is avoided in patients who have radiologically occult metastases.Patients may also undergo palliative laparoscopic gastric and biliary bypass if indicated.Faster wound healing may also translate into a shorter waiting time before initiating adjuvantchemotherapy and/or radiation therapy. If the patient develops a wound infection, theinfection should be more readily manageable with smaller incisions. Although not provenclinically relevant in humans, the reduction in perioperative stress associated withlaparoscopic resection may translate to a cancer benefit for some patients. One reportcompared markers <strong>of</strong> systemic inflammatory response in 15 subjects undergoing leftpancreatectomy. Eight had hand-access laparoscopic procedures and the rest had standardopen surgery. The subjects in the laparoscopic group had statistically lower C-reactiveprotein levels than the open group on postoperative days one (5.5 mg/dL versus 9.7 mg/dL)and three (8.5 mg/dL versus 17.7 mg/dL), suggesting that the laparoscopic approach to leftpancreatectomy is associated with less inflammation. While this report is underpowered, itsupports the notion that MIS cancer surgery may induce less <strong>of</strong> a systemic insult to the bodythan standard open cancer surgery. More work in this area is necessary before any firmconclusions can be drawn. An important issue to consider is that <strong>of</strong> training surgeons toperform these complex procedures laparoscopically. Not all pancreatectomies are amenableto the laparoscopic approach, even in the most skilled hands. As such, only a percentage <strong>of</strong>cases will be performed this way and expectations to educate surgeons adequately toperform advanced laparoscopic procedures can be unrealistic, resulting in more "on-the-job"training. Another aspect that draws some controversy is that <strong>of</strong> the totally laparoscopicprocedure versus the hand-access approach. No laparoscopic instrument provides the tactilefeedback possible to obtain with the hand. Finally, it is important to remember that if the

procedure is failing to progress laparoscopically, or if cancer surgery principles are likely tobe violated, the surgeon (and the patient) must be willing to abort the laparoscopic approachand complete the operation using standard open technique. During the next few years wecan expect to see more robust outcome data with laparoscopic pancreatectomy. Theexpectation is that more data will come to light demonstrating benefits <strong>of</strong> laparoscopicpancreatic resection as compared with open technique for selected patients. Several groupsare considering randomized trials to look at these endpoints. Although more retrospectiveand prospectively maintained data will certainly be presented, it is less likely that randomizeddata specifically examining the question <strong>of</strong> laparoscopic versus open pancreatectomy forcancer will mature, due to some <strong>of</strong> the limitations discussed above. Additional areas <strong>of</strong>discovery are in staple line reinforcement for left pancreatectomy and suturing technology forpancreatico-intestinal anastomosis. Robotic surgery may have a role in pancreatic surgery.Improving optics and visualization with flexible endoscopes with provide novel surgical viewspotentially improving the safety <strong>of</strong> laparoscopy. Another area in laparoscopic surgery that isgaining momentum is that <strong>of</strong> Natural Orifice Transluminal Endoscopic Surgery (NOTES).NOTES represents the "holy grail" <strong>of</strong> incisionless surgery. Can we enucleate a small tumor<strong>of</strong>f the pancreatic body by passing an endoscope through the gastric (or colonic) wall, andbring the specimen out via the mouth or anus? Can we use this approach for formal leftpancreatectomies? Pioneers have already developed a porcine model <strong>of</strong> leftpancreatectomy. This technology must clear several hurdles before it is cancer ready;however, technology is moving at a rapid pace [510].Spleen-preserving laparoscopicallyLaparoscopic resection for small lesions <strong>of</strong> the pancreas has recently gained popularity. Itwas reported the initial experience with a new approach to laparoscopic spleen-preservingdistal pancreatectomy so that the maximum amount <strong>of</strong> normal pancreas can be preservedwhile ensuring adequate resection margins and preservation <strong>of</strong> the spleen and splenicvessels. Three patients underwent laparoscopic distal pancreatectomy with spleen andsplenic vessel preservation over a 2-month period. Two patients underwent resection usingthe conventional medial-to-lateral dissection as the lesion was close to the body or proximaltail <strong>of</strong> the pancreas. The third patient had a lesion in the distal tail <strong>of</strong> the pancreas andsurgery was carried out in a lateral-to-medial manner. This new approach minimizedexcessive sacrifice <strong>of</strong> normal pancreatic tissue for such distally located lesions. The splenicartery and vein were preserved in all cases and there was no significant difference in clinicaloutcome, operative time or intraoperative blood loss. It was concluded that although theconventional “medial-to-lateral” approach is recommended for more proximal tumours <strong>of</strong> thepancreas, distal lesions can be safely addressed using the “lateral-to-medial” approach [511].NOTESNatural orifice transluminal endoscopic surgery (NOTES) research has primarily involvedcase series reports <strong>of</strong> low-risk procedures. To compare endoscopic transgastric distalpancreatectomy (ETDP) and laparoscopic distal pancreatectomy a prospective trial in 41swine, laparoscopic pancreatectomy was performed with 3 trocars and stapled transection <strong>of</strong>the pancreas. ETDP was performed via a gastrotomy, with 1 trocar for visualization, by usingendoloop placement, snare transection, and purse-string gastrotomy closure. Swine weresurvived for 8 days. The procedure time for ETDP was significantly greater than for LDP.Pancreatic specimen weight was smilar. Postoperatively, 26 <strong>of</strong> 28 animals thrived. In thelaparoscopic group, 1 death caused by pancreatic leak and renal failure occurred on day 1.In the ETDP group, 1 death caused by pneumothorax occurred intraoperatively. Thenecropsy, CT, and histologic examinations revealed focal resection-margin necrosis in 3 to 7swine in the ETDP group with no proximal necrosis or pancreatitis. The groups wereequivalent clinically, by survival, and by serum and peritoneal fluid analysis. The gastrotomy

closure was associated with small serosal adhesions, but no gross abscess or necrosis.Thus, there was no clinical or survival difference between NOTES and laparoscopicapproaches [512].Renal function at pancreatoduodenectomyA retrospective study was conducted to compare measured creatinine clearance (Ccr) withestimated glomerular filtration rate (eGFR) as a preoperative renal function test in patientsundergoing pancreatoduodenectomy. The records <strong>of</strong> 139 patients undergoingpancreatoduodenectomy were enrolled, and preoperative Ccr, a 3-variable equation foreGFR (eGFR3) and a 5-variable equation for eGFR (eGFR5) were estimated. The maximumincreases in the postoperative serum creatinine and urea nitrogen levels were comparedbetween the groups with normal and abnormal levels relative to Ccr, eGFR3, and eGFR5.There were 30 patients with abnormal Ccr levels, 17 with abnormal eGFR3 levels, and 16with abnormal eGFR5 levels. Postoperative serum creatinine and urea nitrogen levels weresignificantly higher in patients with eGFR3 and eGFR5 abnormal levels than in patients witheGFR3 and eGFR5 normal levels. Postoperative serum creatinine and urea nitrogen levelstended to be higher in patients with Ccr abnormal level. The sensitivity and specificity <strong>of</strong>eGFR3 and eGFR5 for postoperative renal dysfunction were better than those <strong>of</strong> Ccr, andmultivariate analysis showed that eGFR5 was the only independent predictive factor forpostoperative renal dysfunction. Thus means that the eGFR5 and eGFR3, rather than thecreatinine clearence, are recommended as preoperative renal function test in patientsundergoing pancreatoduodenectomy [513].Glucose monitoringPeroperativelyTo evaluate a closed-loop system providing continuous monitoring and strict control <strong>of</strong>perioperative blood glucose following pancreatic resection it was performed a prospective,randomized clinical trial in 30 patients who had pancreatic resection for pancreatic neoplasm.Perioperative blood glucose levels were continuously monitored using an artificial endocrinepancreas (STG-22). Glucose levels were controlled using either the sliding scale method(sliding scale group, n=13) or the artificial pancreas (artificial pancreas group, n=17).Incidence <strong>of</strong> severe hypoglycemia (

Glucos metabolism after pancreatectomyThe aim <strong>of</strong> this study was to investigate the mechanisms <strong>of</strong> the change in glucosemetabolism after a pancreatoduodenectomy (PD). Oral glucose tolerance tests wereperformed in 17 patients before and 1 month after a PD. The changes in plasma glucose andinsulin concentrations, homeostasis model <strong>of</strong> insulin resistance, and insulinogenic index(beta-cell function) were analyzed. Two additional factors, gastric emptying function andplasma glucagon-like peptide-1 (GLP-1) concentration that possibly affect perioperativeglucose metabolism were also assessed. The plasma glucose and insulin concentrationswere significantly lower after the operation, especially in preoperative diabetic patients. beta-Cell function did not change after the operation. On the other hand, insulin resistancebecame normal 1 month after the operation. The value <strong>of</strong> gastric emptying function after theoperation was not statistically different in comparison with that before the operation.Postoperative plasma GLP-1 concentration was significantly higher than the preoperativevalue. It was concluded that beta-cell function is maintained after a pancreatoduodenectomy,whereas the improvement <strong>of</strong> insulin resistance may cause a short-term transientimprovement <strong>of</strong> the glucose metabolism after the operation. The significance <strong>of</strong> increasedpostoperative GLP-1 concentration remains an unsolved issue [515].PalliationInadequate nutrient intake is common in cancer patients and is associated with pooroutcomes. Social factors may contribute to inadequate nutrient intake, although they havenot been studied. The purpose <strong>of</strong> one study was to investigate social factors that maycontribute to undereating in older adults with cancer. Participants included 30 patients, 17women and 13 men, aged 70-99 years, who were diagnosed with pancreatic, colon, breast,lymphoma, skin, and head and neck cancers. Both participants and caregivers interpretedweight loss as a positive health outcome <strong>of</strong> cancer. Furthermore, some patients who had lostweight worked to keep the weight <strong>of</strong>f by going on special diets. Patients and caregiversimbued certain foods with health-promoting qualities without corroborating scientificevidence. Cancer- and treatment-related alterations in self-identity due to changes in theirbodies, in taste, and in the manner in which they must eat caused cancer patients toexperience frustration and embarrassment, which led to reduced nutritional intake. Despitetheir compromised nutritional status, patients did not discuss food and eating habits with theirphysicians. Behaviors and attitudes <strong>of</strong> patients and caregivers may lead to negative changesin eating behaviors beyond the cancer itself or its treatment or sequelae. Many <strong>of</strong> thesebehaviors are potentially modifiable with appropriate education, communication, andintervention [516].Palliative stentingIn the endoscopic management <strong>of</strong> unresectable malignant biliary obstructions by placement<strong>of</strong> a metallic stent, longer patency and a lower incidence <strong>of</strong> stent occlusion are desirablegoals. With its mesh structure, the uncovered metallic stent is occluded mainly by tumor ortissue ingrowth, making it impossible to remove. The covered metallic stent was developedto overcome these disadvantages, and was shown to maintain patency longer than theuncovered in one randomized study. The most important characteristic <strong>of</strong> the covered stentis that it is removable, allowing it to be used in patients with resectable malignancies andbenign strictures. In addition, the drug-eluting covered metallic stent provides an additionalapproach to the treatment <strong>of</strong> biliary malignancies. The covered stent may also change thetreatment paradigm for biliary strictures and strictures due to chronic pancreatitis. Thecovered metallic stent is analogous to a large-bore, expandable plastic stent and is effectiveboth as an endoprosthesis and a dilating or anti-cancer device. However, to better

understand the utility <strong>of</strong> these devices, one need to first consider mechanical properties suchas radial force (expansion force) and axial force (straightening force) [517].Endoscopic biliary drainage is widely accepted as palliative treatment in patients withpancreatic cancer. One study was designed to compare self-expanding metal stent andpolyethylene stent in a homogeneous patient group with advanced pancreatic cancer. Thestudy included 154 patients initially treated with a metal or plastic stent. Median survival time,stent patency, and stent-associated hospital admissions were evaluated. The mediansurvival time in patients treated with metal and plastic stent was 6 and 4 months,respectively. Self-expanding metal stents have a significantly higher patency rate thanpolyethylene stents. Stent occlusion was observed in 21 (33 %) <strong>of</strong> 63 patients in the plasticstent group after a median period <strong>of</strong> 57 days and in 17 (19 %) <strong>of</strong> 91 patients in the metalstent group after a median period <strong>of</strong> 126 days. The total time <strong>of</strong> hospital stay after initialimplantation <strong>of</strong> metal or plastic stent was 7 and 17 days, respectively. It was concluded thatself-expanding metal stents have a longer patency than polyethylene stents. Additionally, thenumber <strong>of</strong> stent-associated hospital admissions and the total time <strong>of</strong> hospital stay werehigher in the plastic stent group. The median survival time was not significantly different inboth groups [518].Prediction <strong>of</strong> survivalThe pancreatic nomogram, originally developed in the Memorial Sloan-Kettering CancerCenter in the USA, combines clinicopathological and operative data to predict diseasespecificsurvival at 1, 2 and 3 years from initial resection. An external patient cohort from aretrospective pancreatic adenocarcinoma database at the Academic Medical Centre inAmsterdam was used to test the validity <strong>of</strong> the pancreatic adenocarcinoma nomogram. Thecohort included 263 consecutive patients who had surgery between 1985 and 2004. Data forall the necessary variables were available for 256 patients (97 %). At the last follow-up, 35patients were alive, with a median follow-up <strong>of</strong> 27 (range 3-114) months. The 1-, 2- and 3-year disease-specific survival rates were 61, 30 and 16 percent respectively. The nomogramconcordance index was 0.61. The calibration analysis <strong>of</strong> the model showed that the predictedsurvival did not significantly deviate from the actual survival. The Memorial Sloan-KetteringCancer Center pancreatic cancer nomogram provided an accurate survival prediction. It mayaid in counselling patients and in stratification <strong>of</strong> patients for clinical trials [519].Identification <strong>of</strong> defined patient groups based on a prognostic index may improve theprediction <strong>of</strong> survival and selection <strong>of</strong> therapy for patients with pancreatic cancer. Manyprognostic factors have been identified <strong>of</strong>ten based on retrospective, underpowered studieswith unclear analyses. Data from 653 patients were analysed. Continuous variables are <strong>of</strong>tensimplified assuming a linear relationship with log hazard or introducing a step function(dichotomising). Misspecification may lead to inappropriate conclusions but has not beenpreviously investigated in pancreatic cancer studies. Models based on standard assumptionswere compared with a novel approach using nonlinear fractional polynomial transformations.The model based on fractional polynomial-transformed covariates was most appropriate andconfirmed five previously reported prognostic factors: albumin, CA 19-9, alkalinephosphatase, LDH and metastases, and identified three additional factors not previouslyreported: WBC, AST and BUN. The effects <strong>of</strong> CA 19-9, alkaline phosphatase, AST and BUNmay go unrecognised due to simplistic assumptions made in statistical modelling. Weadvocate a multivariable approach that uses information contained within continuousvariables appropriately. The functional form <strong>of</strong> the relationship between continuouscovariates and survival should always be assessed [520].

Quality <strong>of</strong> lifeOne study was designed to assess postoperative changes in the quality <strong>of</strong> life (QoL) <strong>of</strong>patients after surgical treatment for pancreatic cancer in a prospective single-centre studythat included 54 patients with pancreatic cancer. Patients with potentially resectable tumoursunderwent pancreaticoduodenectomy (n=26), a double-bypass procedure (DBP) (n=17) orlaparotomy (n=11). They were asked to complete a questionnaire before and at 1, 2, 3 and 6months after surgery. QoL was assessed using the EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires (European Organization for Research and Treatment <strong>of</strong> CancerQuality <strong>of</strong> Life Questionnaire C30 and PAN26). The patients did not demonstrate significantdifferences in the assessment <strong>of</strong> their global health status. Although, after resection, patientsgave a positive assessment <strong>of</strong> most parameters in question, after DBP they reported someaggravation <strong>of</strong> most <strong>of</strong> the symptoms. The majority <strong>of</strong> patients did not have aggravatedsymptoms after laparotomy. It was concluded that the study had shown the value <strong>of</strong>conducting both curative and palliative resection for QoL. Bypass procedures should beperformed in cases <strong>of</strong> non-resectable pancreatic cancer with accompanying jaundice and/orgastric outlet obstruction in patients with a life expectancy <strong>of</strong> at least 6 Montis [521].Quality <strong>of</strong> carePancreatic cancer outcomes vary considerably among hospitals. Assessing pancreaticcancer care by using quality indicators could help reduce this variability. However, validquality indicators are not currently available for pancreatic cancer management, and acomposite assessment <strong>of</strong> the quality <strong>of</strong> pancreatic cancer care in the United States has notbeen done. Potential quality indicators were therefore identified from the <strong>literature</strong>,consensus guidelines, and interviews with experts. A panel <strong>of</strong> 20 pancreatic cancer expertsranked potential quality indicators for validity based on the RAND/UCLA AppropriatenessMethodology. The rankings were rated as valid (high or moderate validity) or not valid.Adherence with valid indicators at both the patient and the hospital levels and a compositemeasure <strong>of</strong> adherence at the hospital level were assessed using data from the NationalCancer Data Base (2004-2005) for 49 065 patients treated at 1134 hospitals. Summarystatistics were calculated for each individual candidate quality indicator to assess the medianranking and distribution. Of the 50 potential quality indicators identified, 43 were rated asvalid (29 as high and 14 as moderate validity). Of the 43 valid indicators, 11 (26 %) assessedstructural factors, 19 (44 %) assessed clinical processes <strong>of</strong> care, four (9 %) assessedtreatment appropriateness, four (9 %) assessed efficiency, and five (12 %) assessedoutcomes. Patient-level adherence with individual indicators ranged from 50 percent to 97percent, whereas hospital-level adherence with individual indicators ranged from 7 to 100percent. Of the 10 component indicators (contributing 1 point each) that were used todevelop the composite score, most hospitals were adherent with fewer than half <strong>of</strong> theindicators (median score = 4; interquartile range = 3-5). Based on the quality indicatorsdeveloped in this study, there is considerable variability in the quality <strong>of</strong> pancreatic cancercare in the United States. Hospitals can use these indicators to evaluate the pancreaticcancer care they provide and to identify potential quality improvement opportunities [522].OrganizationThe authors systematically <strong>review</strong>ed the association between provider case volume andmortality in 101 publications involving greater than 1 million patients with esophageal, gastric,hepatic, pancreatic, colon, or rectal cancer, <strong>of</strong> whom more than 70,000 died. The majority <strong>of</strong>studies addressed the relation between hospital surgical case volume and short-termperioperative mortality. Few studies addressed surgeon case volume or evaluated long-termsurvival outcomes. Common methodologic limitations were failure to control for potential

confounders, post hoc categorization <strong>of</strong> provider volume, and unit <strong>of</strong> analysis errors. Asignificant volume effect was evident for the majority <strong>of</strong> gastrointestinal cancers; with eachdoubling <strong>of</strong> hospital case volume, the odds <strong>of</strong> perioperative death decreased by 0.1 to 0.23.The authors calculated that between 10 and 50 patients per year, depending on cancer type,needed to be moved from a "low-volume" hospital to a "high-volume" hospital to prevent 1additional volume-associated perioperative death. Despite this, approximately one-third <strong>of</strong> allanalyses did not find a significant volume effect on mortality. The heterogeneity <strong>of</strong> resultsfrom individual studies calls into question the validity <strong>of</strong> case volume as a proxy for carequality, and leads the authors to conclude that more direct quality measures and the validity<strong>of</strong> their use to inform policy should also be explored [523].ChemotherapyGemcitabine has been standard therapy for advanced pancreatic cancer for well over adecade. The addition <strong>of</strong> capecitabine or erlotinib to gemcitabine has resulted in modestlyimproved, although still poor, overall survival. The majority <strong>of</strong> the recently completedrandomized trials, however, have failed to demonstate an improvement <strong>of</strong> newer treatmentsover single-agent gemcitabine. Efforts currently underway center on new cytotoxicchemotherapy drugs, as well as novel targeted agents inhibiting various molecular pathways.Newly discovered proteins and cellular elements involved in tumor growth and invasion arepotential therapeutic targets, and have become the focus <strong>of</strong> current trials, as well as futureclinical trials. A better understanding <strong>of</strong> the biology <strong>of</strong> the disease at the basic science level,and epidemiology and risk factors from a public-health perspective, are needed. Continuedresearch is clearly warranted with the goal <strong>of</strong> improving survival and optimizing treatmentoutcomes in locally advanced and metastatic pancreatic cancer [524].Within a multi-centre, randomised phase II trial, 95 patients with locally advanced pancreaticcancer were assigned to three different chemoradiotherapy regimens: patients receivedconventionally fractionated radiotherapy <strong>of</strong> 50 Gy and were randomised to concurrent 5-fluorouracil (350 mg m 2 per day on each day <strong>of</strong> radiotherapy, RT-5-FU arm), concurrentgemcitabine (300 mg m 2 ), and cisplatin (30 mg m 2 ) on days 1, 8, 22, and 29 (RT-GC arm), orthe same concurrent treatment followed by sequential full-dose gemcitabine (1000 mg m 2 )and cisplatin (50 mg m 2 ) every 2 weeks (RT-GC+GC arm). Primary end point was the overallsurvival (OS) rate after 9 months. The 9-month OS rate was 58 percent in the RT-5-FU arm,52 percent in the RT-GC arm, and 45 percent in the RT-GC+GC arm. Corresponding mediansurvival times were 9.6, 9.3, and 7.3 months, respectively. The intent-to-treat response ratewas 19, 22, and 13 percent, respectively. Median progression-free survival was estimatedwith 4.0, 5.6, and 6.0 months. Grade 3/4 haematological toxicities were more frequent in thetwo GC-containing arms, no grade 3/4 febrile neutropaenia was observed. This means thatnone <strong>of</strong> the three chemoradiotherapy regimens tested met the investigators' definition forefficacy; the median OS was similar to those previously reported with gemcitabine alone inlocally advanced pancreatic cancer [525].Adjuvants and neoadjuvantsNeoadjuvant radiochemotherapyIt was explored surgical results after neoadjuvant chemoradiation therapy (NACRT) forpatients with pancreatic cancer that extended beyond the pancreas. Sixty-eight consecutivepatients with pancreatic cancer who underwent pancreatic resection were included. Twentysevenpatients underwent surgical resection after NACRT (NACRT group). The other 41patients were classified as surgery-alone group. Surgical results were compared in patientswho underwent curative resection (R0/1) who were followed up for at least 25 months andunderwent no adjuvant therapy. A significantly lower frequency <strong>of</strong> lymph node metastasis

was observed in the NACRT group. The frequency <strong>of</strong> residual tumor grading in the NACRTgroup was significantly different from that in surgery-alone (R0/1/2 %, 52/15/33 vs 22/51/27).In R0/1 cases, overall survival and disease-free survival rates in the NACRT group (n=18)were significantly longer than in surgery-alone (n=30). The rate <strong>of</strong> local recurrence in theNACRT group was significantly less than in surgery-alone (11 % vs 47 %). It was concludedthat this single-institution experience indicates that neoadjuvant chemoradiation therapy isable to increase the resectability rate with clear margins and to decrease the rate <strong>of</strong>metastatic lymph nodes, resulting in improved prognosis <strong>of</strong> curative cases with pancreaticcancer that extended beyond the pancreas [526].Adjuvant chemoradiationThe role <strong>of</strong> adjuvant chemoradiation therapy (CRT) in pancreatic cancer remainscontroversial. The primary aim <strong>of</strong> one study was therefore to determine if CRT improvedsurvival in patients with resected pancreatic cancer in a large, multiinstitutional cohort <strong>of</strong>patients. Patients undergoing resection for pancreatic adenocarcinoma from seven academicmedical institutions were included. Exclusion criteria included patients with T4 or M1 disease,R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy statuswas unknown. There were 747 patients included in the initial evaluation. Primary analysiswas performed between patients that had surgery alone (n=374) and those receivingadjuvant CRT (n=299). Median follow-up time was 12 months and 15 months, respectively,for survivors. Median overall survival for patients receiving adjuvant CRT was significantlylonger than for those undergoing operation alone (20 vs 15 months). On subset andmultivariate analysis, adjuvant CRT demonstrated a significant survival advantage onlyamong patients who had lymph node (LN)-positive disease (hazard ratio 0.48, 95 % CI 0.36to 0.64) and not for LN-negative patients (hazard ratio 0.81, 95 % CI 0.56 to 1.18). Diseasefreesurvival in patients with LN-negative disease who received adjuvant CRT wassignificantly worse than in patients who had surgery alone (15 months vs 19 months). Thusthis large multiinstitutional study emphasizes the importance <strong>of</strong> analyzing subsets <strong>of</strong> patientswith pancreas adenocarcinoma who have LN metastasis. Benefit <strong>of</strong> adjuvant CRT is seenonly in patients with LN-positive disease, regardless <strong>of</strong> resection margin status. CRT inpatients with LN-negative disease may contribute to reduced disease-free survival [527].Pre- plus postoperative chemoradiationTo evaluate both the feasibility and efficacy <strong>of</strong> our combined therapy, which consisted <strong>of</strong>preoperative chemoradiation, surgery, and postoperative liver perfusion chemotherapy (LPC)for patients with T3 (extended beyond the pancreatic confines) cancer <strong>of</strong> the pankreas 38patients with T3-pancreatic cancers consented to receive a combination <strong>of</strong> preoperativechemoradiation, surgery, and postoperative LPC 2002 to 2007. With the aid <strong>of</strong> 3D radiationplanning, irradiation fields were constructed that included both the primary pancreatic tumorand retropancreatic tissues while taking care to exclude any section <strong>of</strong> the gastrointestinaltract. The total dose <strong>of</strong> radiation was 50 Gy (2 Gy x 25 fractions/5 weeks) and wasadministered in combination with gemcitabine treatments (1000 mg/m/week x 9/3 months).Preoperative restaging via computerized tomography and intraoperative inspection wereused to determine if pancreatectomy was indicated. For resected cases, one catheter wasplaced into the gastroduodenal artery and another one into the superior mesenteric vein.Postoperatively, 5-FU (125 mg/day x 28 days) was infused via each <strong>of</strong> these 2 routes.Preoperative chemoradiation was completed for all 38 patients, including 3 patients whorequired gemcitabine-dose reduction. Seven patients (18 %) did not undergo surgicalresection because either distant metastases or progressive local tumors had been detectedafter chemoradiation. The remaining 31 patients (82 %) underwent pancreatectomy pluspostoperative perfusion chemotherapy, without postoperative or in-hospital mortality. The 5-year survival rate after pancreatectomy was 53 percent, with low incidences <strong>of</strong> both localrecurrence (9 %) and liver metastasis (7 %). Postoperative histopathologic study revealed amarked degenerative change in cancer tissue, showing negative surgical margins (R0) for 30patients (96 %) and negative nodal involvement for 28 patients (90 %) [528].

Adjuvant 5-FUThe ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364deaths) were used to estimate the effectiveness <strong>of</strong> adjuvant 5FU/FA vs resection alone forpancreatic cancer using meta-analysis. The pooled hazard ratio <strong>of</strong> 0.70 (95 % confidenceinterval 0.55 to 0.88), and the median survival <strong>of</strong> 23 (95 % confidence interval 20 to 27)months with 5FU/FA versus 17 (14 to 19) months with resection alone supports the use <strong>of</strong>adjuvant 5FU/FA in pancreatic cancer [529].Liver perfusion chemotherapy (LPC) for pancreatic cancer has been rarely undertaken in apostoperative adjuvant setting. It was evaluated the feasibility and antitumor efficacy <strong>of</strong> LPCwith 5-fluorouracil (5-FU) followed by gemcitabine treatment 27 consecutive patients whounderwent pancreatic resection and subsequent LPC + gemcitabine treatment during a 3-year period. The liver was infused with 5-FU (125 mg/body per day per route) via both routes<strong>of</strong> hepatic artery and portal vein for more than 21 days. After that, gemcitabine (1000 mg/m 2 )was administered biweekly. Portal vein thrombosis developed in 1 patient, but 89 percent <strong>of</strong>patients tolerated LPC for more than 21 days with no life-threatening complication. Systemicadministration <strong>of</strong> gemcitabine was accomplished in 93 percent; however, 1 patient died <strong>of</strong>serious capillary leak syndrome. No grade 4 toxicity was recorded, except for that patient.Median survival time and disease-free survival were 28 and 25 months, respectively. Hepaticrelapse was observed in 26 percent (n=7). Survival was in favor <strong>of</strong> paraaortic node-negativecases (n=20) with a 2-year survival <strong>of</strong> 69 percent. This adjuvant chemotherapy showspromising survival benefit and seems to be indicative to paraaortic node-negative tumors[530].5-Fluorouracil-cisplatin chemoradiationThe aim <strong>of</strong> one study was to assess the outcome <strong>of</strong> patients who received neoadjuvant 5-fluorouracil-cisplatin chemoradiation (CRT) for stage I/III pancreatic adenocarcinoma. Eligiblepatients (n=101) received radiation therapy (45 Gy) associated with continuous infusion <strong>of</strong> 5-fluorouracil accompanied by a cisplatin bolus. Of the 102 patients enrolled in the study, 26patients had progression <strong>of</strong> cancer during treatment and were deemed unresectable; 1patient died during CRT <strong>of</strong> septic shock. Sixty-two <strong>of</strong> 75 remaining patients underwentpancreaticoduodenectomy. The overall median survival <strong>of</strong> all 102 patients in the study was17 months, with a 5-year survival <strong>of</strong> 10 percent. For patients who underwent resection, themedian survival was 23 months. Correspondingly, the median survival was 11 months for the40 unresected patients. The 5-year survivals for resected and unresected patients were 18and 0 percent, respectively. A complete pathological response to neoadjuvant CRT wasnoted for 8 patients (13 %). Margin and lymph node positivity was present in 5 (8 %) and 15(24 %) patients, respectively. There was documented local recurrence in 8 (13 %) anddistant recurrence in 36 (58 %) patients, with the liver being the most common site [531].Adjuvant radiotherapyThe role <strong>of</strong> adjuvant radiotherapy (RT) for pancreatic cancer remains controversial despitethe completion <strong>of</strong> three multi-institutional randomized trials. One study examined the survivalimpact <strong>of</strong> postoperative radiotherapy in a large population-based database. Patients withpancreatic cancer diagnosed from 1988 to 2003 were identified in the Surveillance,Epidemiology, and End Results (SEER) database. The cohort was limited to patients whounderwent resection <strong>of</strong> nonmetastatic disease to yield a population <strong>of</strong> 3252 patients. Theprimary end point was overall survival. Survival analyses were conducted using correctionsfor perioperative mortality as well as a propensity score analysis to account for baselinedifferences in patient characteristics. Multiple independent factors were significantlyassociated with RT use, including patient age and disease stage. In general, youngerpatients and those with more advanced disease were more likely to receive radiotherapy.Disease stage significantly affected survival. For patients who survived at least 6 months,adjuvant RT was associated with increased survival (hazard ratio, 0.87; 95 % confidence

interval 0.80 to 0.96]. On subgroup analysis, only stage IIB (T1-3N1) patients enjoyed astatistically significant benefit associated with radiotherapy (hazaed ratio, 0.70; 95 %confidence interval 0.62 to 0.79). Although radiotherapy is associated with a survival benefitfor nonmetastatic patients as a whole, this trend appears to predominantly derive from asurvival benefit in patients with stage IIB disease [532].Adjuvants among elderlyIt was conducted a population-based study to describe the utilization, determinants, andsurvival effects <strong>of</strong> adjuvant therapies after surgery among older patients with pancreaticcancer. Using Surveillance, Epidemiology, and End Results-Medicare data, it was identifiedpatients older than 65 years who received surgical resection for pancreatic cancer during1992-2002. Approximately 49 percent <strong>of</strong> patients received adjuvant therapy after surgery.Patient factors associated with increased receipt <strong>of</strong> adjuvant therapy included more recentdiagnosis, younger age, stage II disease, higher income, and geographic location. Hospitalfactors associated with increased receipt <strong>of</strong> adjuvant therapy included cooperative groupmembership and larger size. Adjuvant treatments associated with a significant reduction in 2-year mortality (relative to surgery alone) were chemoradiation or radiation alone but notchemotherapy alone. The findings suggest that adjuvant chemoradiation and, to a lesserdegree, radiation only are associated with a reduction in the risk <strong>of</strong> mortality among olderpatients who undergo surgery for pancreatic cancer. However, receipt <strong>of</strong> adjuvant therapyvaried by period and geography as well as by certain patient and hospital factors [533].Palliative cytotoxic treatmentEvaluation <strong>of</strong> effectsA study was conducted to assess changes in tumor vascularity using contrast-enhancedultrasonography in patients with pancreatic carcinoma under systemic chemotherapy and toexamine the correlation among vascular change, clinicopathologic factors, and outcome.Forty-one consecutive patients with histopathologically confirmed pancreatic carcinoma whohad distant metastases and were under systemic chemotherapy were recruited. Contrastenhancedultrasonography was performed before and after 1 and 2 cycles <strong>of</strong> treatment.Thevascular signals from the tumor were continuously recorded,and the highest signal intensitywas selected and classified into 5 categories by their intensity. As for the tumor responsedetermined by dynamic computed tomography after 2 cycles, 6 patients showed a partialresponse, 25 remained stable, and in 10 patients, the disease progressed. A significantrelationship was observed between vascular change after 1 cycle and tumor response.Progression-free survival and overall survival were significantly short in the case <strong>of</strong> patientsshowing increased vascularity after 1 and 2 cycles <strong>of</strong> chemotherapy, compared with thosewho did not. It was concluded that contrast-enhanced ultrasonography was useful toevaluate tumor vascular changes and thereby the effect <strong>of</strong> systemic chemotherapy, as wellas the prognosis <strong>of</strong> patients with advanced pancreatic carcinoma [534].GemcitabineGemcitabine is an anti-cancer drug known to be safe and effective for pancreatic or biliarytract cancers, but lung injury is also known to be a rare side effect that sometimes becomessevere. It was report seven cases <strong>of</strong> lung injury during gemcitabine treatment. Drug-inducedlung injury was suspected in all cases. The male : female ratio was 5:2, and the averagepatient age was 71. Four had pancreatic cancers and three had biliary tract cancers.Gemcitabine had been administered an average 5.9 times at a dose <strong>of</strong> 1141 mg. Patientsshowed a diffuse or patchy shadow mainly in the lower lung on computed tomographyexamination. Grades <strong>of</strong> adverse events were greater than 3 in all cases. Three patients died<strong>of</strong> the lung injury. Five cases had pulmonary emphysema, 2 had metastatic lung tumor asunderlying pulmonary lesions, and these were assumed to have been important risk factorsfor drug-induced interstitial lung injury during gemcitabine treatment [535].

A 67-year-old male with pancreatic cancer (cStage IVb) was given gemcitabine on days 1, 8and 15, and this was repeated on 29 days at dose <strong>of</strong> 800 mg/m(2) in outpatient clinic. After 2courses, he suffered from dyspnea and fever. Laboratory examination showed that theserum levels <strong>of</strong> white cell count, C-reactive protein, lactate dehydrogenase and KL-6 wereelevated. Chest X-ray and CT revealed diffuse bilateral interstitial infiltrates. He wasdiagnosed with drug induced interstitial pneumonia due to gemcitabine. Corticosteroidtherapy consisting <strong>of</strong> methylprednisolone (1,000 mg/day) for three days followed byprednisolone was effective and he was discharged on the 29th day after admission. Acutepulmonary toxicity induced by gemcitabine could lead to severe complication [536].Gemcitabine plus cisplatinThe antitumor activity and toxicity <strong>of</strong> a multi-step treatment were evaluated in patients withlocally advanced, inoperable, or incompletely resected adenocarcinomas in 54 patients, 63percent with pancreatic cancer and 37 percent with biliary tract tumors. The patients received3 courses <strong>of</strong> cisplatin-gemcitabine induction chemotherapy. Progression-free (PF) patientswere given consolidation radiotherapy with concurrent capecitabine. PF patients had, asmaintenance immunotherapy interleukin 2 (1.8 x 106 IU) and 13-cis-retinoic acid (5 mg/kg).Thirty-eight patients, 27 with pancreatic and 11 with biliary tract adenocarcinomas, PF aftercisplatin/gemcitabine, were treated with consolidation radiotherapy with concurrentcapecitabine. Fourteen progressive free patients, 7 with pancreatic and 7 with biliary tractcancers, received maintenance immunotherapy. Median PF and overall survivals (OS) for all54 patients were 7 and 12 months, respectively. Patients treated with maintenanceimmunotherapy had a median PF survival <strong>of</strong> 16 months, whereas median OS had not beenreached yet, after a median follow-up <strong>of</strong> 28 months. Toxicity grades 3 and 4 forhematological and gastrointestinal was seen in 30 and 37 percent <strong>of</strong> patients, respectively;grades 1 and 2 autoimmune reactions were seen in 28 percent <strong>of</strong> patients. It was concludedthat these results support the efficacy and safety <strong>of</strong> a multi-step sequential treatment inpatients with locally advanced, inoperable or incompletely resected pancreatic and biliarytract adenocarcinomas [537].Gemcitabine plus S-1The patient was a 54-year-old male. He underwent resection <strong>of</strong> the pancreatic body tailregion to treat pancreatic body tail cancer. On histopathological examination, the stump <strong>of</strong>the extirpated specimen was positive for tumor cells. After surgery, 10 courses <strong>of</strong> therapywith gemcitabine hydrochloride (GEM, 1, 000 mg/m 2 , 3-week administration followed by 1-week discontinuation) were performed, and follow-up was continued. When a local relapsewas detected chemotherapy with GEM was administered for 1 year and 9 months. However,when an increase in the recurrent lesion size and right lung metastasis were noted theregimen was switched to combination therapy with S-1 and GEM (S-1 60 mg/m 2 day,continuous administration on days 1 to 14 and 2-week discontinuation; and GEM 1, 000 mg/m 2 , administered on days 8 and 15). After the end <strong>of</strong> the 11th course, PET-CT revealed thedisappearance <strong>of</strong> FDG accumulation in the recurrent and metastatic lesion sites. During thetreatment period, there were no grade 3 or higher adverse reactions [538].A retrospective study aimed to evaluate the anti-tumor activity and toxicity <strong>of</strong> combinationchemotherapy with gemcitabine (GEM) and oral S-1 or UFT in patients with advanced ormetastatic pancreatic cancer. Ninety-four patients received chemotherapy. Among them,sixty-three were treated with GEM alone, twenty-two with UFT and GEM (UFT/GEM), andnine with S-1 and GEM ( S-1/GEM). The median survival time was 9 months with GEM, 7months with UFT/GEM, and 23 months with S-1/GEM. The overall response rate was 11percent, 10 percent, and 22 percent, respectively. The 1-year survival rate was 30 percent,36 percent, and 86 percent, respectively. Although the treatment-related adverse effectswere not infrequent in patients treated with S-1/GEM, they were moderate in intensity. Thecombination chemotherapy with S-1/GEM was well tolerated and yielded a high response

ate in patients with pancreatic cancer [539].Gemcitabine and iridotecanSingle-agent gemcitabine has been established as standard treatment for advancedpancreatic cancer since clinical studies have shown an improvement in overall survival andsignificant clinical benefit when compared to the best supportive care despite low overallobjective response. Several phase II studies have tested other single agents and differentgemcitabine-based regimens in pancreatic cancer, but both response and survival rates haveremained low. Irinotecan, a topoisomerase I inhibitor currently approved for the treatment <strong>of</strong>metastatic colon cancer, has also demonstrated improved response rate in patients withpancreatic cancer. Our purpose was to determine the activity and toxicity <strong>of</strong> this regimen inpatients with The or metastatic pancreatic cancer. Patients with histologically confirmedpancreatic adenocarcinoma received gemcitabine 1000 mg/m 2 plus irinotecan 100 mg/m 2intravenously on days 1, 8, and 15 <strong>of</strong> a 28-day cycle for 6-8 months. From 2004 to 2006, 33patients were entered into this study, 32 <strong>of</strong> whom were evaluable for treatment response,toxicity, median time to progression, and median survival. Characteristics included a medianage <strong>of</strong> 63 years (range 41-79). One patient discontinued treatment due to adverse effects.The total number <strong>of</strong> cycles administered was 188 and the median number <strong>of</strong> cycles forpatients was 6 (range 2-7). Thirty-two patients were assessable for toxicity and response.Grade 3 hematological toxicity occurred in 9 percent <strong>of</strong> patients and was primarilyneutropenia. No grade >2 gastrointestinal toxicities or death due to treatment were observed.The most frequent nonhematological adverse event was fatigue. Ten patients responded totreatment with two complete responses (6 %) and eight partial responses (25 %), for anoverall response rate <strong>of</strong> 31 percent; 11 patients achieved stable disease (34 %). The mediantime to tumor progression and the median survival were 9 (95 % confidence interval 6.0 to12.4) and 12 (95 % confidence interval 7.7 to 15.9) months, respectively, with a 2-yearsurvival <strong>of</strong> 22 percent. On the basis <strong>of</strong> this trial, the combination <strong>of</strong> gemcitabine plusirinotecan, administered in a weekly schedule and at this dose, is well tolerated and <strong>of</strong>fersencouraging activity in the treatment <strong>of</strong> advanced and/or metastatic pancreatic cancer [540].Gemcitabine and proton irradiationOne study evaluated the efficacy <strong>of</strong> combining proton irradiation with gemcitabine, and therole the inhibitor <strong>of</strong> apoptosis proteins survivin and X-linked inhibitor <strong>of</strong> apoptosis protein(XIAP) play in the radiosensitive versus radioresistant status <strong>of</strong> pancreatic cancer. Theradioresistant (PANC-1) and radiosensitive (MIA PaCa-2) pancreatic carcinoma cells'response to combined gemcitabine and proton irradiation was compared. Gemcitabine andproton irradiation resulted in increased survivin levels with little apoptosis. However,combination therapy resulted in robust apoptotic induction with a concomitant survivin andXIAP reduction in the MIA PaCa-2 cells with little effect in the PANC-1 cells. Small interferingRNA studies confirmed a role for XIAP in the radioresistance <strong>of</strong> PANC-1 cells. The datademonstrate that combining gemcitabine and proton irradiation enhances apoptosis inhuman pancreatic cancer cells when XIAP levels decrease. Therefore, XIAP may play animportant role in human pancreatic cancer proton radioresistance [541].Gemcitabine experimentallyA test the efficacy <strong>of</strong> liposomal gemcitabine (GemLip) on primary tumor and metastasesusing the pancreatic tumor cell line AsPC1 implanted orthotopically into nude mice wasmade. In vitro, the IC 50 s for GemLip and gemcitabine were 20 nM and 140 nM, respectively.However, when applied against established tumors, GemLip (8 mg/kg) blocked tumor growthfor 5 consecutive weeks according to bioluminescence measurements in vivo. Gemcitabine(240 mg/kg) had no effect on luciferase-monitored tumor growth. When analyzed at the time<strong>of</strong> necropsy, GemLip strongly reduced tumor size, whereas gemcitabine only weakly affectedtumor size. Empty liposomes had no effect on the tumor size. GemLip and empty liposomesboth significantly interfered with the metastatic spread to the liver, as measured usingluciferase assays. In addition, they showed effects against spleen, as well as peritoneal

metastases [542].5-FluorouracilTwenty-one patients with unresectable locally advanced pancreatic cancer were evaluated inthis retrospective analysis. They received extra-beam radiotherapy (50.4-54 Gy/28-30fractions) with concurrent continuous infusion <strong>of</strong> 5-FU( 250 mg/m 2 day) between 1999 and2007. The radiation field included primary tumor and adjacent lymph nodes. Twenty patients(95 %) completed chemoradiotherapy, whereas one patient quit radiotherapy due tovomiting. No lethal side effects were observed. The response rate was 10 percent. One <strong>of</strong>the patients judged to have stable disease underwent resection after maintenancechemotherapy. The median progression free survival and the median overall survival were 6and 12 months, respectively. In eleven patients (52 %), the initial sites <strong>of</strong> diseaseprogression were local or peritoneum without liver metastases, suggesting systemic effects<strong>of</strong> this treatment. In conclusion, the authors said that 5-FU based chemoradiotherapyis welltolerated and provides definite benefits against unresectable locally advanced pancreaticcancer [543].Oxaliplatin plus 5-fluorouracilA phase II study was performed to assess the activity <strong>of</strong> oxaliplatin plus 5-fluorouracil (5-FU)modulated by leucovorin, as second-line treatment in locally advanced or metastaticpancreas adenocarcinoma pretreated with gemcitabine-containing schedule. Patientsreceived weekly intravenous infusions <strong>of</strong> oxaliplatin 40 mg/m 2 , 5-FU 500 mg/m 2 , andleucovorin 250 mg/m 2 (3 weeks on, 1 week <strong>of</strong>f). Twenty-three patients affected withmetastatic (16) or locally advanced (7) pancreas adenocarcinoma were involved in thisstudy. A total <strong>of</strong> 148 weeks <strong>of</strong> chemotherapy was delivered (median 2 courses each patient).Among 17 assessable patients, no objective response was registered and 4 patients hadstable disease, whereas 13 had tumor progression. Median duration <strong>of</strong> stable disease was14 weeks. Median time to progression <strong>of</strong> disease (TTP) was 12 weeks [95 % confidenceinterval 8 to 16]. Kaplan-Meier estimated median overall survival (OS) was 17 week (95 %confidence interval 4 to 30) and 3 months survival rate was 70 percent. Seven patientsexperienced grade 3 to 4 toxicity. The regimen was associated with 36 percent clinicalbenefit [544].Capcitabine and celeoxibIt was evaluated a fully oral regimen <strong>of</strong> capecitabine and celecoxib (CapCel) as second-linetreatment in 35 patients with documented progressive pancreatic cancer after first-linetreatment were enrolled. Capecitabine was administered at a dose <strong>of</strong> 1,000 mg/m 2 b.i.d. for 2consecutive weeks followed by 1 week <strong>of</strong> rest; celecoxib was given continuously at 200 mgb.i.d. Progression-free survival at 3 months was the primary study endpoint. The CapCelcombination was associated with an overall response rate <strong>of</strong> 9 percent and median survivalduration <strong>of</strong> 19 weeks. Sixty percent <strong>of</strong> patients were free from progression 3 months after thestart <strong>of</strong> treatment. Multivariate analysis identified a positive clinical benefit response and adecline in CA 19.9 serum levels >25 percent compared with baseline levels as independentpredictors <strong>of</strong> prolonged survival. The treatment protocol was well tolerated with negligiblehematological toxicity. The most common grade 3 non-hematological toxicities werehypertransaminasemia, diarrhea and asthenia. It was concluded that CapCel combination isa safe treatment option with moderate activity in patients with pancreatic/biliary tract cancerafter failure <strong>of</strong> a previous gemcitabine-containing regimen [545].Gemcitabine plus uracil-tegafur and cyclophosphamideIn a retrospective analysis, it was compared the effectiveness and tolerability <strong>of</strong> gemcitabine(GEM) plus uracil/tegafur and cyclophosphamide with single-agent GEM as 1st-linechemotherapy for unresectable or recurrent pancreatic cancer. Thirty-three patients receivedcombination therapy and 25 patients were treated with GEM alone. Tumor response rate was14 percent versus 9 percent, median progression-free survival was 3 versus 4 months, and

median survival time was 7 versus 7 months in the combination and GEM groups,respectively. Complete response was observed just in 2 cases <strong>of</strong> the combination group, and1 <strong>of</strong> them has been relapse-free for 3 years. In a subgroup <strong>of</strong> patients with good performancestatus, combination therapy prolonged median survival time significantly (9 vs 6 months).This combination therapy is well tolerated and may provide superior benefits to GEMmonotherapy [546].Uracil-tegafurIt was reported a case <strong>of</strong> pancreas head cancer with liver metastasis treated with uraciltegafur(UFT) and gemcitabine combined chemotherapy. The histopathological diagnosiswas adenocarcinoma, so it was inserted a self-expandable metallic stent (EMS) in thisinoperable pancreas head cancer. It was performed nine courses <strong>of</strong> UFT and gemcitabine(GEM) combination chemotherapy. Renewed liver metastases did not appear, and thepancreas head tumor partially responded. Pancreatoduodenectomy was performed. Aftertreatment with an additional 11 courses <strong>of</strong> chemotherapy, it was given S-1 orally because <strong>of</strong>a tumor recurrence. The patient survived for 24 months from the first laparotomy [547].FOLFOXOnly a few clinical trials have been conducted in patients with advanced pancreatic cancerafter failure <strong>of</strong> first-line gemcitabine-based chemotherapy. Therefore, there is no currentconsensus on the treatment <strong>of</strong> these patients. It was conducted a randomised phase II study<strong>of</strong> the modified FOLFIRI.3 (mFOLFIRI.3; a regimen combining 5-fluorouracil (5-FU), folinicacid, and irinotecan) and modified FOLFOX (mFOLFOX; a regimen combining folinic acid, 5-FU, and oxaliplatin) regimens as second-line treatments in patients with gemcitabinerefractorypancreatic cancer. The primary end point was the 6-month overall survival rate.The mFOlFIRI.3 regimen consisted <strong>of</strong> irinotecan (70 mg m 2 ; days 1 and 3), leucovorin (400mg m 2 ; day 1), and 5-FU (2000 mg m 2 ; days 1 and 2) every 2 weeks. The mFOLFOXregimen was composed <strong>of</strong> oxaliplatin (85 mg m 2 ; day 1), leucovorin (400 mg m 2 ; day 1), and5-FU (2000 mg m 2 ; days 1 and 2) every 2 weeks. Sixty-one patients were randomised tomFOLFIRI.3 (n=31) or mFOLFOX (n=30) regimen. The six-month survival rates were 27percent (95 % confidence interval 13 to 46 %) and 30 percent (95 % confidence interval 15 to49 %), respectively. The median overall survival periods were 17 and 15 weeks, respectively.Disease control was achieved in 23 percent (95 % confidence interval 10 to 42 %) and 17percent <strong>of</strong> the patients (95 % confidence interval 6 to 35 %), respectively. The number <strong>of</strong>patients with at least one grade 3/4 toxicity was identical (11 patients, 38 %) in both groups:neutropenia (7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen),asthaenia (1 vs 4), vomiting (3 in both), diarrhoea (2 vs 0), and mucositis (1 vs 2). It wasconcluded that both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageabletoxicity, <strong>of</strong>fering modest activities as second-line treatments for patients with advancedpancreatic cancer, previously treated with gemcitabine [548].FlavopiridolPancreatic adenocarcinoma harbors frequent alterations in p16, resulting in cell cycledysregulation. A phase I study <strong>of</strong> docetaxel and flavopiridol, a pan-cyclin-dependent kinaseinhibitor, demonstrated encouraging clinical activity in pancreatic cancer. This phase II studywas designed to further define the efficacy and toxicity <strong>of</strong> this regimen in patients withpreviously treated pancreatic cancer. Patients with gemcitabine-refractory, metastaticpancreatic cancer were treated with docetaxel 35 mg/m 2 followed by flavopiridol 80 mg/m 2 ondays 1, 8, and 15 <strong>of</strong> a 28-day cycle. Tumor measurements were performed every two cycles.Ten patients were enrolled, and 9 were evaluable for response. No objective responses wereobserved; however, 3 patients (33 %) achieved transient stable disease, with one <strong>of</strong> thesepatients achieving a 20 percent reduction in tumor size. Median survival was 4 months, withno patients alive at the time <strong>of</strong> analysis. Adverse events were significant, with 7 patients (78%) requiring >1 dose reduction for transaminitis (11 %), grade 4 neutropenia (33 %), grade 3fatigue (44 %), and grade 3 diarrhea (22 %). It was concluded that the combination <strong>of</strong>

flavopiridol and docetaxel has minimal activity and significant toxicity in this patientpopulation. These results reflect the challenges <strong>of</strong> treating patients with pancreatic cancer ina second-line setting where the risk/benefit equation is tightly balanced [549].S-1The prognosis for advanced pancreatic cancer with peritoneal dissemination is extremelypoor, and no effective standard therapy has been established. It was presented a case <strong>of</strong> avery old patient whose quality <strong>of</strong> life improved shortly after administration <strong>of</strong> only S-1 to treatadvanced pancreatic cancer with peritoneal dissemination. Considering his general conditiondue to old age, the regimen for oral S-1 (80 mg/body/day) was set at 4 consecutive weeks <strong>of</strong>administration followed by a 2-week rest period. His abdominal circumference decreased andhis appetite improved by 14 days following commencement <strong>of</strong> the therapy. The bloodexamination one month following commencement showed a significant decrease in the tumormarker. There was no adverse drug reaction. Six months later CT scanning showed that theascites had disappeared and that the low-density area at the tail <strong>of</strong> the pancreas hadbecome less obvious. The tumor marker and biochemical parameters were within standardranges. Twelve months since the therapy began: there still has been no adverse drugreaction and his quality <strong>of</strong> life has been good [550].EGFR-inhibitorIt was evaluated the epidermal growth factor receptor (EGFR) inhibitor gefitinib anddocetaxel in a phase II study following gemcitabine failure. EGFR overexpression was notrequired. The initial docetaxel dose was 75 mg/m 2 on day 1 every 21 days. Due to febrileneutropenia in 8 <strong>of</strong> the first 18 patients, the dose was reduced to 60 mg/m 2 . Gefitinib, 250mg/day orally, was given continuously. Forty-one patients received treatment and wereevaluable. Febrile neutropenia was seen in 11 patients (27 %), with most events occurring atthe docetaxel dose <strong>of</strong> 75 mg/m 2 (8 <strong>of</strong> 18 patients). Common treatment-related grade 3/4toxicities were: fatigue (7 %), nausea (7 %), diarrhea (5 %) and vomiting (2 %). There was 1partial response and stable disease in 19 patients. Time to progression was 2 months andmedian survival was 5 months (95 % confidence interval 2.9-5.7). This means that thecombination <strong>of</strong> gefitinib and docetaxel showed evidence <strong>of</strong> limited efficacy [551].Radiotherapy with 5-FU, Gemcitabine or S-1In one study, it was examined the safety and efficacy <strong>of</strong> chemoradiation in cases with localrecurrence <strong>of</strong> pancreatic or biliary cancer after primary resection. Seven consecutive patientswith recurrence <strong>of</strong> carcinoma <strong>of</strong> pancreas (n=3) and biliary system (n =4) were treatedchemoradiotherapy. Local recurrence occurred around the portal vein in 6 patients andremnant pancreas in one patient respectively. Disease free survival after primary surgerywas 22 months (range: 5-84). All patients received 50 Gy <strong>of</strong> conformal three-dimensionalradiotherapy with concurrent 5-FU, Gemcitabine or S-1. Grade 3 <strong>of</strong> anorexia and elevation <strong>of</strong>transaminase level occurred in one patient respectively. Local tumor response was observedin two patients <strong>of</strong> pancreatic and biliary cancer respectively. Median survival calculated fromthe start <strong>of</strong> the chemoradiotherapy was 15 months (range: 6-24) in pancreatic cancer and 14months (range: 11-20)in biliary cancer. The data suggest that chemoradiotherapy is feasibleand effective treatment option in patients who present local recurrence after primary surgeryin pancreatic or biliary cancer [552].ImmunotherapyDendritic cell (DC) therapy frequently induces a measurable immune response. Howeverclinical responses are seen in a minority <strong>of</strong> patients, presumably due to insufficientexpansion <strong>of</strong> antigen-specific cytotoxic T lymphocytes (CTLs) capable <strong>of</strong> eradicating tumorcells. To increase therapeutic efficacy <strong>of</strong> DC-based vaccination, we have undertaken the firstclinical trial involving a combination therapy <strong>of</strong> gemcitabine (GEM) with immunotherapy forpatients with inoperable locally advanced pancreatic cancer. Five patients received thetreatment course, which consisted <strong>of</strong> intravenous GEM administration at 1000 mg/m 2 (day 1)

and the endoscopic ultrasound-guided fine-needle injection <strong>of</strong> OK432-pulsed DCs into atumor, followed by intravenous infusion <strong>of</strong> lymphokine-activated killer cells stimulated withanti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. No serioustreatment-related adverse events were observed during the study period. Three <strong>of</strong> the 5patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2had long stable disease more than 6 months. In the patient with partial remission, it has beenshown that DC-based vaccination combined with GEM administration induces tumor antigenspecificCTLs. It was concluded that combined therapy was considered to be synergisticallyeffective and may have a role in the therapy <strong>of</strong> pancreatic cancer for inducing tumor antigenspecificCTLs [553].Anti-gastrinsThe experience <strong>of</strong> synthesising a novel gastrin receptor antagonist gastrazole and taking itinto 3 small clinical studies in pancreatic cancer in man is described. The need for such acompound is illustrated by the observation that inhibition <strong>of</strong> gastric acid secretion by H2receptor antagonists results in hypergastrinaemia. A large number <strong>of</strong> cell types have gastrinreceptors including pancreatic cancer cells which have been shown to be stimulated bygastrin. Small numbers <strong>of</strong> pancreatic cancer patients given gastrazole by continuousintravenous infusion showed prolonged survival compared with best supportive care orplacebo, and equivalent survival to those given 5 fluouracil. The results suggest a greaterbenefit for patients with early stage disease. An alternative gastrin receptor antagonist YF476 is also described which has the advantage <strong>of</strong> efficacy given by the oral route. This newcompound requires to be studied in pancreatic cancer and other diseases associated withhypergastrinaemia [554].Monoclonal antibodiesRadiolabeled PAM4 IgG, a monoclonal antibody that recognizes a unique epitopeassociated with a mucin found almost exclusively in pancreatic cancer, has shownencouraging therapeutic effects in animal models and in early clinical testing ( 90 Y-humanized PAM4 IgG, 90 Y-clivatuzumab tetraxetan). The studies reported hereinexamine a new pretargeting procedure for delivering therapeutic radionuclides. It wasshown that PAM4-based PT-RAIT with 90 Y hapten peptide is an effective treatmentfor pancreatic cancer, with less toxicity than90 Y-PAM4 IgG, in this model.Combinations with gemcitabine and dose fractionation <strong>of</strong> the PT-RAIT enhancedtherapeutic responses [555].REG4 as predictive agentPreoperative chemoradiotherapy is one <strong>of</strong> the key strategies for the improvement <strong>of</strong>survival in pancreatic cancer; however, no method to predict the response has yetbeen established. The aim <strong>of</strong> one study was to prospectively evaluate the predictivevalue <strong>of</strong> REG4, a new member <strong>of</strong> the regenerating (REG) islet-derived family <strong>of</strong>proteins. Stably REG4-expressing cells were established from a pancreatic cancercell line and exposed in vitro to gamma-ray or gemcitabine to investigate therelevance <strong>of</strong> REG4 to the resistance to chemotherapy or radiotherapy. In 23 patientswith resectable pancreatic cancer, the serum concentration <strong>of</strong> REG4 was measuredbefore preoperative chemoradiotherapy, and the histologic response was evaluatedafter the surgery. A 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide(MTT) assay and fluorescence activated cell scanning (FACS) revealed that REG4-overexpressing cells were resistant to gamma-radiation but showed a modestresistance to gemcitabine. The patients with a higher REG4 level, but notcarcinoembryonic antigen or CA-19-9, showed an unfavorable histologic response tochemoradiotherapy. The patients showing a higher REG4 level experienced localrecurrence postoperatively. These data demonstrated in vitro and in vivo that REG4protein overexpression was associated with an unfavorable response to preoperativechemoradiotherapy. REG4 can clinically be used as a predictive biomarker [556].

Inhibition by propranololPropranolol inhibited pancreatic cancer cell proliferation by blocking signaling through thebeta-adrenoceptor. It was hypothesized that propranolol may suppress pancreatic cancer cellgrowth through induction <strong>of</strong> apoptosis. The beta-adrenoceptor antagonist propranolol, beta1-adrenoceptor antagonist metoprolol, and beta2-adrenoceptor antagonist butoxamine wereused to induce apoptosis in pancreatic cancer cells. The mRNA and protein expression <strong>of</strong>beta1- and beta2-adrenoceptors was analyzed using reverse transcriptase-polymerase chainreaction and Western blot. The pancreatic cancer cell line expressed mRNA and protein forboth <strong>of</strong> beta1- and beta2-adrenoceptors. The Hoechst staining, TUNEL, and flow cytometryassay documented that the 3 drugs increased the number <strong>of</strong> apoptotic cells; the rate <strong>of</strong>apoptosis was the highest using butoxamine followed by propranolol, whereas the least wasusing metoprolol. beta-Adrenoceptor antagonists therapy affected caspase 3 and caspase 9expression. It was concluded that the rate <strong>of</strong> apoptosis in pancreatic cancer cells was higherafter treatment with butoxamine than propranolol, suggesting that propranolol inducesapoptosis in pancreatic cancer cells via the beta2-adrenoceptors principally [557].HyperthermiaThe aim <strong>of</strong> one study was to evaluate the efficacy and toxicity <strong>of</strong> concurrentchemoradiotherapy (CRT) with gemcitabine plus regional hyperthermia (HT) for locallyadvanced pancreatic carcinoma. A total <strong>of</strong> 29 patients with locally advanced pancreaticcancer treated with concurrent CRT using gemcitabine were retrospectively analyzed.Radiotherapy was administered with a median total dose <strong>of</strong> 61 Gy. Of the 29 patients, 20 (69%) also underwent regional HT during CRT (CRHT group). The remaining 9 patients did notreceive regional HT (CRT group) because <strong>of</strong> a common bile duct stent placement, patientrefusal, older age, or obesity. The efficacy and toxicity <strong>of</strong> the treatments and the predictors <strong>of</strong>good outcome were evaluated. The median disease progression-free and overall survivaltimes were significantly better for the CRHT group than for the CRT group (9 vs 5months,and 19 vs 10 months), respectively. Grade 3-4 hematological toxicities for the CRHT groupwere detected in eight patients (40 %) and grade 3 nonhematologic toxicity in one (diarrhea)[558].RadiochemoradiationIt was presented an overview <strong>of</strong> phase III trials in adjuvant therapy for pancreatic cancer and<strong>review</strong>ed outcomes at the Mayo Clinic after adjuvant radiochemotherapy (RT/CT) forresected pancreatic cancer. A <strong>literature</strong> <strong>review</strong> and a retrospective <strong>review</strong> <strong>of</strong> 472 patientswho underwent an R0 resection for T1-3N0-1M0 invasive carcinoma <strong>of</strong> the pancreas from1975 to 2005 at the Mayo Clinic, Rochester, MN, was performed. Patients with metastatic orunresectable disease at the time <strong>of</strong> surgery, positive surgical margins, or indolent tumors andthose treated with intraoperative radiotherapy were excluded from the analysis. Medianradiotherapy dose was 50.4 Gy in 28 fractions, with 98 percent <strong>of</strong> patients receivingconcurrent 5-fluorouracil-based chemotherapy. Median follow-up was 2.7 years. Medianoverall survival (OS) was 1.8 years. Median OS after adjuvant RT/CT was 2.1 vs 1.6 yearsfor surgery alone, which was a significant difference The 2-years overall survival was 50percent versus 39 percent, and 5-years was 28 percent versus 17 percent for patientsreceiving RT/CT versus surgery alone. Univariate and multivariate analysis revealed thatadverse prognostic factors were positive lymph nodes (risk ratio [RR] 1.3) and high histologicgrade (RR 1.2). T3 tumor status was found significant on univariate analysis only (RR 1.1).The authors concluded that the results from recent clinical trials support the use <strong>of</strong> adjuvantchemotherapy in resected pancreatic cancer. Results from the Mayo Clinic suggest improvedoutcomes after the administration <strong>of</strong> adjuvant radiochemotherapy after a complete resection<strong>of</strong> invasive pancreatic malignancies [559].Treatment <strong>of</strong> recurrent diseaseChemoradiotherapy for the unresectable pancreatic cancer and biliary cancer has been usedfor improving survival. In one study, it was examined its safety and efficacy in cases with the

local recurrence <strong>of</strong> pancreatic or biliary cancer after primary resection. Seven consecutivepatients with recurrence <strong>of</strong> carcinoma <strong>of</strong> pancreas (n=3) and biliary system (n =4) weretreated chemoradiotherapy. Local recurrence occurred around the portal vein in 6 patientsand remnant pancreas in one patient respectively. Disease free survival after primary surgerywas 22 months (range: 5-84). All patients received 50 Gy <strong>of</strong> conformal three-dimensionalradiotherapy with concurrent 5-FU, Gemcitabine or S-1. Grade 3 <strong>of</strong> anorexia and elevation <strong>of</strong>transaminase level occurred in one patient respectively. Local tumor response was observedin two patients <strong>of</strong> pancreatic and biliary cancer respectively. Median survival calculated fromthe start <strong>of</strong> the chemoradiotherapy was 15 months (range: 6-24) in pancreatic cancer and 14months (range: 11-20) in biliary cancer [560].Prognostic investigationsOne study was conducted to assess changes in tumor vascularity using contrast-enhancedultrasonography in patients with pancreatic carcinoma under systemic chemotherapy and toexamine the correlation among vascular change, clinicopathologic factors, and outcome.Forty-one consecutive patients with histopathologically confirmed pancreatic carcinoma whohad distant metastases and were under systemic chemotherapy were recruited. Contrastenhancedultrasonography was performed before and after 1 and 2 cycles <strong>of</strong> treatment. Thevascular signals from the tumor were continuously recorded, and the highest signal intensitywas selected and classified into 5 categories by their intensity. As for the tumor responsedetermined by dynamic computed tomography after 2 cycles, 6 patients showed a partialresponse, 25 remained stable, and in 10 patients, the disease progressed. A significantrelationship was observed between vascular change after 1 cycle and tumor response.Progression-free survival and overall survival were significantly short in the case <strong>of</strong> patientsshowing increased vascularity after 1 and 2 cycles <strong>of</strong> chemotherapy, compared with thosewho did not. It was concluded that contrast-enhanced ultrasonography was useful toevaluate tumor vascular changes and thereby the effect <strong>of</strong> systemic chemotherapy, as wellas the prognosis <strong>of</strong> patients with advanced pancreatic carcinoma [561].Radiotherapy (calculation)To assess carbon ion beam dose variation due to bowel gas movement in pancreaticradiotherapy 10 pancreatic cancer inpatients were subject to diagnostic contrast-enhanceddynamic helical CT examination under breath-holding conditions, which included multiplephasedynamic CT with arterial, venous, and delayed phases. The arterial-venous phase andarterial-delayed phase intervals were 35 and 145 s, respectively. A compensating bolus wasdesigned to cover the target obtained at the arterial phase. Carbon ion dose distribution wascalculated by applying the bolus to the CT data sets at the other two phases. Doseconformation to the clinical target volume was degraded by beam overshoot/undershoot dueto bowel gas movement. The D95 for clinical target volume was degraded from 98 percent(range, 98.0-99.1 %) <strong>of</strong> the prescribed dose to 95 percent (range, 88.0-99.0 %) at 145 s.Excessive dosing to normal tissues varied among tissues and was, for example, 12.2GyE/13.1 GyE (0 s/145 s) for the cord and 38.8 GyE/39.8 GyE (0 s/145 s) for the duodenum.The magnitude <strong>of</strong> beam overshoot/undershoot was particularly exacerbated from the anteriorand left directions. It was concluded that bowel gas movement causes dosimetric variation tothe target during treatment for radiotherapy. The effect <strong>of</strong> bowel gas movement varies withbeam angle, with greatest influence on the anterior-posterior and left-right beams [562].Radiotherapy (educational)Before a multicentre trial <strong>of</strong> 3-D conformal radiotherapy to treat cancer <strong>of</strong> the pancreas,participating clinicians were asked to complete an accreditation exercise. This involvedplanning two test cases according to the study protocol, then returning hard copies <strong>of</strong> theplans and dosimetric data for <strong>review</strong>. Any radiation technique that achieved the specifiedconstraints was allowed. Eighteen treatment plans were assessed. Seven plans wereprescribed incorrect doses and two <strong>of</strong> the planning target volumes did not comply withprotocol guidelines. All plans met predefined normal tissue dose constraints. The identified

errors were attributable to unforeseen ambiguities in protocol documentation. They wereaddressed by feedback and corresponding amendments to protocol documentation.Summary radiobiological measures including total weighted normal tissue equivalent uniformdose varied significantly between centres. This accreditation exercise successfully identifiedsignificant potential sources <strong>of</strong> protocol violations, which were then easily corrected. It wasbelieved that this process should be applied to all clinical trials involving radiotherapy. Due tothe limitations <strong>of</strong> data analysis with hard-copy information only, it is recommended thatcomplete planning datasets from treatment-planning systems be collected through a digitalsubmission process [563].Novel agentsPancreatic cancer is a particularly challenging malignancy, given its usually advanced stageat diagnosis and its rather limited treatment options. Gemcitabine has been standard therapyfor advanced pancreatic cancer for well over a decade. The addition <strong>of</strong> capecitabine orerlotinib to gemcitabine has resulted in modestly improved, although still poor, overallsurvival. The majority <strong>of</strong> the recently completed randomized trials, however, have failed todemonstate an improvement <strong>of</strong> newer treatments over single-agent gemcitabine. Effortscurrently underway center on new cytotoxic chemotherapy drugs, as well as novel targetedagents inhibiting various molecular pathways. Newly discovered proteins and cellularelements involved in tumor growth and invasion are potential therapeutic targets, and havebecome the focus <strong>of</strong> current trials, as well as future clinical trials. A better understanding <strong>of</strong>the biology <strong>of</strong> the disease at the basic science level, and epidemiology and risk factors froma public-health perspective, are needed [564].Stem cell transplantationAdvanced unresectable pancreatic cancer has an extremely poor prognosis despite intensivechemotherapy. As a new therapeutic modality, it was investigated nonmyeloablativeallogeneic hematopoietic stem cell transplantation from a related donor. Five patients withchemotherapy-resistant pancreatic cancer received allogeneic peripheral blood stem celltransplantation after a conditioning regimen consisting <strong>of</strong> low-dose total body irradiation andfludarabine. The prophylaxis for graft-versus-host disease consisted <strong>of</strong> mycophenolatem<strong>of</strong>etil and cyclosporine. The median age <strong>of</strong> the 5 patients was 54 years, and the medianduration from diagnosis to nonmyeloablative allogeneic hematopoietic stem celltransplantation was 10 months. Three <strong>of</strong> the 5 patients achieved complete donor chimerism<strong>of</strong> peripheral T cells, at a median time <strong>of</strong> day 42. Acute graft-versus-host disease developedin 3 patients: grade 2 in 2 patients and grade 1 in 1. Tumor reduction was observed in 2patients: 1 patient showed disappearance <strong>of</strong> the pancreatic tumor, and the other patientshowed approximately 20 percent reduction <strong>of</strong> the tumor. Marked elevation <strong>of</strong> tumor necrosisfactor-alpha was observed as the tumor regressed. It was concluded that lthough advancedpancreatic cancer progresses rapidly, some graft-versus-tumor effects and pivotal role <strong>of</strong>tumor necrosis factor-alpha were suggested [565].BetulinBetulin and betulinic acid are naturally occurring pentacyclic triterpenes showing cytotoxicitytowards a number <strong>of</strong> cancer cell lines. These compounds can be found in the bark <strong>of</strong> themany plants. In one report it was compared the cytotoxic activity <strong>of</strong> crude birch bark extractand purified betulin and betulinic acid towards human gastric carcinoma (EPG85-257) andhuman pancreatic carcinoma (EPP85-181) drug-sensitive and drug-resistant (daunorubicinand mitoxantrone) cell lines. The results show significant differences in sensitivity betweencell lines depending on the compound used, and suggest that both betulin and betulinic acidcan be considered as a promising leads in the treatment <strong>of</strong> cancer [566].

CurcuminCurcumin has been shown to inhibit the growth <strong>of</strong> various types <strong>of</strong> cancer cells; however, atconcentrations much above the clinically achievable levels in humans. The concentration <strong>of</strong>curcumin achieved in the plasma after oral administration in humans was estimated to bearound 1.8 microM. Now it was reported that treatment <strong>of</strong> BxPC-3 human pancreatic cancercells with a low and single exposure <strong>of</strong> 2.5 microM curcumin for 24 h causes significantarrest <strong>of</strong> cells in the G2/M phase and induces significant apoptosis. Immunoblot studiesrevealed increased phosphorylation <strong>of</strong> H2A.X at Ser-139 and Chk1 at Ser-280 and adecrease in DNA polymerase-beta level in curcumin-treated cells. Phosphorylation <strong>of</strong> H2A.Xand Chk1 proteins are an indicator <strong>of</strong> DNA damage whereas DNA polymerase-beta plays arole in the repair <strong>of</strong> DNA strand breaks. Normal immortalised human pancreatic ductalepithelial (HPDE-6) cells remained unaffected by curcumin treatment. In addition, we alsoobserved a significant increase in the phosphorylation <strong>of</strong> Chk1 at Ser-345, Cdc25C at Ser-216 and a subtle increase in ATM phosphorylation at Ser-1981. Concomitant decrease in theexpressions <strong>of</strong> cyclin B1 and Cdk1 were seen in curcumin-treated cells. Further, curcumintreatment caused significant cleavage <strong>of</strong> caspase-3 and PARP in BxPC-3 but not in HPDE-6cells. Silencing ATM/Chk1 expression by transfecting BxPC-3 cells with ATM or Chk1-specific SiRNA blocked the phosphorylation <strong>of</strong> ATM, Chk1 and Cdc25C and protected thecells from curcumin-mediated G2/M arrest and apoptosis. The study reflects the critical role<strong>of</strong> ATM/Chk1 in curcumin-mediated G2/M cell cycle arrest and apoptosis in pancreaticcancer cells [567].AloeThe recent advances in the analysis <strong>of</strong> tumor immunobiology suggest the possibility <strong>of</strong>biologically manipulating the efficacy and toxicity <strong>of</strong> cancer chemotherapy by endogenous orexogenous immunomodulating substances. Aloe is one <strong>of</strong> the <strong>of</strong> the most important plantsexhibiting anticancer activity and its antineoplastic property is due to at least three differentmechanisms, based on antiproliferative, immunostimulatory and antioxidant effects. Theantiproliferative action is determined by anthracenic and antraquinonic molecules, while theimmunostimulating activity is mainly due to acemannan. A study was planned to include 240patients with metastatic solid tumor who were randomized to receive chemotherapy with orwithout Aloe. According to tumor histotype and clinical status, lung cancer patients weretreated with cisplatin and etoposide or weekly vinorelbine, colorectal cancer patients receivedoxaliplatin plus 5-fluorouracil (5-FU), gastric cancer patients were treated with weekly 5-FUand pancreatic cancer patients received weekly gemcitabine. Aloe was given orally at 10 mlthrice/daily. The percentage <strong>of</strong> both objective tumor regressions and disease control wassignificantly higher in patients concomitantly treated with Aloe than with chemotherapy alone,as well as the percent <strong>of</strong> 3-year survival patients [568].GinsengSprague-Dawley rats and ginseng from the roots <strong>of</strong> a 6-year-old fresh Panax ginseng C. A.Meyer plant were used in this study. Pancreatitis was induced by intraperitoneal injection <strong>of</strong>diethyldithiocarbamate for 4 weeks. Korean red ginseng was fed orally to rats for the next 3weeks. At week 7, all rats were killed, and pancreatic tissues were analyzed. The resultssuggest that KRG has antioxidant therapeutic effects on superoxide dismutase inhibitorinducedpancreatitis by inhibition <strong>of</strong> nuclear factor kappaB [569].

MORE UNUSUAL TUMORS OF THE PANCREASAnaplastic carcinoma <strong>of</strong> the pancreasAnaplastic carcinoma <strong>of</strong> the pancreas (ACP) is an aggressive variant <strong>of</strong> ductaladenocarcinoma. The aim <strong>of</strong> one study was to describe a single-center experience with theuse <strong>of</strong> endoscopic ultrasound (EUS) with or without fine-needle aspiration (FNA) for thediagnosis <strong>of</strong> ACP. The cytology and surgical pathology databases were searched for adiagnosis <strong>of</strong> ACP between 1992 and 2008. Demographic, clinical, surgical, radiographic,pathological, and EUS data were abstracted. Thirteen patients with ACP were identified,which represented 0.8 percent <strong>of</strong> all pancreatic cancers diagnosed during the study period.Six <strong>of</strong> 13 patients had EUS. Features <strong>of</strong> these 6 tumors: median diameter <strong>of</strong> 42 mm (range,20-100 mm), hypoechoic (n=6), solid (n=3) or mixed solid and cystic (n=3), heterogeneous(n=5) or homogeneous (n=1), and well defined (n=2) or poorly defined (n=4) borders. Fiveunderwent EUS-FNA <strong>of</strong> a pancreatic mass, and cytology demonstrated ACP in 4 and ductaladenocarcinoma in 1. The diagnosis <strong>of</strong> ACP was confirmed after surgical resection in 2 <strong>of</strong>these 5, including one in whom cytology demonstrated only adenocarcinoma. The sixthpatient had EUS without FNA, and surgical pathology after distal pancreatectomy foundACP. It was concluded that anaplastic carcinoma <strong>of</strong> the pancreas has variableendosonographic features [570].Cystic pancreatic tumorsThe diversity in the aggressiveness <strong>of</strong> cystic tumors <strong>of</strong> the pancreas – ranging from theusually benign serous cystadenoma to lesions <strong>of</strong> variable degrees <strong>of</strong> malignancy – wasutilized for the identification <strong>of</strong> molecular factors that are involved in the occurrence <strong>of</strong>malignancy. It was analyzed the transcript pr<strong>of</strong>iles <strong>of</strong> different cystic tumor types. The resultswere confirmed at the protein level by immunohistochemistry. Also, functional studies withsiRNA silencing were performed. Expression variations at the RNA and protein level wereidentified that are closely correlated with the degree <strong>of</strong> malignancy. Besides, all tumors couldbe classified effectively by this means. Many <strong>of</strong> the identified factors had not previously beenknown to be associated with malignant cystic lesions. siRNA silencing <strong>of</strong> the gene with themost prominent variation – the anti-apoptotic factor FASTK (Fas-activated serine/threoninekinase) – revealed a regulative effect on several genes known to be relevant to thedevelopment <strong>of</strong> tumors. It was concluded that by a molecular analysis <strong>of</strong> rare types <strong>of</strong>pancreatic cancer, which are less frequent in terms <strong>of</strong> disease, variations could be identifiedthat could be critical for the regulation <strong>of</strong> malignancy and thus relevant to the treatment <strong>of</strong>also the majority <strong>of</strong> pancreatic tumors [571].Early diagnosis <strong>of</strong> cancer in pancreatic cysts is important for timely referral to surgery. Theaim <strong>of</strong> one study was to develop a predictive model for pancreatic cyst malignancy toimprove patient selection for surgical resection. It was performed retrospective analyses <strong>of</strong>endoscopic ultrasound (EUS) and pathology databases identifying pancreatic cysts withavailable final pathological diagnoses. Main-duct intraductal papillary mucinous neoplasms(IPMNs) were excluded due to the clear indication for surgery. Patient demographics andsymptoms, cyst morphology, and cyst fluid characteristics were studied as candidate riskfactors for malignancy. 270 patients with pancreatic cysts were identified and analyzed (41 %men, mean age 62 years). Final pathological diagnoses were branch-duct IPMN (n=118, 50% malignant), serous cystadenoma (n=71), pseudocyst (n=37), mucinous cystadenoma/adenocarcinoma (n=36), islet cell tumor (n=4), simple cyst (n=3), and ductaladenocarcinoma with cystic degeneration (n=1). Optimal cut-<strong>of</strong>f points for surgical resectionwere cyst fluid carcinoembryonic antigen (CEA) < 3,594 ng/ml, age >50, and cyst size >1.5cm. Cyst malignancy was independently associated with weight loss (odds ratio 3.9), cyst

size >1.5 cm (odds ratio 2.4), and high CEA (odds ratio 5.3). In white patients >50 years oldpresenting with weight loss and cyst size >1.5 cm, the likelihood <strong>of</strong> malignancy was nearlysixfold greater than in those patients who had none <strong>of</strong> these factors (odds ratio 5.8, 95 %confidence interval 2.1 to 16.1). It was concluded that risk factors other than cyst size areimportant for determination <strong>of</strong> malignancy in pancreatic cysts. Exceptionally high cyst fluidCEA levels and certain patient-related factors may help to better predict cyst malignancy andthe need for surgical treatment [572].Neoplastic changes represent an important part <strong>of</strong> cystic deposits in pancreas. It ismorphologically non-homogenous group <strong>of</strong> neoplasms with different occurrence dependingon sex and age, different localization and different biologic properties. Together 13 patientswith histologically proved cystic neoplasm <strong>of</strong> pancreas underwent surgery during the period<strong>of</strong> ten years from 1997 to 2007. They represent 6 percent <strong>of</strong> all patients operated forpancreatic tumor (213 patients). Women (9 patients) represented more than two thirds <strong>of</strong> alloperated patients and deposits were more <strong>of</strong>ten localized in the head <strong>of</strong> pancreas (8). Themost frequent operation was partial duodenopancreatectomy (7) and most frequentlycystadenocarcinoma was identified histologically (5 times). Median survival <strong>of</strong> these patientsis 54 months. Left sided resection, done in 5 cases, identified benign tumor in all patients; norecurrence was found in 2 years follow-up. It wasconcluded that cystic neoplasms localizedin the pancreatic head are more frequent in men than in women and predominantlymalignant, on the contrary localization in the tail <strong>of</strong> pancreas is particularly in younger womenlinked with benign tumor [573].Cystic lesions <strong>of</strong> the pancreas are being recognized with increasing frequency and havebecome a more common finding in clinical practice because <strong>of</strong> the widespread use <strong>of</strong>advanced imaging modalities and the sharp drop in the mortality rate <strong>of</strong> pancreatic surgery.Consequently, in the past 2 decades, the nature <strong>of</strong> many cystic tumors in this organ hasbeen better characterized, and significant developments have taken place in theclassification and in our understanding <strong>of</strong> pancreatic cystic lesions. In contrast to solidtumors, most <strong>of</strong> which are invasive ductal adenocarcinomas with dismal prognosis, cysticlesions <strong>of</strong> the pancreas are <strong>of</strong>ten either benign or low-grade indolent neoplasia. However,those that are mucinous, namely, intraductal papillary mucinous neoplasms and mucinouscystic neoplasms, constitute an important category because they have well-establishedmalignant potential, representing an adenoma-carcinoma sequence. Those that arenonmucinous such as serous tumors, congenital cysts, lymphoepithelial cysts, and squamoidcyst <strong>of</strong> pancreatic ducts have no malignant potential. Only rare nonmucinous cystic tumorsthat occur as a result <strong>of</strong> degenerative/necrotic changes in otherwise solid neoplasia, such ascystic ductal adenocarcinomas, cystic pancreatic endocrine neoplasia, and solidpseudopapillaryneoplasm, are also malignant and have variable degrees <strong>of</strong> aggressiveness[574].Intraductal papillary mucinous neoplasm (IPMN)Intraductal papillary mucinous tumours (IPMT) were described as a distinct entity in I982.The extent <strong>of</strong> surgical resection for this disease remains controversial. Twelve patients with adiagnosis <strong>of</strong> IPMT were included in the present retrospective study. Ten out <strong>of</strong> twelvepatients had symptoms suggesting chronic pancreatitis. Two patients were not operated ondue to biopsy-verified metastases in the liver. Nine patients were treated with a totalpancreatectomy and one with a pancreaticoduodenectomy. In the ten patients operated onfor IPMT, histological examination showed eight non-invasive- and two invasive carcinomas.In six cases, multifocal extensive intraductal changes were found, affecting either most <strong>of</strong> orthe whole pancreas. There was no perioperative mortality. Six patients were alive at followupwithout recurrence and four patients were dead, two <strong>of</strong> them with recurrence [575].

Growth rateOne study reported the growth rate in two cases <strong>of</strong> main duct pancreatic intraductal papillarymucinousneoplasms (MD-IPMNs) demonstrating significant changes over several years'observation. The first patient was a 74-year-old woman with an incidental finding <strong>of</strong> diffusedilatation <strong>of</strong> the main pancreatic duct (MPD). Endoscopic retrograde pancreatography (ERP)identified a 5 mm filling defect. Three years later computed tomography (CT) revealed a 20mm mass occupying the MPD. The second patient was a 67-year-old woman who presentedwith back pain. Abdominal CT revealed a 5 mm mass in the dilated MPD. Five years later,CT and ERP showed a 20 mm mass occupying the markedly dilated MPD. Both patientssubsequently underwent pancreatectomy. Histologically, the tumors showed an intraductalpapillary growth occupying the dilated main pancreatic duct and comprised <strong>of</strong> mucincontainingcolumnar epithelial cells. The tumor volume doubling time <strong>of</strong> these MD-IPMNswas 141 and 304 days in patient 1 and 2, respectively, with a mean <strong>of</strong> 223 days. The presentreports demonstrate the ability <strong>of</strong> benign MD-IPMNs to grow at a significant rate, supportingthe current consensus guidelines that MD-IPMNs require surgical resection [576].Ways <strong>of</strong> detectionTo define how patients with pancreatic cysts are being diagnosed and treated 401 patientswere evaluated between 2004 and 2007. Pancreatic cysts were incidentally discovered in 71percent (284 <strong>of</strong> 401) <strong>of</strong> patients. There was no statistically significant difference in age (60 vs63 years), cyst size (31 vs 27 mm), or histological diagnosis between symptomatic patientsand patients with incidentally discovered cysts. Whereas the majority <strong>of</strong> symptomatic patientshad their cystic neoplasms resected on diagnosis, 50 percent (142 <strong>of</strong> 284) <strong>of</strong> incidentallydiscovered cysts were initially managed nonoperatively. Of the patients who were managedwith surveillance, 13 (8 %) subsequently underwent resection after a median <strong>of</strong> 2.1 yearsbecause <strong>of</strong> an increase in cyst size, development <strong>of</strong> symptoms, increasing tumor markers,worrisome endoscopic ultrasonography findings, or patient anxiety. The most commondiagnosis among resected lesions was either main-duct intraductal papillary mucinousneoplasm (25 %) or branch-duct intraductal papillary mucinous neoplasm (23 %). Invasivecancer was found in 29 <strong>of</strong> 256 (11 %) resected cystic neoplasms, 9 <strong>of</strong> which wereincidentally discovered, and in 7 percent (1 <strong>of</strong> 13) <strong>of</strong> patients who underwent watchful waitingprior to resection. Incidentally discovered pancreatic cystic neoplasms composed 71 percent<strong>of</strong> our series, <strong>of</strong> which 50 percent were immediately resected. Subsequent morphologicchanges or development <strong>of</strong> symptoms prompted an operation in 8 percent <strong>of</strong> patients after aperiod <strong>of</strong> surveillance. Invasive malignancy was present in 11 percent <strong>of</strong> all resectedspecimens but in 38 percent <strong>of</strong> main-duct intraductal papillary mucinous neoplasms [577].Intraductal papillary mucinous neoplasms have gained recognition in recent years aspremalignant precursors to pancreatic cancer that enable early detection and <strong>of</strong>ten are foundincidentally at imaging. Accurate diagnosis and optimal, finely tuned management <strong>of</strong> theselesions are important and require collaboration across various disciplines, includingradiology, endoscopy, surgery, and pathology. Several imaging modalities can visualizethese lesions adequately, each with specific advantages and disadvantages. Multidetectorcomputed tomography and magnetic resonance cholangiopancreatography are generally thefirst-line imaging modalities; endoscopic imaging such as endoscopic ultrasound andendoscopic retrograde cholangiopancreatography are beneficial when the former 2modalities are equivocal. Surgical candidates generally include patients with main ductlesions or branch duct lesions greater than 3 cm or any possessing a solid component. Amanagement algorithm indicating when surgery should be pursued was proposed. Fornonsurgical and postsurgical patients, follow-up management is important to monitor growthand recurrence, and risks from repeated radiation exposure should be taken into account.Furthermore, issues <strong>of</strong> multifocality and increased predisposition <strong>of</strong> the pancreas to ductal

adenocarcinoma must be addressed at follow-up evaluation. A follow-up managementalgorithm also was also proposed in the <strong>review</strong> [578]Risk <strong>of</strong> cancerAlthough branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are slowgrowingtumors with a favorable prognosis, the synchronous occurrence <strong>of</strong> pancreatic ductaladenocarcinomas (PDAs) in patients with BD-IPMNs has been reported. One study wasaimed to elucidate the development <strong>of</strong> PDAs in long-term follow-up patients with BD-IPMNs.It was investigated 89 BD-IPMN patients who had no mural nodules and followed them upconservatively at least 2 years (median follow-up, 64 months; range, 25-158 months). Allsubjects underwent examinations by imaging modalities including endoscopic retrogradepancreatography. It was calculated the standardized incidence ratio (SIR) from vital statistics.Among the 89 patients, 4 cases <strong>of</strong> PDAs distant from BD-IPMN were observed in 552patient-years <strong>of</strong> follow-up (7.2 per 1000 patient-years). The expected number was 0.25, andthe SIR <strong>of</strong> PDAs was 15.8 (95 % confidence interval 4.3 to 40.4). Subgroup analysesshowed that the incidence <strong>of</strong> PDAs was significantly increased in patients 70 years or older(SIR 16.7; 95 % confidence interval 3.4 to 48.7) and in women (SIR 22.5; 95 % confidenceinterval 2.7 to 81.1). It was concluded that patients with BD-IPMNs are at a high risk forpancreatic adenocarcinomas. During the follow-up, careful examination is required to detectthe development <strong>of</strong> PDAs in patients with BD-IPMNs [579].The biologic and clinical behavior <strong>of</strong> intraductal papillary mucinous neoplasms <strong>of</strong> thepancreas (IPMNs) and IPMN-associated adenocarcinomas is different from ductal pancreaticcancer in having a less aggressive tumor growth and significantly improved survival. Up todate, the molecular mechanisms underlying the clinical behavior <strong>of</strong> IPMNs are incompletelyunderstood. Now 128 cystic pancreatic lesions were prospectively identified during thecourse <strong>of</strong> 2 years. From the corresponding surgical specimens, 57 IPMNs were separatedand subdivided by histologic criteria into those with low-grade dysplasia, moderate dysplasia,high-grade dysplasia, and invasive cancer. Twenty specimens were suitable for DNAisolation and subsequent performance <strong>of</strong> array CGH. While none <strong>of</strong> the IPMNs with lowgradedysplasia displayed detectable chromosomal aberrations, IPMNs with moderate andhigh-grade dysplasia showed frequent copy number alterations. Commonly lost regions werelocated on chromosome 5q, 6q, 10q, 11q, 13q, 18q, and 22q. The incidence <strong>of</strong> loss <strong>of</strong>chromosome 5q, 6q, and 11q was significantly higher in IPMNs with high-grade dysplasia orinvasion compared with PDAC. Ten <strong>of</strong> 13 IPMNs with moderate dysplasia or malignancy hadloss <strong>of</strong> part or all <strong>of</strong> chromosome 6q, with a minimal deleted region between linear positions78.0 and 130.0. This study is the first to use array CGH to characterize IPMNs. Recurrentcytogenetic alterations were identified and were different than those described in PDAC.Array CGH may help distinguish between these 2 entities and give insight into thedifferences in their biology and prognosis [580].A 52-year-old man with a history <strong>of</strong> distal gastrectomy for gastric cancer was admittedbecause <strong>of</strong> jaundice. CT scan revealed double tumors in the pancreatic head and bodyconcomitant with multicystic lesions <strong>of</strong> the pancreas. Total pancreatectomy with splenectomyand remnant gastrectomy was performed. Final histological diagnosis was double invasiveductal carcinomas <strong>of</strong> the pancreas head and tail with multifocal branch duct intraductalpapillary mucinous adenomas <strong>of</strong> the pancreas. The present case suggests that entirepancreas might have malignant potential in patients with intraductal papillary mucinousneoplasms [581].A consensus conference has recommended close observation <strong>of</strong> branch duct intraductalpapillary mucinous neoplasms (BD-IPMNs) smaller than 30 mm, without symptoms or muralnodules. One study investigated whether these recommendations could be validated in a

single-centre experience <strong>of</strong> BD-IPMNs. Some 190 patients with radiological imaging orhistological findings consistent with BD-IPMN were enrolled between 1998 and 2005. Thosewith less than 6 months' follow-up and no histological confirmation were excluded. BD-IPMNwas diagnosed by computed tomography and pancreatography in 105 patients andpathologically in 85. Eighteen patients had adenoma, 53 borderline malignancy, fivecarcinoma in situ and nine invasive carcinoma. Findings associated with malignancy werethe presence <strong>of</strong> radiologically suspicious features and a cyst size <strong>of</strong> at least 30 mm. Hadconsensus guidelines been applied, 54 patients would have undergone pancreatic resection,whereas only 28 <strong>of</strong> these patients actually had a resection; 12 <strong>of</strong> the latter patients had amalignancy compared with none <strong>of</strong> the 26 patients who were treated conservatively. It wasconcluded that a simple increase in cyst size is not a reliable predictor <strong>of</strong> malignancy.Observation is recommended for patients with a BD-IPMN smaller than 30 mm showing nosuspicious features on imaging [582].Intraductal papillary mucinous neoplasm (IPMN) was first described by Ohashi et al as"mucin-producing cancer" that affected the main pancreatic duct and produced excessivequantities <strong>of</strong> mucus, which filled and distended the ductal system. Prediction <strong>of</strong> malignancy<strong>of</strong> IPMN is important not only for indication <strong>of</strong> operation but for selection <strong>of</strong> operativeprocedure. International Consensus Guidelines recommended to resect all main duct andmixed variant IPMNs, and also recommended to resect branch duct IPMNs with symptoms.However, the criteria for resection in the branch duct IPMNs are still unclear. One studyaimed to determine the predictive factors for malignancy in IPMN, particularly cancerinvasion in IPMNs. It was <strong>review</strong>ed 26 cases with IPMN operated from 2003 to 2007. Amongthem, 21 cases were branched type, and the others were main duct type. It was measureddiameter <strong>of</strong> main pancreatic duct, cystic lesion size and intramural nodule size by endoscopicultrasonography or computed tomography and serum levels <strong>of</strong> CEA and CA19-9. As forfactors to predict malignancy only in branched type, the intramural nodules size and wassignificantly larger in the cases with cancer than that in the cases without cancer. Theanalysis all types IPMNs showed significant difference in the main duct diameter between 15benign and 11 malignant cases (5.5 + 4.0 mm vs 10.9 + 4.5 mm). Moreover, among the 11cases whose diameter <strong>of</strong> main pancreatic duct was less than 7 mm, no malignancy wasdetected. These results suggest that the diameter <strong>of</strong> main pancreatic duct as well asintramural nodules size is useful for prediction <strong>of</strong> malignancy and that minimally-invasivesurgery such as spleen-preserving distal pancreatectomy can be safely indicated for thecases whose diameter <strong>of</strong> main pancreatic duct is less than 7 mm [583].It was investigated preoperative findings that are useful to distinguish intraductal papillarymucinousneoplasm (IPMN) subtypes. One hundred twenty-three patients who underwentpancreatectomy for IPMN were analyzed clinicopathologically and radiologically. InvasiveIPM carcinomas (IPMCs) were subdivided into early-stage nonaggressive (minimally invasiveIPMC [MI-IPMC]) and more advanced and aggressive (invasive carcinoma originating inIPMC [IC-IPMC]) subtypes according to recently proposed pathological criteria. The lesionsconsisted <strong>of</strong> 27 IPMNs with low-grade dysplasia, 14 IPMNs with moderate dysplasia, 21IPMNs with high-grade dysplasia, 30 MI-IPMCs, and 31 IC-IPMCs. Multidetector-rowcomputed tomography detected a component <strong>of</strong> invasive carcinoma in IC-IPMC with 86percent sensitivity and 100 percent specificity. In patients with IPMNs other than IC-IPMC,multivariate analysis demonstrated 3 significant predictive factors <strong>of</strong> malignancy: IPMN size(>40 mm), IPMN duct type (main pancreatic duct or mixed type), and the presence <strong>of</strong> a muralnodule or thick septum. The diagnostic score obtained using these 3 factors showed a strongcorrelation with the presence <strong>of</strong> malignancy. It was concluded that regarded preoperativeevaluation <strong>of</strong> patients with IPMN, it is recommended to rule out IC-IPMC using multidetectorrowcomputed tomography and then to categorize IPMN other than IC-IPMC according tomalignant potential based on the diagnostic score [584].

Molecular biologyCD44v6The purpose <strong>of</strong> thone is study was to examine CD44v6 expression in intraductal papillarymucinous neoplasms (IPMNs) and clarify the role <strong>of</strong> CD44v6 in progression, invasion,metastasis, and morphogenesis <strong>of</strong> IPMNs. One hundred fifty-one samples <strong>of</strong> IPMNs and 30normal controls were subjected to immunohistochemical analysis for CD44v6. The IPMNswere divided into 4 groups according to the grade <strong>of</strong> atypia (adenoma, borderline IPMN,noninvasive carcinoma, and invasive carcinoma) and 5 subtypes according to histologicalphenotype (gastric, intestinal, pancreatobiliary, oncocytic, and unclassified). Whereas normalductal epithelium did not express CD44v6, CD44v6 expression was observed from the earlystage <strong>of</strong> IPMNs and up-regulated in the progression <strong>of</strong> IPMNs to invasive carcinoma.CD44v6 expression in intestinal-type IPMNs was significantly lower compared with that inother subtypes. Whereas no correlation was observed between lymph node metastasis andCD44v6 expression in invasive IPM carcinomas, the invasion pattern was significantlycorrelated to CD44v6 expression. These data indicate that CD44v6 expression determinesthe morphology and aggressiveness <strong>of</strong> IPMNs and is involved in development and invasion<strong>of</strong> IPMNs [585].CD133The rate <strong>of</strong> intraductal papillary mucinous neoplasm (IPMN) progression is much slower thanthat <strong>of</strong> invasive ductal adenocarcinomas. The identification <strong>of</strong> a clinicopathological marker todistinguish IPMNs from ductal adenocarcinomas is important for understanding the molecularmechanisms <strong>of</strong> pancreatic cancer. It was examined the expression pattern <strong>of</strong> the cell surfacemarker CD133, which has been used to identify putative cancer stem cells from solid tumors,in adult pancreatic ductal adenocarcinomas (n=10) and IPMNs (n=34). CD133 expressionwas detected in the centroacinar region and intralobular ductal cells <strong>of</strong> normal pancreas.CD133 expression was also observed in ductal adenocarcinomas. In contrast, CD133expression was not observed in the mucin-producing epithelial cells and carcinoma cells onIPMNs. These results demonstrate that the expression <strong>of</strong> CD133 is down-regulated inIPMNs, suggesting that loss <strong>of</strong> CD133 expression might be a useful clinicopathologicalmarker distinguishing IPMNs from ductal adenocarcinomas [586].KOCTo evaluate if immunocytochemical expression <strong>of</strong> K homology domain containing proteinoverexpresssed in cancer (KOC) in biliary brushings and fine needle aspiration improves thediagnostic capability <strong>of</strong> cytology for intraductal papillary mucinous neoplasm (IPMN) andpancreatic ductal adenocarcinoma 14 pancreatic cancers, 15 IPMNs and 7 chronicpancreatitis cases were investigated. The cytology smears and surgical specimens werestained with antibody to KOC (1:500). The intensity (scale 0-3+) and percentage <strong>of</strong> cellsstaining were evaluated in pathologic lesions, and diffuse (>75 % <strong>of</strong> cells) staining <strong>of</strong> 3+intensity was considered positive. There was 100 percent specificity for diagnosingpancreatic cancer. The sensitivity was greater in histology (79 %) than cytology (71 %). Allchronic pancreatitis and IPMN cases, including IPMN with high grade dysplasia, werenegative. Benign epithelium adjacent to pancreatic cancer or IPMN was also negative. Thisstudy demonstrated that pancreatic adenocarcinoma can be differentiated from IPMN andbenign ductal epithelium using KOC expression. This could be useful in cytologic caseswhere atypical features preclude a definitive diagnosis <strong>of</strong> malignancy [587].WWOXIt has previously been shown that WW domain-containing oxidoreductase (WWOX) hastumour-suppressing effects and that its expression is frequently reduced in pancreaticcarcinoma. In one study, it was examined WWOX expression in intraductal papillarymucinous neoplasm <strong>of</strong> the pancreas (IPMN) to assess the function <strong>of</strong> WWOX in pancreatic

duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chainreaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas andintraductal papillary mucinous carcinomas, loss or reduced WWOX immunoreactivity wasdetected in 3 (15 %) <strong>of</strong> 20 IPMAs and 17 (81 %) <strong>of</strong> 21 IPMCs. In addition, hypermethylation<strong>of</strong> the WWOX regulatory site was detected in 1 (33 %) <strong>of</strong> 3 WWOX(-) IPMAs and 9 (53 %) <strong>of</strong>17 WWOX(-) IPMCs, suggesting that hypermethylation may possibly be important in thesuppression <strong>of</strong> WWOX expression. Reduction <strong>of</strong> WWOX expression was significantlycorrelated with a higher Ki-67 labelling index but was not correlated with the ssDNA apoptoticbody index. Interestingly, decreased WWOX expression was significantly correlated with loss<strong>of</strong> SMAD4 expression in these IPMNs. The results indicate that downregulation <strong>of</strong> WWOXexpression by the WWOX regulatory region hypermethylation is critical for transformation <strong>of</strong>pancreatic duct [588].ImagingTo retrospectively evaluate the usefulness <strong>of</strong> multidetector computed tomography (MDCT)with multiplanar reformations (MPRs) and curved planar reformations (CPRs) for detectingprotruding lesions in intraductal papillary mucinous neoplasms <strong>of</strong> the pancreas (IPMNs) ascompared with single-detector CT (SDCT) and endoscopic ultrasonography (EUS) 86patients with IPMNs were imaged either with SDCT (n=52) or MDCT with MPRs/CPRs andEUS (n=34). The diagnostic accuracy <strong>of</strong> each imaging modality for identifying protrudinglesions was compared with histological samples. Among the patients in whom protrudinglesions were histopathologically identified, the lesions were detected in 9 <strong>of</strong> the 33 patientssubjected to SDCT (52 % accuracy), in 17 <strong>of</strong> the 25 patients subjected to MDCT with MPRsand CPRs (77 % accuracy), and in 21 <strong>of</strong> the 25 patients subjected to EUS (71 % accuracy).Thus, significant difference was observed between MDCT and SDCT regarding accuracy;however, no significant difference was seen between MDCT and EUS. Protruding lesions <strong>of</strong>less than 10 mm in height were significantly better visualized with MDCT (53 %) than withSDCT (13 %) [589].CTA retrospective study evaluated the suitability <strong>of</strong> computed tomography (CT) to detectmalignancy while following patients with branch-type IPMN, most <strong>of</strong> which are benign andmay be treated with observation alone was performed. Forty-two surgical specimensresected from patients with a diagnosis <strong>of</strong> branch-type IPMN were pathologically classifiedas benign (n=26), which included hyperplasia and adenoma, or malignant (n=16), includingmoderate dysplasia or adenocarcinoma. It was compared the differences in the sizes <strong>of</strong> thetumor and main pancreatic duct (MPD) and the presence <strong>of</strong> mural nodules on CT betweenthe groups. In the malignant group, it was observed a significantly larger tumor size (48 vs 24mm) and significantly increased dilation <strong>of</strong> the MPD (9.3 vs 5.0 mm) than those seen in thebenign group. The accuracy <strong>of</strong> CT diagnosis <strong>of</strong> mural nodules, however, was only 62percent. A tumor diameter > 40 mm or an MPD diameter >10 mm predicted malignancy witha sensitivity and negative predictive value <strong>of</strong> 94 and 96 percent, respectively. It wasconcluded that either tumor size or MPD dilation detected by CT could predict the majority <strong>of</strong>malignant branch-type IPMNs. Increases in these morphological characteristics on CTimages during the follow-up period would be an accurate method to predict a diagnosis <strong>of</strong>malignancy [590].MRIThe purpose <strong>of</strong> this study was to compare 2-dimensional (2D) and 3D magnetic resonancecholangiopancreatography (MRCP) for image quality and diagnostic performance in theevaluation <strong>of</strong> pathologically verified intraductal papillary mucinous neoplasm (IPMN) <strong>of</strong> thepancreas. Twenty-one patients (14 women and 7 men; mean age, 69 years; range, 43-93years) who underwent 2D and 3D MRCPs on a 1.5-T system for pathologically confirmed

IPMN were studied. Two-dimensional MRCP protocol included multiplanar thin- and thickslabsingle-shot fast spin-echo imaging, coronal single-shot fast spin-echo, and transverseT2-weighted fast spin-echo imaging. Three-dimensional MRCP was performed using a fastrecoveryfast spin-echo sequence with single-volume acquisition and maximum intensityprojection reconstructions. Using a 5-point scale, 2 readers independently evaluated MRCPsfor image quality, visualization <strong>of</strong> the pancreatic duct, and visualization <strong>of</strong> the cystic lesions.Intraductal papillary mucinous neoplasm's morphological features (septa, mural nodules, andduct communication) were also graded similarly to predict benignity or malignancy. Apancreatic surgeon <strong>review</strong>ed the 21 MRCPs to determine the usefulness <strong>of</strong> 3D MRCPcompared with that <strong>of</strong> 2D MRCP for surgical planning. Of the 21 IPMNs, 11 were side-branchIPMNs and 10 were main-duct-lesions IPMNs with side-branch involvement. A statisticallysignificant improvement in image quality and visualization <strong>of</strong> the PD and cystic lesion wasdemonstrated with 3D MRCP in comparison with that demonstrated with 2D MRCP. Themorphological details <strong>of</strong> IPMN were also identified, with higher confidence with 3D MRCP incomparison with that using 2D MRCP. Two-dimensional and 3D MRCPs performed similarlyfor predicting benign and malignant lesions, with sensitivity ranging from 50 to 67 percentand specificity ranging from 87 to 93 percent. The pancreatic surgeon preferred 3D to 2DMRCP for surgical evaluation and planning in 14 <strong>of</strong> 21 cases. It was thus concluded thatcompared with 2D MRCP, 3D MRCP provides better image quality, <strong>of</strong>fers superior evaluation<strong>of</strong> the pancreatic duct and morphological details <strong>of</strong> IPMN, and is preferred for surgicalplanning [591].EUSBecause <strong>of</strong> greater recognition and improved imaging capabilities, intraductal papillarymucinous neoplasms (IPMNs) are being diagnosed with increasing frequency. IPMNs <strong>of</strong> themain pancreatic duct cause symptoms and lead to pancreatitis. Side-branch IPMNs arethought to cause symptoms less frequently, and their association with pancreatitis is not welldefined. A total <strong>of</strong> 305 patients underwent EUS examinations between 2002 and 2006 forpancreatic cystic lesions. The main outcome measure was the frequency <strong>of</strong> acute or chronicpancreatitis that was not procedurally related. Thirty-two patients had side-branch IPMNs,and 11 (34 %) had pancreatitis. Three patients reported a single episode, and 8 patientsreported having recurrent episodes <strong>of</strong> pancreatitis. Overall, 17 (53 %) patients had symptomspossibly attributable to side-branch IPMN. Female sex (73 % vs 38 %) and multiplepancreatic lesions (54 % vs 24 %) were more commonly seen in those with pancreatitis, butwere not statistically significant factors. Larger cyst size or cyst fluid marker levels did notappear associated with pancreatitis occurrence. EUS-FNA demonstrated communicationwith the pancreatic duct in 94 percent and thick, mucinous fluid in 84 percent. It wasconcluded that pancreatitis was frequently associated with the presence <strong>of</strong> side-branchIPMNs in our referral practice. Side-branch IPMNs should be considered in the differentialdiagnosis <strong>of</strong> patients with recurrent pancreatitis with cystic lesions seen on imaging studies.EUS-FNA was the most useful modality in helping to differentiate side-branch IPMNs fromother lesions [592].Differential diagnosesCystic and neuroendocrine pancreatic neoplasms are quite rare tumors which diagnosis is<strong>of</strong>ten difficult due to their non specific symptomatology and limited diagnostic accuracy <strong>of</strong>conventional diagnostic instruments. A young woman was now admitted with abdominal painand dyspepsia. Instrumental diagnosis revealed a cystic pancreatic lesion which seems to bemalignant as CEA <strong>of</strong> pancreatic liquid was increased. The patient underwent distal splenopancreatectomyand postoperative histological examination found IPMN associated withMCN and furthermore there was occasional diagnosis <strong>of</strong> a small neuroendocrine tumor in thepancreatic tail. Radical surgical treatment is indicated in many cases <strong>of</strong> main duct IPMN andin case <strong>of</strong> MCN with signs <strong>of</strong> malignant transformation. Surgical treatment is also the goldstandard for pancreatic neuroendocrine tumors if they are singular and in M0 stage [593].

Extrapancreatic tumorsThe purpose <strong>of</strong> one study was to evaluate the incidence and clinicopathological features <strong>of</strong>extrapancreatic tumors associated with IPMN. Thirty-seven patients with IPMN <strong>of</strong> thepancreas, confirmed by surgical resection and typical findings <strong>of</strong> endoscopic ultrasonographyand CT imaging between 1998 and 2006 were included. Seventeen patients were diagnosedwith surgical resection and biopsy, and others by typical imaging findings <strong>of</strong> IPMN. Thesepatients were examined for the development <strong>of</strong> extrapancreatic tumors. Of 37 patients withIPMN, 14 (38 %) had 18 extrapancreatic tumors, and 10 (27 %) had 13 extrapancreaticmalignancies. Five, six, and two extrapancreatic malignancies had been diagnosed before,during, and after the diagnosis <strong>of</strong> IPMN. Gastric adenocarcinoma (3 patients) and colorectalcarcinoma (3 patients) were the most common neoplasms. Other extrapancreatic tumorsincluded lung cancer (n=2), prostatic cancer (n=1), renal cell carcinoma (n=1),cholangiocellular carcinoma (n=1), urinary bladder cancer (n=1), and gallbladder cancer(n=1), respectively. As benign tumor, there were two gallbladder adenoma, one gastricadenoma, one colonic adenoma and one benign ovarian cystic neoplasm, respectively. Itwas concluded that IPMN is associated with high incidence <strong>of</strong> extrapancreatic tumors,particularly gastric and colorectal neoplasms. Upper gastrointestinal endoscopy andcolonoscopy should be done, and systemic surveillance for the possible occurrence <strong>of</strong> othertumors may allow early detection <strong>of</strong> extrapancreatic tumor in patients with IPMN [594].Predictive factorsNoninvasive intraductal papillary mucinous neoplasms (IPMNs) have a favorable prognosis;however, the prognosis <strong>of</strong> invasive intraductal papillary mucinous carcinoma (invasive IPMC)is poor. Identification <strong>of</strong> predictive factors for differentiating IPMC from benign IPMNs wouldassist in providing appropriate treatment. In a retrospective study (1999-2006) 54 patientswith IPMN who underwent surgery; histologic examination showed benign adenomas in 29,carcinoma in situ in 14, and invasive carcinoma in 11 patients. Age <strong>of</strong> 70 years or older,presence <strong>of</strong> mural nodules, mural nodule size <strong>of</strong> 5 mm or larger, and carcinoembryonicantigen (CEA) level in pancreatic juice <strong>of</strong> 110 ng/mL or higher (as obtained by preoperativeendoscopic retrograde pancreatography) were predictive <strong>of</strong> a malignant IPMN by univariateanalysis, and a CEA level <strong>of</strong> 110 ng/mL or higher in pancreatic juice was identified as theonly independent predictive factor for the malignant entity. The presence <strong>of</strong> jaundice or bodyweight loss, main pancreatic duct type, presence <strong>of</strong> mural nodules, mural nodule size <strong>of</strong> 5mm or larger, and CEA level in the pancreatic juice <strong>of</strong> 110 ng/mL or higher were all predictive<strong>of</strong> invasive IPMCs by univariate analysis. The authors concluded that measurement <strong>of</strong> theCEA level in pancreatic juice should be considered in the diagnosis <strong>of</strong> IPMC [595].In immune suppressed patientsIn immunosuppressed patients with branch duct intraductal papillary mucinous neoplasm(IPMN-Br) associated with solid organ transplantation, the risk <strong>of</strong> major pancreatic surgeryhas to be weighed against the risk <strong>of</strong> progression to malignancy. Recent studies show thatIPMN-Br without consensus indications for resection can be followed conservatively. It wascompared clinical and imaging data at diagnosis and follow-up <strong>of</strong> 33 IPMN-Br patients withsolid organ transplant (T-IPMN-Br) with those <strong>of</strong> 57 IPMN-Br patients who did not undergotransplantation (NT-IPMN-Br). In T-IPMN-Br, it was noted pre- and post-transplant imagingand cyst characteristics. T-IPMN-Br patients were significantly younger than the NT-IPMN-Brpatients (63 vs 68 years). The median duration <strong>of</strong> follow-up for the groups was similar (29 vs28 months). Consensus indications for resection were present in 24 percent (8/33) <strong>of</strong> T-IPMN-Br patients and 32 percent (18/57) <strong>of</strong> NT-IPMN-Br. New consensus indications forresection were noted in 6 percent (2/33) <strong>of</strong> patients in the T-IPMN-Br group during a medianfollow-up <strong>of</strong> 17 months (range, 3-100 months) compared with 4 percent (2/57) <strong>of</strong> patients in

the NT-IPMN-Br group. Eleven patients (10 NT-IPMN-Br, 1 T-IPMN-Br) underwent surgeryduring follow-up. Only one NT-IPMN-Br patient was diagnosed with malignancy; all othershad benign IPMN-Br. It was concluded that in participants with IPMN-Br, short-term follow-upafter solid organ transplant was not associated with any significant change in cystcharacteristics suggesting that incidental IPMN-Br, even in the setting <strong>of</strong> immunosuppressionpost-transplant, can be followed conservatively [596].Frozen section at operationThe clinical significance <strong>of</strong> a positive intraoperative frozen section analysis <strong>of</strong> the pancreaticmargin, especially for adenoma or borderline lesion, is not well understood during operationsfor intraductal papillary mucinous neoplasm <strong>of</strong> the pancreas. Data from 130 consecutivepatients who underwent intraductal papillary mucinous neoplasm resection in a singleinstitution were therefore retrospectively analyzed. In the first intraoperative frozen sectionanalysis, 26 patients were positive for adenoma or borderline lesion, 10 for carcinoma in situ,2 for cancer cells floating in the duct, and 6 for invasive cancer. Twenty-nine patientsunderwent additional resection, and 105 patients finally achieved a negative pancreaticmargin. Among 18 patients with a positive pancreatic margin for adenoma or borderlinelesion, only 1 had a recurrence. All 20 patients who suffered a recurrence harbored invasiveintraductal papillary mucinous carcinoma in resected specimens. In multivariate analysis,predictive factors <strong>of</strong> recurrence after intraductal papillary mucinous carcinoma resection werethe presence <strong>of</strong> lymph node metastasis, serosal invasion, and a high level <strong>of</strong> serumcarbohydrate antigen 19-9. The presence <strong>of</strong> adenoma or borderline lesion at the pancreaticmargin does not always warrant further resection because <strong>of</strong> the low recurrence rate in theremnant pancreas. Recurrence after intraductal papillary mucinous neoplasm resection isinfluenced primarily by the presence and extent <strong>of</strong> invasive cancer rather than the status <strong>of</strong>the pancreatic margin [597].HemodialysisPancreatic cystic lesions are not necessarily rare, and it is important to diagnose whetherpancreatic cystic lesions are neoplastic such as intraductal papillary mucinous neoplasm(IPMN) because <strong>of</strong> its malignant potential. Reports on pancreatic cystic lesions inhemodialysis patients are limited. The aim <strong>of</strong> one study was to clarify the prevalence andcharacteristics <strong>of</strong> pancreatic cystic lesions in hemodialysis patients. It was <strong>review</strong>ed 1012consecutive hemodialysis patients and 11,100 patients (controls) without renal disease whounderwent transabdominal ultrasonography between 2003 and 2005. Patients' sex ratio(female-to-male) was less, and the age was older in hemodialysis patients. The prevalenceboth <strong>of</strong> pancreatic cystic lesions and IPMNs was significantly higher in hemodialysis patientsthan in controls (9.3 % vs 1.3 % and 2.8 % vs 0.2 %). The incidence <strong>of</strong> IPMNs inhemodialysis patients with pancreatic cystic lesions was higher than that in controls withpancreatic cystic lesions (30 % vs 17 %). Multivariate logistic regression analysis revealedthat the odds ratios <strong>of</strong> pancreatic cystic lesions and IPMNs were 6.4 and 9.3 in hemodialysispatients compared with controls [598].Serous cystadenomasWith more widespread use <strong>of</strong> imaging, cystic neoplasms <strong>of</strong> the pancreas are beingdiagnosed with increased frequency. Serous cystadenomas are the most common type <strong>of</strong>cystic neoplasm <strong>of</strong> the pancreas and have a natural history and malignant potential differentthan that <strong>of</strong> other cystic neoplasms. Although characteristic findings on imaging may besupportive, definitive diagnosis <strong>of</strong> these lesions <strong>of</strong>ten cannot be made by imaging alone.Endoscopic ultrasound with fine needle aspiration and cyst aspiration may facilitate the

diagnosis, and after definitive diagnosis, patients with lesions that are small andasymptomatic may be followed with serial imaging. If definitive diagnosis cannot be made orif the patient is symptomatic, resection is warranted. In addition, large (> 4 cm) serouscystadenomas should be resected in appropriate surgical candidates given their propensityfor growth and developing symptoms [599].Many patients with benign serous cystadenoma (SCA) <strong>of</strong> the pancreas will undergo resectionbecause <strong>of</strong> the inability to reliably discriminate between SCA and premalignant mucinouscysts (intraductal papillary mucinous neoplasm – IPMN – mucinous cystic neoplasm –MCN]). Cyst fluid from patients with SCA (n=15), non main-duct and noninvasive IPMN(n=32), and noninvasive MCN (n=12) was aspirated at the time <strong>of</strong> operative resection andanalyzed. Commercially available and custom designed multiplex assays (Luminex) wereperformed using a biomarker panel developed for pancreatic cancer. Differential proteinexpression (fluorescence intensity, FI) was compared between the 3 groups for each protein.Unsupervised sample clustering (hierarchical clustering) and supervised sampleclassification (prediction analysis for microarrays – PAM) was then performed. Significantdifferential protein expression was identified between SCA and IPMN (34/51 proteins, 67 %)and between SCA and MCN (13/51 proteins, 25 %). The majority <strong>of</strong> proteins were downregulatedin IPMN and MCN compared with SCA. The only proteins significantlyoverexpressed in the cyst fluid <strong>of</strong> patients with mucinous cysts were CEA (median FI: IPMN11.4, MCN 13.0, SCA 5.3) and CA72.4 (median FI: IPMN 10.4, MCN 10.5, SCA 9.9).Unsupervised cluster analysis demonstrated distinct clustering <strong>of</strong> SCA and IPMN with somecross-over between MCN. Supervised sample classification with 14 proteins had an overallaccuracy rate <strong>of</strong> 92 percent between SCA and IPMN. In this study differential cyst fluidprotein expression was observed between SCA and IPMN for the majority <strong>of</strong> proteinsassessed and multimarker sample classification accurately discriminated between SCA andIPMN in 92 percent <strong>of</strong> patients [600].Diffuse serous cystadenomas <strong>of</strong> the pancreas are extremely rare, with only 8 cases reportedpreviously, and have been associated with neuroendocrine tumors in only two patients.Some have been seen in von Hippel-Lindau disease. The management <strong>of</strong> these tumorsposes a challenge due to their rarity and uncertain malignant potential. It was reported acase <strong>of</strong> diffuse serous cystadenoma associated with neuroendocrine carcinoma in a 35-yearoldwoman. A 35-year-old woman with mild abdominal pain was diagnosed as having acystic pancreatic mass on ultrasonography. On contrast-enhanced CT scan, MRI and MRCPimaging, a spongy lesion was found to replace the entire pancreas, and was diagnosed asdiffuse serous cystadenoma. Serum biochemistry for amylase, lipase, CA 19-9 and CEA wasnormal. Screening for retinal and CNS lesions was also unremarkable. A totalpancreatectomy was performed, and the patient recovered well. Histopathologicalexamination <strong>of</strong> the specimen revealed microcysts and macrocysts replacing the entirepancreas, the largest being 3.5 cm. The cysts were lined with a single layer <strong>of</strong> cuboidal t<strong>of</strong>lattened cells. An endocrine tumor abutting the cystic component was found, havingneoplastic cells in a trabecular pattern. Metastasis <strong>of</strong> the neuroendocrine component wasseen in the adherent lymph nodes. A diagnosis <strong>of</strong> diffuse serous cystadenoma associatedwith neuroendocrine carcinoma was made. It was concluded that diffuse serouscystadenomas <strong>of</strong> the pancreas are extremely rare tumors. In young patients, they mayharbour associated malignancy, and may be the first presentation <strong>of</strong> von Hippel-Lindaudisease. Aggressive surgical resection with long-term follow-up may be worthwhile in thisgroup <strong>of</strong> patients [601].Serous microcystic adenomaThe diagnosis <strong>of</strong> serous microcystic adenoma (SMA) is usually straightforward. For smallbiopsies and/or unusual variants, the differential diagnosis includes other pancreatic or

metastatic neoplasms showing cystic or clear cell features. It was therefore evaluatedimmunostains for potential use in the diagnosis <strong>of</strong> SMA. Cases <strong>of</strong> SMA were identified fromarchival files. Tissue cores (2 per block) were arrayed to create a microarray <strong>of</strong> coresmeasuring 2 mm each. Additionally, microarrays previously constructed from 56 pancreaticadenocarcinomas and 64 pancreatic endocrine tumors (PENs) were studied. Themicroarrays were stained with calponin, chromogranin, CD10, alpha-inhibin, and monoclonalneuron-specific enolase (m-NSE). Subsequently, some were stained with MUC6, melan-A,D2-40, h-caldesmon, smooth muscle actin, and smooth muscle myosin. For SMAs, stainingwas seen with calponin (85 %), alpha-inhibin (96 %), and m-NSE (96 %). Focal weakstaining was seen with MUC6 (65%). All SMAs were negative with chromogranin, CD10,melan-A, D2-40, h-caldesmon, smooth muscle actin, and smooth muscle myosin. In contrast,calponin was negative in all pancreatic cancers and PENs. Staining for alpha-inhibin wasabsent in pancreatic cancers and present in 4 percent <strong>of</strong> PENs; whereas immunoreactivityfor m-NSE was present in 27 percent <strong>of</strong> pancreatic cancers and 74 percent <strong>of</strong> PENs.Chromogranin staining was present in 9 percent <strong>of</strong> pancreatic cancers and 100 percent <strong>of</strong>PENs. An immunohistochemical pr<strong>of</strong>ile <strong>of</strong> staining with calponin, alpha-inhibin, and m-NSEand absent staining with chromogranin supports the diagnosis <strong>of</strong> SMA, and distinguishesSMA from pancreatic cancers and pancreatic endokrine tumors. Calponin and alpha-inhibinare the most useful positive markers for serous microcystic adenoma, and are negative inmost entities in the differential diagnosis [602].Serous microcystic adenoma with oncocytic changeIt was reported a case <strong>of</strong> pancreatic serous microcystic adenoma with extensive oncocyticchange in a 73-year-old woman. Histologically the tumor consisted <strong>of</strong> numerous small cysts,separated by thin or broad fibrous septa. These cysts were lined with uniform cells havingabundant eosinophilic granular cytoplasm, which was negatively or weakly stained with PAS.Immunohistochemically, the cyst-lining cells were positive for cytokeratin (CK) 7, CK19,MUC1, MUC6, alpha-inhibin, and neuron-specific enolase (NSE), and negative for CK8,CK20, MUC2, and MUC5AC; these immunopr<strong>of</strong>iles coincide with those <strong>of</strong> serous microcysticadenoma. Immunostaining with anti-mitochondrial antibody showed dense granular positivityin the cytoplasm, which suggested an oncocytic phenotype. Thus, the case was considered avariant <strong>of</strong> serous microcystic adenoma characterized by extensive oncocytic change. It maypose problems in the differential diagnosis <strong>of</strong> the cystic pancreatic tumors with oncocyticchange, but can be diagnosed on histology and immunohistochemistry [603].Mucinous adenomaA 60-year-old woman was referred for evaluation <strong>of</strong> a cystic mass in the pancreatic body thatextended to the tail. Transabdominal ultrasonography demonstrated an oval cystic mass 24cm in diameter, filled with debris. On the cyst wall there was a wide-based, smooth-surfaced,heterogeneous high-echoic protrusion that was 5 cm in diameter. On CT the protrusionshowed internal enhancement. Endoscopic pancreatography showed no intraductal mucin orcommunication with the cyst. A distal pancreatectomy was performed under the diagnosis <strong>of</strong>mucinous cystadenocarcinoma. Grossly there was a brownish, hemispherical protrusion intothe thin monolocular cyst. The cut surface <strong>of</strong> the protrusion showed a peripheral yellowbrownisharea and an internal wine-colored area. Histopathologically the cyst wall consisted<strong>of</strong> tall columnar cells without atypical nuclei, ovarian-type stroma beneath the epithelium, andfibrotic tissue with abundant capillary vessels, suggestive <strong>of</strong> a mucinous cystadenoma. Theprotrusion was composed <strong>of</strong> peripheral organized hematoma without a covering epithelium,and internal hemorrhage and many capillary vessels, with no evidence <strong>of</strong> tumor cell necrosis.These histopathological findings appear to be similar to those <strong>of</strong> chronic expandinghematoma. The formation <strong>of</strong> a huge mural hematoma in a mucinous cystic neoplasm canoccur as a repair process after the breaking <strong>of</strong> intrawall vessels [604].

Solid and pseudopapillary tumor (Frantz's tumor)Solid and pseudopapillary tumor (Frantz's tumor) is a rare low-grade neoplasm <strong>of</strong> thepancreas. It was reported six new cases. A retrospective <strong>review</strong> was considered on sixTunisan patients who had solid and pseudopapillary tumor <strong>of</strong> the pancreas. A <strong>review</strong> <strong>of</strong>medical registries and morphological analysis with immunohistochemical study were carriedout in all cases. Four patients were female and two patients were male with a median age <strong>of</strong>28 years (range: 14-68 years). Abdominal pain was the most common initial symptoms (5/6cases). Abdominal computed tomography and/or ultrasonography was used in all the cases.The tumour was in the tail <strong>of</strong> the pancreas in 4 patients and in the body <strong>of</strong> the pancreas inone patient; one tumor involved all the pancreas. The median diameter <strong>of</strong> the tumor was 17cm (range: 8-35 cm). Three tumors had an extrapancreatic extension. All patients underwentsurgical resection. No adjuvant therapy was recommended. The mean follow up period was24 months (range: 5-78 months). Only one patient died during the surgery. Except for thispatient, none experienced tumor recurrence or tumor-related mortality during the follow upperiod. Solid and pseudopapillary tumour <strong>of</strong> the pancreas is an uncommon neoplasm whichshows distinct clinicopathologically characteristics. Despite diverse studies, its histogenesisremains undetermined. This tumor should be distinguished from other pancreatic neoplasmsbecause its prognosis is excellent after surgical resection [605].Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors with malignant potential.Longterm outcomes were evaluated in 37 patients with an SPN who were followed from 1970to 2008. Thirty-three (89 %) were women, and median age at diagnosis was 32 years. Mostpatients were symptomatic; the most common symptom was abdominal pain (81 %). Thirtysixpatients underwent resection; one patient with distant metastases was not operated on.There were no 30-day mortalities. Median tumor size was 4.5 cm. Thirty-four patientsunderwent an R0 resection, 1 had an R1 resection, and 1 had an R2 resection. Two patientshad lymph node metastases, and one patient had perineural invasion. After resection, 34 (94%) patients remain alive. One patient died <strong>of</strong> unknown causes 9 years after resection, andanother died <strong>of</strong> unrelated causes 26 years after operation. The patient with widespreaddisease who didn't have resection died 11 months after diagnosis. Thirty-five <strong>of</strong> the 36patients having resection remained disease free, including those who died <strong>of</strong> unrelatedcauses (median follow-up, 5 years). One patient developed a recurrence 8 years aftercomplete resection. She was treated with gemcitabine and remained alive 14 months afterrecurrence. It was concluded that formal surgical resection may be performed safely and isassociated with longterm survival [606].Solid pseudopapillary tumor (SPT) <strong>of</strong> the pancreas is rare. One study was performed toanalyze the expression <strong>of</strong> Wnt signal target genes (matrix metalloproteinase-7, MMP-7,cyclin-D1, and c-myc) and Ki-67 in resected SPTs to determine their clinicopathologiccharacteristics according to their expression. From 1995 to 2005, 23 patients underwentpancreatic resections for SPT <strong>of</strong> the pancreas. Among 23 formalin-fixed, paraffin-embeddedtissues, 12 were evaluated as a pilot study. Immunohistochemistry was performed usingvarious detection and antigen retrieval methods to detect MMP-7, cyclin-D1, c-myc, and Ki-67. The expression <strong>of</strong> Wnt target genes was correlated with clinicopathologic features <strong>of</strong> thepatients. Solid pseudopapillary tumors <strong>of</strong> the pancreas always showed cytoplasmic/nuclearaccumulation <strong>of</strong> beta-catenin, frequent expression <strong>of</strong> cyclin-D1, and low proliferation index.MMP-7, cyclin-D1, c-myc, and Ki-67 were not correlated with microscopic featuressuggesting malignant potential. Tumor size was closely related to microscopic features <strong>of</strong>malignant potential and apparently has an inverse relationship with the expression <strong>of</strong> cyclin-D1 and Ki-67. Low proliferative index and associated MMP-7 expression may cause anunpredictable clinical course in this tumor. Subtle changes in the intracellular environment,not pathologic (morphologic) changes, may elucidate the unpredictable clinical course <strong>of</strong> thistumor [607].

Solid pseudopapillary neoplasms <strong>of</strong> the pancreas (SPN) account for less than 1 percent <strong>of</strong> allpancreatic tumors. A multi-institutional retrospective <strong>review</strong> was conducted <strong>of</strong> all 21 patientswho underwent surgical resection from 1994 to 2008. Twenty patients were female. Medianage at presentation was 34 years. The most common presenting symptom was abdominalpain (67 %). All patients underwent resection: distal pancreatectomy (9), centralpancreatectomy (6), pancreaticoduodenectomy (5), and laparoscopic excision/enucleation(1). A R(0) resection was obtained in all patients. Median tumor size was 5.5 cm. AJCCstages were stage I (18), stage II (1), stage III (2), and stage IV (0). Postsurgicalcomplications occurred in 52 percent <strong>of</strong> patients, with pancreatic fistulae being the mostcommon (29 %). The median follow-up time was 55 months. All patients remain alive withoutevidence <strong>of</strong> recurrence. It was concluded that solid pseudopapillary neoplasms <strong>of</strong> thepancreas are atypical pancreatic tumors. SPN usually occur in young women who presentwith abdominal pain. Oncologic outcomes in patients who undergo surgical resection areexcellent [608].Solid pseudopapillary neoplasms <strong>of</strong> the pancreas have been seen in both genders, multipleraces, and at a wide range <strong>of</strong> ages. The genetic mechanism behind the development <strong>of</strong> SPNis distinct from the more lethal ductal carcinoma <strong>of</strong> the pancreas. This difference is reflectedin the favorable outcome for patients with SPN. Surgery is typically curative in patients withlocalized disease and possibly in patients with limited metastasis or local extension. Noconsensus exists on an effective systemic therapy. There are no reliable predictors fordisease-specific mortality or recurrence in the minority <strong>of</strong> patients who develop aggressivedisease [609].Solid psudopapillary tumor is an uncommon pancreatic neoplasm <strong>of</strong> low malignant potentialthat most frequently affect young woman. Solid-psudopapillary tumor are histologically,clinically, and prognostically quite distinct from the more common ductal adenocarcinoma. Itwas now experienced a 36-year-old male who was suspected to have extrapancreatic tumorbased on atypical radiologic imaging study, young age, and male sex, and finally diagnosedas solid-psudopapillary tumor on immunohistochemical stain examination [610].In a childSolid pseudopapillary tumors <strong>of</strong> the pancreas are extremely rare and mostly seen in youngfemales. It is <strong>of</strong>ten diagnosed incidentally or during investigations <strong>of</strong> gastrointestinalcomplaints. It was now reported the case <strong>of</strong> a 15-year old teenager who presented withpainful abdominal tumefaction. Imaging findings were a 12 cm solid and cystic massoriginating from the tail <strong>of</strong> the pancreas. A distal pancreatectomy with splenectomy wasperformed. Pathologic examination concluded to solid pseudopapillary tumor. Histologicalexamination confirms the diagnosis and allows, with the help <strong>of</strong> immunohistochemical study,to rule out some differential diagnoses such as pancreatoblastoma, acinar tumors andendocrine tumors [611].DiagnosisThe aim <strong>of</strong> one study was to investigate differential imaging features between benign andmalignant solid pseudopapillary neoplasms (SPN) <strong>of</strong> the pancreas on computed tomographicand magnetic resonance imagings. Between 2001 and 2007, it was identified 30 patientswith confirmed SPN by surgery. The computed tomographic and magnetic resonance imageswere <strong>review</strong>ed by 3 radiologists in consensus. Each tumor was analyzed for the followingcategories: location <strong>of</strong> tumor, tumor margin, proportion <strong>of</strong> solid component, morphology <strong>of</strong>capsule, growth pattern, calcification, and presence <strong>of</strong> upstream pancreatic ductal dilatation.Benign SPN usually had oval/round or smoothly lobulated margins, and malignant SPNsignificantly more commonly had focal lobulated margins. Presence <strong>of</strong> completeencapsulation was more frequently seen in benign SPN, whereas focal discontinuity <strong>of</strong>

capsule was significantly more commonly seen in malignant SPN. There was no statisticaldifference between benign and malignant tumors in other imaging findings. Thus, a focallobulated margin and a focal discontinuity <strong>of</strong> the capsule may suggest malignant SPN,whereas a round or smoothly lobulated margin and a complete encapsulation were morecommonly seen in benign SPN [612].Differential diagnosisPancreatic endocrine neoplasm (PEN) and solid pseudopapillary neoplasm <strong>of</strong> the pancreas(SPN) frequently pose diagnostic challenges. It was sought to determine which markerscould provide the best immunophenotypic characterization <strong>of</strong> PEN and SPN, allowingseparation on limited cytology samples. It was retrieved 22 resected PEN (n=12) and SPN(n=10) tumors to serve as a training set for the performance <strong>of</strong> extensiveimmunohistochemical staining. Based on these results, we selected a subset <strong>of</strong> antibodiesfor application to 25 fine-needle aspiration (FNA) samples from PEN (n=16) and SPN (n=9).Chromogranin A, synaptophysin, CD56, and progesterone receptor (PR) highlighted PENcases in the training set; E-cadherin was noted in a membranous pattern. SPN cases weremost immunoreactive for alpha 1 -antitrypsin, vimentin, CD10, and PR, with nuclear stainingfor beta-catenin; E-cadherin did not show a membranous pattern. Among all FNA samplestested, the immunohistochemical staining <strong>of</strong> E-cadherin, beta-catenin, and CD10demonstrated the greatest difference between PEN and SPN. The pattern <strong>of</strong> E-cadherin/beta-catenin expression was highly specific for distinguishing PEN from SPN. Onlimited FNA samples, the characteristic expression <strong>of</strong> E-cadherin/beta-catenin and theexpression <strong>of</strong> CD10 can be used to distinguish PEN from SPN [613].Solid and cystic pseudopapillary tumorsSolid and cystic pseudopapillary tumor (SCPT) is an uncommon cancer that typically affectsyoung women. Most patients with SCPT have a favorable prognosis provided a completeresection is attained. There are anecdotal reports <strong>of</strong> the use <strong>of</strong> neoadjuvant chemotherapy orradiation therapy for patients with unresectable tumors. In one report the case <strong>of</strong> a 14-yearoldfemale with SCPT who was successfully downsized with gemcitabine before definitivesurgical resection was described [614].Intraductal tubular carcinomaPresented was an unusual case <strong>of</strong> intraductal tubular carcinoma, intestinal type, <strong>of</strong> thepancreas. The tumor was characterized by intraductal adenoma with a few malignant foci,and also by entire involvement <strong>of</strong> the main pancreatic duct and no involvement <strong>of</strong> itsbranches. A 67-year-old man was admitted to hospital because <strong>of</strong> abdominal pain. On ERCPirregular pancreatic duct was seen. No mucus secretion was observed on endoscopy.Because a biopsy showed tubular atypical cells, pancreato-duodenectomy was performed.Grossly, the entire main pancreatic duct had intraductal tumor, sparing its branches. Nointraductal mucus was noted. Microscopically, the entire main pancreatic duct hadproliferation <strong>of</strong> tubular adenomatous tumor without secretory mucins. Goblet cells werepresent in some areas. No pyloric type tubules were recognized. Malignant transformationwas present in a few areas. No invasive features were recognized. On mucin histochemistrythe tumor cell cytoplasm contained a little or no neutral and acidic mucus, and no secretorymucins were recognized. Immunohistochemically, the tumor cells were positive forcytokeratins (CK), CK 8, 9, 18, 19 and 20, epithelial membrane antigen, CDX2, carbohydrateantigen 19-9, and Ki-67 (labeling 30 %), MUC2, MUC5AC and MUC6, and CD10. The tumorcells were negative for C-erbB2, MUC1, trypsin, pancreatic amylase and pancreatic lipase.

The tumor cells were negative for p53 protein, but the malignant foci were positive for p53protein and had high Ki-67 antigen (labeling 60 %). The patient was free <strong>of</strong> disease 4 yearsafter the operation [615].Adenosquamous carcinomaPancreatic adenosquamous carcinoma is a rare morphological variant <strong>of</strong> pancreaticadenocarcinoma with an especially poor prognosis. The purpose <strong>of</strong> one study was to identifyclinicopathologic features associated with prognosis, assess whether the percentage <strong>of</strong>squamous differentiation in pancreatic adenosquamous carcinoma is associated with aninferior prognosis, and examine the impact <strong>of</strong> adjuvant chemoradiation therapy on overallsurvival. Forty-five (1.2 %) <strong>of</strong> 3651 patients who underwent pancreatic resection at the JohnsHopkins Hospital between 1986 and 2007 were identified with adenocarcinoma <strong>of</strong> thepancreas with any squamous differentiation. All pathologic specimens were re-<strong>review</strong>ed.Statistical analyses were performed on the 38 patients amenable to adjuvant chemoradiationtherapy for whom clinical outcome data could be obtained. Median age was 68 years (61 %male). Sixty-one percent underwent pancreaticoduodenectomy. Median tumor size was 5.0cm. Seventy-six percent <strong>of</strong> carcinomas were node positive, 37 percent were margin-positiveresections, and 68 percent had 30 percent or more squamous differentiation. Median overallsurvival <strong>of</strong> the pancreatic adenosquamous carcinoma cohort was 11 months (range, 2-141months; 95 % confidence interval, 8 to 13 months). Adjuvant chemoradiation therapy wasassociated with significantly superior overall survival in patients with pancreaticadenosquamous carcinoma. Adjuvant chemoradiation therapy was associated withsignificantly improved survival in patients with tumors 3 cm or larger and vascular orperineural invasion. The proportion <strong>of</strong> squamous differentiation was not associated withmedian overall survival. Survival after pancreatic resection <strong>of</strong> pancreatic adenosquamouscarcinoma was poor. Treatment with adjuvant chemoradiation therapy was associated withimproved survival. The proportion <strong>of</strong> squamous differentiation in resected pancreaticadenosquamous carcinoma specimens does not appear to impact overall survival [616].Pancreatic lymphomaAn invasive process in the pancreas was found in a 60-year-old woman and a 50-year-oldman with abdominal symptoms. Generally, such findings turn out to be adenocarcinoma.However, these patients had lymphoma. Primary pancreatic lymphoma or localization <strong>of</strong>lymphoma in the pancreas are rare and chemotherapy may be curative. Therefore, obtainingtissue for histopathological confirmation <strong>of</strong> the diagnosis is very important. Both patientsunderwent chemotherapy. The first patient was in complete remission one month after thelast chemotherapy cycle. In the second, the disease went into remission, but he suddenlydied <strong>of</strong> sepsis after the fourth chemotherapy cycle [617].Primary pancreatic lymphoma is non-Hodgkin lymphoma primarily involving the pancreas,which is rare in pancreatic diseases. The aim <strong>of</strong> one work was to summarize the diagnosticand therapeutic experience <strong>of</strong> primary pancreatic lymphoma. It was retrospectively <strong>review</strong>edthe clinical data <strong>of</strong> 7 cases <strong>of</strong> primary pancreatic lymphoma admitted in the past 3 years. The<strong>literature</strong> <strong>review</strong> identified 157 additional cases, and a total <strong>of</strong> 164 cases had been analyzed.In this series, only 30 percent had a successful non-operative diagnosis. The curative rate <strong>of</strong>the surgery-adjuvant chemotherapy group was higher than that <strong>of</strong> the chemotherapy alonegroup. Obtaining specimens through surgery is an effective diagnostic tool. Surgicalresection in combination with postoperative chemotherapy plays a therapeutic role [618].

Small cell carcinoma <strong>of</strong> the pancreasA 58-year-old man who complained <strong>of</strong> an abdominal tumor was admitted to hospital.Abdominal CT scan showed that a 15-cm tumor occupied the entire right upper abdomenand that there were ascites and liver metastases. A liver biopsy was performed. The liverbiopsy showed a small cell carcinoma pattern, but no definitive origin <strong>of</strong> the tumor wasdetermined. Considering the extensive peritoneal invasion and multiple liver metastases, thepatient received 2 courses <strong>of</strong> cisplatin/etoposide chemotherapy, but his tumor became largerwith concomitant abdominal pain and nausea. The patient suddenly died due to multipleorgan failure caused by tumor necrosis. The autopsy revealed a pathological diagnosis <strong>of</strong>primary small cell carcinoma <strong>of</strong> the pancreas [619].Non pancreatic periampullary tumorsLymph node ratio (LNR) has been associated with long-term survival in patients withpancreatic adenocarcinoma; however, this has not been demonstrated in other periampullarymalignancies. The purpose <strong>of</strong> one study was to determine if LNR is associated with survivalin other periampullary malignancies. A retrospective <strong>review</strong> <strong>of</strong> a prospective database <strong>of</strong> 522pancreaticoduodenectomies performed between 1988 and 2007 was undertaken. Patientswith positive lymph node status were placed into the following groups: LNR = 0; LNR < 0.2;LNR < 0.4; and LNR >0.4. Of the 364 malignancies identified, there were 219 (60 %)pancreatic adenocarcinomas, 36 (10 %) duodenal adenocarcinomas, 75 (21 %) ampullaryadenocarcinomas, and 35 (10 %) cholangiocarcinomas. Positive lymph node status affectedpatient survival in all malignancies studied. Increasing LNR was significabtly associated withdecreased survival in both pancreatic and perimapullary cancers [620].Papilla <strong>of</strong> Vater tumorsCarcinoids <strong>of</strong> the ampulla <strong>of</strong> Vater are the most rare primary ampullary tumors. There wasnoted a frequent association <strong>of</strong> the endocrine tumors with type 1 neur<strong>of</strong>ibromatosis alsoknown as von Recklinghausen disease. There are only 8 cases <strong>of</strong> papilla duodenalis minorcarcinoids described in the <strong>literature</strong>. Authors describe herein the first carcinoid <strong>of</strong> papilladuodenalis minor case associated with multiple synchronic jejunal leiomyomas and vonRecklinghausen disease, manifested with proximal intestinal obstruction [621].One paper reported a case <strong>of</strong> a carcinoma that probably developed from the peribiliary glandwithin the ampulla <strong>of</strong> Vater based on the histopathological findings <strong>of</strong> the resectedspecimens. There were no malignant findings on gastrointestinal endoscopy and computedthomography. Endoscopic retrograde cholangiopancreatography revealed no tumor in themain pancreatic duct or the common bile duct or ampulla <strong>of</strong> Vater. Pylorus-preservingpanctreaticoduodenectomy was performed with a diagnosis <strong>of</strong> duodenal stenosis <strong>of</strong> unknowncause. The histopathological findings revealed that a moderately to poorly differentiatedadenocarcinoma originating near the peribiliary gland in the ampulla <strong>of</strong> Vater was extensivelydistributed in the submucosal layer <strong>of</strong> the duodenum. Based on these findings, a diagnosis <strong>of</strong>a carcinoma <strong>of</strong> the ampulla <strong>of</strong> Vater arising from the peribiliary gland was most likely [622].A 45-year-old man: pointed out von Recklinghausen disease at 18 years <strong>of</strong> age. He had acheckup in a close inspection purpose <strong>of</strong> a duodenum tumor. It was diagnosed an accessorypapilla carcinoid, and pancreas divisum was doubted. Local resection <strong>of</strong> the accessorypapilla was performed and picked out a carcinoid <strong>of</strong> 7 mm size [623].

Duodenal tumorsColorectal polyposis is the main feature <strong>of</strong> familial adenomatous polyposis (FAP), but benignand malignant lesions have also been described in the stomach, duodenum, small bowel,biliary tract and pancreas. There are few reports on FAP patients with duodenal polyps thatdeveloped at a younger age and even fewer on cases with dysplastic degeneration. Theprogression to carcinoma usually presents quite late in the clinical history <strong>of</strong> FAP patients,typically at least 20 to 25 years after proctocolectomy. One report described the rare case <strong>of</strong>a patient presenting with duodenal adenomas with dysplastic changes and tumor infiltrationas the first sign <strong>of</strong> FAP, who was treated by pancreaticoduodenectomy followed byproctocolectomy for subsequent dysplastic changes in colonic polyps [624].Local excisionLocal surgical treatment <strong>of</strong> periampullary neoplasms seems attractive in the context <strong>of</strong> thereduced morbidity and mortality than the more radical treatment options. The aim <strong>of</strong> ourstudy was to compare local excision <strong>of</strong> the ampulla with standard pancreaticoduodenectomyfor the treatment <strong>of</strong> periampullary cancer in terms <strong>of</strong> overall survival. Inclusion criteria wereprimary tumor < 2 cm with no evidence <strong>of</strong> lymph node involvement or distant metastasis onabdominal computed tomography. Between 2000 and 2004, 23 patients were enrolled ontothis study (9 in the local excision group and 14 in the standard pancreatic resection group).The two groups were homogeneous with respect to age and gender as well as the size andorigin <strong>of</strong> the primary neoplasm. There was no correlation <strong>of</strong> the survival with age, gender,presence <strong>of</strong> lymph node metastasis, size <strong>of</strong> the primary tumor, type <strong>of</strong> surgery or histologicgrade. However, the origin <strong>of</strong> the tumor had major impact on survival, with pancreatic tumorshaving the worst prognosis. Hospital stay was significantly reduced in the local excisiontreated patients. The results showed that local excision for periampullary tumors is a viableoption and is well suited for medically unfit patients or those who refuse more radicaltreatment options [625].Metastases to pancreasMetastasectomy with curative intent has become standard practice for the management <strong>of</strong>some malignancies. Resection <strong>of</strong> isolated metastatic colorectal cancer, gastrointestinalstromal tumours, neuroendocrine cancers, renal-cell cancer and sarcoma is associated withlonger survival or even cure. The strongest evidence in favour <strong>of</strong> metastasectomy exists forcolorectal cancer, in which resection <strong>of</strong> limited metastatic disease in some patients isassociated with 5-year survival rates <strong>of</strong> more than 50 percent. High incidence <strong>of</strong> the disease,predictable tumour biology, and development <strong>of</strong> successful chemotherapies has encouragedmetastasectomy. Furthermore, improved safety <strong>of</strong> complex surgeries over the past severaldecades has lowered the threshold for more aggressive surgical intervention. Most <strong>literature</strong>on metastasectomy pertains to the resection <strong>of</strong> disease involving the liver, lung, and brain.However, metastasectomy has been described for almost every organ system, including thepancreas. Pancreatic metastasectomy is most <strong>of</strong>ten done through a formal pancreaticresection such as pancreaticoduodenectomy or distal pancreatectomy. Less <strong>of</strong>ten,pancreatic metastasectomy is done by enucleation or a pancreas sparing operation such asa central pancreatectomy [626].Renal cell carcinomaPancreatic metastasis accounts for 2 percent <strong>of</strong> metastatic renal cell carcinoma cases.Surgical management is typically recommended because <strong>of</strong> the limited value <strong>of</strong>immunotherapy as an effective treatment. Sunitinib recently showed clinical efficacy in

patients with advanced renal cell carcinoma. It was retrospectively studied a population <strong>of</strong> 15adults with pancreatic metastasis <strong>of</strong> renal cell carcinoma at 1 center in France and at 2 in theUnited States who were treated with sunitinib between 2005 and 2007. Sunitinibmonotherapy was given at a dose <strong>of</strong> 50 mg orally in 6-week cycles, consisting <strong>of</strong> 4 weeks <strong>of</strong>treatment followed by 2 weeks <strong>of</strong> rest. At a median follow-up <strong>of</strong> 20 months the overall tumorresponse using Response Evaluation Criteria in Solid Tumors was 34 percent. Median timeto relapse was 20 months. Two deaths were noted but median survival was not attained.Responses in the pancreatic metastasis were seen in 28 percent <strong>of</strong> patients and were stablein 72 percent. The main grade 3 and 4 adverse events were diarrhea in 7 percent <strong>of</strong> casesand fatigue in 7 percent. Only grade 1 increased lipase was noted in 27 percent <strong>of</strong> patientsand no increase in amylase was noted. Sunitinib is effective in patients with pancreaticmetastasis. This raises the question <strong>of</strong> whether patients with metastatic renal cell carcinomalimited to the pancreas may derive greater clinical benefit from anti-angiogenic agents, ratherthan from aggressive surgical resection. However, surgery still remains the only potentialcure in patients with isolated pancreatic metastasis [627].Renal cell carcinoma (Grawitz tumor) is an epithelial tumor able, to develop, in some cases,very late metastases. The most frequent localization are: lung, bones and liver. Pancreaticmetastases are rare and appear late, sometime even after 12 years from primary renaltumor. In these cases the differential diagnosis must be made with primary pancreatictumors. It was presented a case report <strong>of</strong> pancreatic metastatic tumor developed 5 yearsafter right nephrectomy for renal cell carcinoma [628].Metastatic renal cell carcinoma (RCC) is a malignant tumor characterized by great variationin the clinical course and unusual sites <strong>of</strong> metastases. Metastases to the pancreas are, ingeneral, rare. A single center experience in 10 patients with this rare presentation <strong>of</strong>metastatic RCC was presented. In most cases, the course after diagnosis <strong>of</strong> RCC pancreasmetastases was relatively favorable, specifically in patients treated with surgical removal <strong>of</strong>the metastases. The median survival from the diagnosis <strong>of</strong> RCC pancreas metastases was56 months. Long-term survival may be obtained after surgery even with suboptimal systemictherapy. An active therapeutic approach is therefore warranted in these patients [629].Metastatic renal cell carcinoma (RCC) is a malignant tumor characterized by great variationin the clinical course and unusual sites <strong>of</strong> metastases. Metastases to the pancreas are, ingeneral, rare. A retrospective chart <strong>review</strong> <strong>of</strong> 10 patients treated a single institution werepresented. In most cases, the course after diagnosis <strong>of</strong> RCC pancreas metastases wasrelatively favorable, specifically in patients treated with surgical removal <strong>of</strong> the metastases.The median survival from the diagnosis <strong>of</strong> RCC pancreas metastases was 56 months. Thecourse <strong>of</strong> disease in patients with RCC pancreas metastases is <strong>of</strong>ten indolent. Long-termsurvival may be obtained after surgery even with suboptimal systemic therapy [630].The aim <strong>of</strong> one article was to identify patients who pr<strong>of</strong>it from pancreatic resection <strong>of</strong> renalcell carcinoma despite the invasiveness <strong>of</strong> the surgery. Between 1996 and 2007, data from744 patients were collected in a prospective pancreatic surgery database, and patients withmetastasis into the pancreas from renal cell carcinoma were identified. Resective surgerywas performed in 14 patients with metastasis to the pancreas. Most patients were clinicallyasymptomatic. The median interval between primary treatment <strong>of</strong> renal cell carcinoma andoccurrence <strong>of</strong> pancreatic metastasis was 94 months (range 32-158). The morbidity rate was43 percent. Patients with a metastasis size 2.5 cm (44 months). Moreover,the number <strong>of</strong> metastases predicts the survival after resection. It was concluded that inpatients with pancreatic metastases from renal cell carcinoma who have only limited disease,complete resection <strong>of</strong> all lesions can be successfully performed with a low rate <strong>of</strong>complications [631].

Colorectal carcinomaPancreatic metastases from colorectal cancer are very rare, and the possible benefit <strong>of</strong>surgical treatment is not clearly defined. One study was designed to evaluate the outcome <strong>of</strong>patients undergoing pancreatic resection for metastatic colorectal cancer to the pancreas.Nine patients underwent pancreatic resection for metastatic colorectal cancer between 1980and 2006. The primary cancers were colon (n=7) and rectal carcinoma (n=2). The medianinterval between primary treatment and detection <strong>of</strong> pancreatic metastases was 33 months.In three cases pancreatic metastases were synchronous with the primary tumor. Fivepatients underwent pancreaticoduodenectomy, and four underwent distal pancreatectomy. Aleft lateral liver section and three colon resections were simultaneously performed in fourpatients. There was no postoperative mortality, and only two patients experiencedcomplications. Survival averaged 20 (median, 17; range, 5-30) months: seven patients died<strong>of</strong> metastatic disease, one for unrelated disease after five months, and one is alive with livermetastases 30 months after surgery. The authors concluded that surgical resection can beperformed safely in patients with isolated pancreatic metastases from colorectal cancer andin selected patients with associated extrapancreatic disease. Although long-term survival israre, surgery should be included, whenever possible, in the multimodality approach to thisdisease [632].Bronchial carcinomaIt was described the case <strong>of</strong> a 60 year old female smoker who presented with a three monthhistory <strong>of</strong> weight loss (14 Kg), generalized abdominal discomfort and malaise. Chestradiography demonstrated a mass projected inferior to the hilum <strong>of</strong> the right lung. ComputedTomography <strong>of</strong> thorax confirmed a lobulated lesion in the right infrahilar region andsubsequent staging abdominal CT demonstrated a low density lesion in the neck <strong>of</strong> thepancreas. Percutaneous ultrasound guided pancreatic biopsy was performed, histology <strong>of</strong>which demonstrated pancreatic tissue containing a highly necrotic small cell undifferentiatedcarcinoma consistent with metastatic small cell carcinoma <strong>of</strong> the bronchus [633].Hepatocellular carcinomaFibrolamellar carcinoma is a subtype <strong>of</strong> hepatocellular carcinoma with distinctclinicopathologic features including presentation at a younger age. Although early studiessuggested that fibrolamellar carcinoma had a better prognosis than conventionalhepatocellular carcinoma, most later studies have found no difference. Patients <strong>of</strong>ten havelymph node metastases at presentation in addition to the hepatic primary. It was describedan unusual case in a Thai boy who presented with a pancreatic mass that was clinicallysuspected to be a primary pancreatic tumor, but on biopsy was found to be metastaticfibrolamellar carcinoma. This manner <strong>of</strong> presentation has not been previously reported forfibrolamellar carcinoma, nor has metastatic spread to the pancreas [634].Diffuse retroperitoneal cystic abdominal lymphangiomatosisAttributed to congenital malformation <strong>of</strong> lymphatic ducts, diffuse retroperitoneal cysticabdominal lymphangiomatosis has a distribution that <strong>of</strong>ten corresponds to the location <strong>of</strong>primitive fetal lymphatic sacs. Three recognized types are capillary, cavernous and cystic.Multisystem involvement may occur involving spleen, liver, bone, pancreas, s<strong>of</strong>t tissue, limbsand brain. Now a 55-year-old, healthy male with multiple liver lesions and retroperitoneallymphadenopathy presented for retroperitoneal fine needle aspiration, producing 20 mL <strong>of</strong>milky liquid. Immediate cytologic evaluation showed a heterologous population <strong>of</strong> maturelymphocytes with chylomicrons. Flow cytometry revealed a polyclonal population <strong>of</strong> maturelymphocytes. Chemical analysis demonstrated a normal serum cholesterol level and an

elevated triglyceride level. Serum markers were noncontributory. It was <strong>review</strong>ed thedifferential diagnostic considerations leading to obstruction or retention <strong>of</strong> lymphatic fluids(malignancy, surgical, infective and traumatic), with an emphasis on the importance <strong>of</strong> onsitecytologic evaluation, correlation with clinical history and <strong>review</strong> <strong>of</strong> the etiologicconsiderations. The constellation <strong>of</strong> clinical, radiologic, cytologic and laboratory findingspresented in this case are diagnostic <strong>of</strong> diffuse retroperitoneal cystic abdominallynmphangiomatosis [635].Merkel cell carcinomaMerkel cell carcinoma is a relatively infrequent, rapidly progressive and <strong>of</strong>ten fatal cutaneousmalignancy exhibiting neuroendocrine differentiation. It has a penchant for local recurrenceand distant metastasis to various sites, including regional lymph nodes, distant skin, lung,liver, testis and other rare organs, such as the pancreas. There are only 4 cases <strong>of</strong> Merkelcell carcinoma metastatic to the pancreas reported in the English-language <strong>literature</strong>, andthey were all diagnosed by histology from pancreatic resection. A 79-year-old woman with alarge pancreatic tail mass underwent endoscopic ultrasound-guided fine needle aspirationShe had a history <strong>of</strong> Merkel cell carcinoma <strong>of</strong> the upper extremity with wide local excision 15months earlier. Metastatic Merkel cell carcinoma was diagnosed based on thecytomorphology, characteristic immunohistochemical staining pattern, clinical history andcomparison <strong>of</strong> the morphology with that <strong>of</strong> the primary tumor. The cytomorphology andimmunohistochemical pr<strong>of</strong>ile <strong>of</strong> this neoplasm mimicked a pancreatic endocrine tumor [636].Pancreatic tuberculosisTuberculosis <strong>of</strong> the pancreas is a rare entity, and anecdotal reports describing imagingfeatures <strong>of</strong> pancreatic tuberculosis have been described in medical <strong>literature</strong>. The imagingfeatures including computed tomography and ultrasonography in diagnosed cases <strong>of</strong>tubercular involvement <strong>of</strong> the pancreas are described, with an overview <strong>of</strong> clinical featuresand laboratory investigations. It was analyzed records <strong>of</strong> 384 patients <strong>of</strong> diagnosed cases <strong>of</strong>abdominal tuberculosis for involvement <strong>of</strong> pancreas and detected 32 patients (8 %) who hadpancreatic involvement. This included 22 men and 10 women with an age range <strong>of</strong> 19 to 64years (mean age <strong>of</strong> 43 years), who were detected to have pancreatic tuberculosis from 1999to 2004. The criteria for diagnosis <strong>of</strong> tuberculosis were based on ascitic fluid adenosinedeaminase level in 14 patients, fine-needle aspiration cytology <strong>of</strong> lymph nodes in 9 patients,and presence <strong>of</strong> pulmonary tuberculosis on chest radiograph, which was found in 9 patients.On follow-up, 6 months after antituberculous treatment, 25 patients showed response to anti-Koch's treatment, 3 patients had drug-resistant tuberculosis, 2 patients died, and 2 patientswere lost to follow-up. The male/female ratio was 2.2:1. The maximum number <strong>of</strong> patientswas in the fourth decade (30-39 years). The duration <strong>of</strong> symptoms was spanning between 2and 11 months, with a mean duration <strong>of</strong> 6 months. The most common symptom wasabdominal pain localized to the epigastrium. Sixteen patients were seropositive for HIV-1infection. Fourteen patients had history <strong>of</strong> tuberculosis <strong>of</strong> the lungs, whereas 18 patients hadpancreatic and peripancreatic involvement as the primary manifestation. Ultrasonographyshowed bulky inhomogenous pancreas in 5 patients; solitary or multiple hypoechoiccollections were observed in all 7 and 20 patients, respectively. CT findings demonstratedhypodense collections within the pancreas associated with peripancreatic lymphadenopathyin 29 patients. Three patients had a complex pancreatic mass lesion. It was concluded thatpancreatic tuberculosis can present with a variable spectrum <strong>of</strong> imaging findings.Tuberculosis <strong>of</strong> the pancreas should be considered as a diagnostic possibility in patients whopresent with a pancreatic space occupying lesion associated with peripancreaticlymphadenopathy [637].

It was described a case <strong>of</strong> pancreatic tuberculosis in an immunocompromized individual. Afifty-year-old African-American gentleman with history <strong>of</strong> HIV non-compliant on anti-retroviraltherapy presented with epigastric pain for five weeks duration. CT scan <strong>of</strong> abdomen showedlarge necrotic node on the posterior aspect <strong>of</strong> the head <strong>of</strong> pancreas and multiple cysticmasses adjacent to the pancreas. Acid fast bacilli were found on staining <strong>of</strong> CT guidedbiopsy <strong>of</strong> the node. Cultures grew Mycobacterium tuberculosis. Anti-tubercular therapy wasinitiated and resulted in gradual resolution <strong>of</strong> symptoms [638].Pancreatic involvement in tuberculosis is known but uncommon. The clinical manifestationmay vary from painless obstructive jaundice due to pancreatic mass (cyst or abscess) t<strong>of</strong>ever <strong>of</strong> unknown origin. It was reported a case who initially presented as acute pancreatitisrelapsing into chronic pancreatitis as an initial manifestation <strong>of</strong> disseminated tuberculosis[639].Isolated pancreatic tuberculosis (TB) is extremely rare, even in countries where TB isendemic. The recent increased reporting <strong>of</strong> TB <strong>of</strong> the pancreas is related to a worldwideincrease in TB and an increase in emigration from countries where TB is endemic intocountries where more sophisticated healthcare and diagnostic facilities are available. Herein,we report an unusual case <strong>of</strong> isolated pancreatic region TB, which presented with dyspepticsymptoms and was diagnosed by ultrasonography-guided needle aspiration and computedtomography scan <strong>of</strong> the abdomen. Pancreatic TB should be considered as a differentialdiagnosis <strong>of</strong> a pancreatic mass and most patients have an excellent clinical response tostandard antituberculosis regimens [640].

PANCREATIC PSEUDOCYSTS and ANEURYSMSPancreatic pseudocystsThere are currently no diagnostic indicators that are consistently reliable, obtainable, andconclusive for diagnosing and risk-stratifying pancreatic cysts. Proteomic analyses wereperformed to explore pancreatic cyst fluids to yield effective diagnostic biomarkers in 20prospectively recruited research participants. Sequencing <strong>of</strong> more than 350 free peptidesshowed that exopeptidase activities rendered peptidomics <strong>of</strong> cyst fluids unreliable; proteinnicking by proteases in the cyst fluids produced hundreds <strong>of</strong> protein spots from the majorproteins, making 2-dimensional gel proteomics unmanageable; GeLC/MS/MS revealed apanel <strong>of</strong> potential biomarker proteins that correlated with carcinoembryonic antigen (CEA).Conclusions: Two homologs <strong>of</strong> amylase, solubilized molecules <strong>of</strong> 4 mucins, 4 solubilizedCEA-related cell adhesion molecules (CEACAMs), and 4 S100 homologs may be candidatebiomarkers to facilitate future pancreatic cyst diagnosis and risk-stratification. This approachrequired less than 40 microL <strong>of</strong> cyst fluid per sample, <strong>of</strong>fering the possibility to analyze cystssmaller than 1 cm in diameter [641].Precepts about acute pancreatitis, necrotizing pancreatitis, and pancreatic fluid collections orpseudocyst rarely include the impact <strong>of</strong> pancreatic ductal injuries on their natural course andoutcomes. It was previously examined and established a system to categorize ductalchanges and it was now sought a unifying concept that may predict course and directtherapies in these complex patients. It was used a system categorizing ductal changes inpseudocyst <strong>of</strong> the pancreas and severe necrotizing pancreatitis (type I, normal duct; type II,duct stricture; type III, duct occlusion or "disconnected duct"; and type IV, chronicpancreatitis). From 1985 to 2006, a policy was implemented <strong>of</strong> routine imaging (crosssectional,endoscopic retrograde cholangiopancreatography, or magnetic resonancecholangiopancreatography). Clinical outcomes were measured. Among 563 patients withpseudocyst, 142 resolved spontaneously (87 % <strong>of</strong> type I, 5 % <strong>of</strong> type II, and no type III, and 3% <strong>of</strong> type IV). Percutaneous drainage was successful in 83 percent <strong>of</strong> type I, 49 percent <strong>of</strong>type II, and no type III or type IV. Among 174 patients with severe acute pancreatitispercutaneous drainage was successful in 64 percent <strong>of</strong> type I, 38 percent <strong>of</strong> type II, and notype III. Operative debridement was required in 39 percent <strong>of</strong> type I and 83 and 85 percent <strong>of</strong>types II and III, respectively. Persistent fistula after debridement occurred in 27, 54, and 85percent <strong>of</strong> types I, II, and III ducts, respectively. Late complications correlated with ductinjury. Thus, pancreatic ductal changes predict spontaneous resolution, success <strong>of</strong>nonoperative measures, and direct therapies in pseudocyst. Ductal changes also predictpatients with necrotizing pancreatitis who are most likely to have immediate and delayedcomplications [642].The number <strong>of</strong> patients identified with cysts <strong>of</strong> the pancreas is increasing. From 1995 to2008, radiology records were <strong>review</strong>ed for the presence <strong>of</strong> cystic lesions <strong>of</strong> the pancreascharacteristics, patient demographics, and follow-up. Eighty-two patients met the studyinclusion criteria, with a mean age at time <strong>of</strong> diagnosis <strong>of</strong> 64 years. Mean cyst size was 1.4 +1.1 cm, with 76 percent <strong>of</strong> patients having a solitary cyst. Thirteen patients underwentsurgery. Operative intervention was statistically related to symptomatic, loculated cysts withthe presence <strong>of</strong> calcifications. Malignancy was statistically related to symptomatic andloculated cysts. The data show that most pancreatic cysts found on radiographic imaging areasymptomatic, solitary, and small and can be followed safely radiographically [643].DiagnosticsCurrently, the preoperative diagnosis <strong>of</strong> a pancreatic cyst is based on clinical and imagingfindings, frequently in conjunction with chemical analysis <strong>of</strong> cyst fluid and cytologic

evaluation. The purpose <strong>of</strong> these diagnostic tests is to distinguish benign from malignantcysts <strong>of</strong> the pancreas. Accordingly, it is imperative to distinguish pancreatic pseudocystsfrom their mimics. In one study, the authors explored the cytomorphologic features <strong>of</strong>pseudocyst <strong>of</strong> the pancreas and evaluated the role <strong>of</strong> Alcian blue and mucicarmine stains inthe cytologic evaluation <strong>of</strong> pancreatic cysts. Forty-two patients were identified who had aneventual diagnosis <strong>of</strong> pancreatic pseudocyst and had an endoscopic ultrasound-guided fineneedleaspirate available. Clinical and imaging findings and chemical analyses <strong>of</strong> cyst fluidwere recorded. The cytologic preparations were evaluated for gastrointestinal contamination,inflammatory cells, mucin, and pigmented material. The cytomorphologic features <strong>of</strong> 110neoplastic mucinous cysts (intraductal papillary-mucinous neoplasms/mucinous cysticneoplasms <strong>of</strong> the pancreas) were evaluated and compared with the pseudocysts. Themajority <strong>of</strong> patients (95 %) had a prior episode <strong>of</strong> pancreatitis. On imaging, the pseudocystswere unilocular (92 %). In 69 percent <strong>of</strong> cases, the endosonographic diagnosis was that <strong>of</strong> apseudocyst. The mean carcinoembryonic antigen level was 41 ng/mL. In contrast, thecytopathologist rendered a definitive diagnosis <strong>of</strong> pseudocyst in only 10 percent <strong>of</strong> cases.The majority <strong>of</strong> smears (75 %) revealed neutrophils and/or histiocytes. Atypical epithelialclusters were identified in 3 cases, 1 <strong>of</strong> which was diagnosed as suspicious for carcinoma.Yellow pigmented material, which was identified in 13 pseudocysts (31 %), was not observedin neoplastic mucinous cysts. Alcian blue- and mucicarmine-positive material was identifiedin 64 and 40 percent <strong>of</strong> pseudocysts, respectively, and in 57 and 38 percent <strong>of</strong> neoplasticmucinous cysts, respectively. It was concluded that the cytologic features frequently werenonspecific. The presence <strong>of</strong> yellow pigmented material served as a surrogate marker <strong>of</strong> apseudocyst. Special stains for mucin did not distinguish pseudocysts from neoplasticmucinous cysts [644].To retrospectively evaluate the sensitivity and specificity <strong>of</strong> several morphologic findings thatmay be seen with cystic pancreatic lesions, in the diagnosis <strong>of</strong> pseudocyst at magneticresonance (MR) imaging from 2005 to 2007, electronic radiology and pathology databaseswere searched to identify patients with pancreatic cystic neoplasms or pseudocysts whounderwent pancreatic MR imaging. Twenty-two patients with cystic pancreatic neoplasmsthat were confirmed at surgical resection (n=12) or endoscopic ultrasonography with cysticfluid analysis (n=10) were identified. Of 20 patients with pancreatic pseudocysts, seven hadpseudocysts that were identified at pathologic resection and 13 had a clinical history <strong>of</strong>pancreatitis, with initial computed tomography revealing no pancreatic cyst and subsequentfollow-up MR imaging depicting cystic lesions. Two abdominal radiologists independently andrandomly evaluated each case for presence or absence <strong>of</strong> septa and internal dependentdebris and for external cyst morphology on axial and coronal T2-weighted images and threedimensionalgradient-echo T1-weighted images obtained before and after intravenouscontrast agent administration. Logistic regression for correlated data was used to assess theusefulness <strong>of</strong> internal debris, external morphology, and septa for differentiating cysticneoplasms from pseudocysts. The readers' assessments <strong>of</strong> the presence or absence <strong>of</strong>cystic debris were concordant for 40 (95 %) <strong>of</strong> the 42 patients, with a kappa coefficient <strong>of</strong>0.889, which indicated nearly perfect agreement. Thirteen (93 %) <strong>of</strong> 14 lesions found to havedebris by either or both readers were pseudocysts, and only one (4 %) <strong>of</strong> the 22 cysticneoplasms had debris. Both readers were more likely to identify septa within cysticneoplasms than within pseudocysts; however, the difference was not significant for eitherreader. The readers were more likely to observe microlobulated morphology in cysticneoplasms than in pseudocysts, with the difference between these lesion types, in terms <strong>of</strong>prevalence <strong>of</strong> microlobulated morphology, exhibiting a trend toward-but not reachingstatisticalsignificance. It was concluded that the presence <strong>of</strong> internal dependent debrisappears to be a highly specific MR finding for the diagnosis <strong>of</strong> pancreatic pseudocyst [645].EUSEndoscopic ultrasound (EUS) is useful for the treatment <strong>of</strong> sterile pancreatic fluid collections(PFC), either by means <strong>of</strong> transmural drainage or by complete aspiration. The aim <strong>of</strong> one

study was to evaluate the efficacy and safety <strong>of</strong> single-step EUS-guided endoscopicapproaches for treatment <strong>of</strong> sterile PFC. During a 3-year period, 77 consecutive patients withsymptomatic, persistent sterile PFC were evaluated and treated with the linear EUS. It wasexcluded patients with grossly purulent collections, chronic pseudocyst and those whosecytology diagnostic was neoplastic cyst <strong>of</strong> pancreas. 44 patients received a single 10-Frplastic straight stent under EUS or fluoroscopic control (group I) and 33 <strong>of</strong> these underwent asingle-step complete aspiration with a 19-gauge needle (group II). The mean size <strong>of</strong> thesterile PFC was 48 mm in group I and 28 mm in group II. Overall, endoscopic treatment wassuccessful in 70 (91 %) patients. The mean volume aspirated was 25 (18-65) ml. The totalnumber <strong>of</strong> procedures was 50 in group I and 41 punctures in group II. After a mean follow-up<strong>of</strong> 64 + 16 weeks there were 6 complications (14 %): 2 recurrences (referred to surgery), 2developing abscesses (submitted a new EUS-guided endoscopic drainage with success), 1perforation that died (2 %), and 1 case <strong>of</strong> bleeding (sent to surgery) in group I. In group IIthere were only 6 (18 %) recurrences (submitted a new EUS-guided aspiration). None <strong>of</strong> thepatients undergoing single-step aspiration developed infections, perforation or hemorrhage. Itwas concluded that recurrence <strong>of</strong> pancreatic pseudocysts after endoscopic treatment wassimilar, either by means <strong>of</strong> plastic stents or by complete single-step aspiration [646].Other radiologyMost pancreatic pseudocysts are common complications <strong>of</strong> acute or chronic pancreatitis.They usually occur within the pancreas or in peripancreatic tissues, and are visualized asround or oval fluid collections with thin or thick walls on computed tomography (CT) scans.However, pancreatic pseudocysts are <strong>of</strong>ten combined with various complications, e.g.,various organ involvements, infection, hemorrhage with pseudoaneurysm formation, rupturewith fistula formation, or gastrointestinal or biliary obstruction, which may necessitate promptintervention or surgery. A <strong>review</strong> illustrates the CT appearances <strong>of</strong> various complicationsassociated with pancreatic pseudocysts [647].Case reportIt was reporter a huge pancreatic pseudocyst migrating to the psoas muscle and inguinalregion [648].Intrahepatic pancreatic pseudocyst is an extremely rare complication <strong>of</strong> acute pancreatitis.However, it was reported a case <strong>of</strong> a 37-year old diabetic male who presented with mildpancreatitis as predicted by modified Glasgow criteria. Abdominal CT scan showed a lefthepatic subcapsular cyst <strong>of</strong> 9x4 cm that progressively increased in size. CT guided aspiration<strong>of</strong> the cyst yielded 90 ml <strong>of</strong> yellow brown fluid with a high amylase concentration. Bacterialculture <strong>of</strong> the fluid was negative. The patient dramatically improved after aspiration; 3 monthslater the patient was asymptomatic and follow-up abdominal ultrasound has shown completeresolution <strong>of</strong> the cyst [649].It was reported a spontaneous gastric drainage <strong>of</strong> a pancreatic pseudocyst [650].A patient with a pancreatic pseudocyst rupture into the portal vein with a resultantnoninfectious systemic inflammatory response syndrome and subsequent portal veinthrombosis diagnosed by computed tomography and ultrasonography was reported [651].Hemosuccus pancreaticusErosion <strong>of</strong> peripancreatic arteries in acute or chronic pancreatitis is a rare cause <strong>of</strong> bleedinginto gastrointestinal tract - hemosuccus pancreaticus. It was reported a case <strong>of</strong> a patient withchronic pancreatitis who developed acute bleeding into the gastrointestinal tract due to the

perforation <strong>of</strong> a pseudoaneurysm into pancreatic pseudocyst in the area <strong>of</strong> the pancreaticbody. The diagnosis <strong>of</strong> hemosuccus pancreaticus, established by endoscopy andpostcontrast CT examination, was confirmed by angiography. It was stopped the acutebleeding from pseudoaneurysm, unusually well supplied by both gastric arteries byembolization <strong>of</strong> both arteries with metallic coils. It was concluded that angiography plays anirreplaceable role in patients with hemosuccus pancreaticus. The case demonstratesbleeding from pseudoaneurysm supplied by both gastric arteries, whose embolizationproduced an immediate hemostasis and improvment the patient's condition [652].Hemosuccus pancreaticus is a rare cause <strong>of</strong> upper chronic and intermittent gastrointestinalhemorrhage which cannot be easily detected by endoscopy. It is usually due to the rupture <strong>of</strong>a visceral aneurysm into the main pancreatic duct; splenic artery pseudoaneurysmassociated with chronic pancreatitis represents the leading cause <strong>of</strong> this condition. Thediagnosis is based on direct visualization <strong>of</strong> the hemorrhage through the main pancreaticduct at angiography. Given its rarity, difficulties in determining the source <strong>of</strong> bleeding canresult in delayed treatment. It was present a rare case <strong>of</strong> true splenic artery aneurysmfistulized in the main pancreatic duct and misdiagnosed as a bleeding pancreatic pseudocyston preoperative examination which included CT and MRCP [653].Pancreatic aneurysmIt was presented a clinical case <strong>of</strong> successful management <strong>of</strong> an aneurysm <strong>of</strong> the inferiorpancreatoduodenal artery, having resulted from occlusion <strong>of</strong> the celiac trunk and acompensatory increase in the blood flow along it from the superior mesenteric artery into thebasin <strong>of</strong> the celiac trunk. In the case report described, the authors used the technique <strong>of</strong>open surgical revascularization <strong>of</strong> the celiac trunk and autovenous prosthetic repair <strong>of</strong> theaneurysmatically altered inferior pancreatoduodenal artery. The surgical decision-makingwas determined by the fact that the commonly accepted endovascular by-pass <strong>of</strong> theaneurysm would have resulted in the development <strong>of</strong> ischaemia in the basin <strong>of</strong> the celiactrunk and unpredictable alterations in the organs supplied thereby [654].Although rare, a pancreatic arteriovenous malformation can have serious consequences. Adiagnosis <strong>of</strong> arteriovenous malformation requires evidence <strong>of</strong> aberrant communicationbetween the arterial and the venous systems. One report described a case where the use <strong>of</strong>multi-detector row CT and specific post-processing methods provided a diagnosis <strong>of</strong>arteriovenous malformation. This minimally invasive diagnostic approach resulted in a clear,precise and comprehensive visual representation <strong>of</strong> the pancreatic arteriovenousmalformation. A 60-year-old man with right hypochondriac pain presented with a mass in thehead <strong>of</strong> the pancreas. The hypochondriac pain resolved spontaneously and physicalexamination revealed no abnormal findings. A multi-detector row CT study was performed.The data obtained in the arterial phase demonstrated a high-contrast mass in the head <strong>of</strong> thepancreas and early enhancement <strong>of</strong> the portal vein. A maximum intensity projection methodclarified the aberrant vascular communication. Changes in Hounsfield numbers wereobserved using a multi-planar reformation method. A volume-rendering method was used tocreate a 3D model which demonstrated the spatial relationship between the aberrantvascular communication and the surrounding tissue. An annual follow-up study using thistechnique showed no significant alteration [655].

PANCREATIC TRAUMAEfforts to determine the suitability <strong>of</strong> low-grade pancreatic injuries for nonoperativemanagement have been hindered by the inaccuracy <strong>of</strong> older computed tomography (CT)technology for detecting pancreatic injury (PI). A retrospective, multicenter AmericanAssociation for the Surgery <strong>of</strong> Trauma-sponsored trial examined the sensitivity <strong>of</strong> newer 16-and 64-multidetector CT (MDCT) for detecting pancreatic injury, and sensitivity/specificity forthe identification <strong>of</strong> pancreatic ductal injury (PDI). Patients who received a preoperative 16-or 64-MDCT followed by laparotomy with a documented pancreatic injury were enrolled.Preoperative MDCT scans were classified as indicating the presence (+) or absence (-) <strong>of</strong>pancreatic injury and pancreatic ductal injury. Operative notes were <strong>review</strong>ed and all patientswere confirmed as PI (+), and then classified as PDI (+) or (-). As all patients had pancreaticinjury, an analysis <strong>of</strong> pancreatic injury specificity was not possible. PI patients formed thepool for further pancreatic ductal injury analysis. As sensitivity and specificity data wereavailable for pancreatic ductal injury, multivariate logistic regression was performed forpancreatic ductal injury patients using the presence or absence <strong>of</strong> agreement between CTand operative note findings as an independent variable. Twenty centers enrolled 206pancreatic injury patients, including 71 PDI (+) patients. Intravenous contrast was used in203 studies; 69 studies used presence <strong>of</strong> oral contrast. Eight-nine percent were bluntmechanisms, and 96 percent were able to have their duct status operatively classified as PDI(+) or (-). The sensitivity <strong>of</strong> 16-MDCT for all pancreatic injury was 60 percent, whereas 64-MDCT was 47 percent. For pancreatic ductal injury, the sensitivities <strong>of</strong> 16- and 64-MDCTwere 54 percent and 52 percent, respectively, with specificities <strong>of</strong> 95 percent for 16-MDCTscanners and 90 percent for 64-MDCT scanners. Logistic regression showed that nocovariates were associated with an increased likelihood <strong>of</strong> detecting pancreatic ductal injuryfor either 16- or 64-MDCT scanners. The area under the curve was 0.66 for the 16-MDCTpancreatic ductal injury analysis and 0.77 for the 64-MDCT pancreatic ductal injury analysis.This means that both 16- and 64-MDCT have low sensitivity for detecting pancreatic injuryand pancreatic ductal injury, while exhibiting a high specificity for pancreatic ductal injury.Their use as decision-making tools for the nonoperative management <strong>of</strong> pancreatic injuryare, therefore, limited [656].The authors reported a case <strong>of</strong> a grade III pancreatic injury resulting from a blunt abdominaltrauma, referred to our department for observation and treated with distalsplenopancreatectomy. Pancreatic traumas account for approximately 3-5 percent <strong>of</strong> bluntabdominal injuries. In cases <strong>of</strong> isolated pancreatic injuries failure to recognise injury to theWirsung duct is the main cause <strong>of</strong> morbidity and mortality. Spiral CT with contrast medium isthe standard investigation in haemodynamically stable traumatised patients, with a sensitivity<strong>of</strong> approximately 90 percent in the most recent series. However, at least initially, the extent <strong>of</strong>the pancreatic damage is not proportional to the severity <strong>of</strong> the clinical and instrumentalpicture. The patients need to be continuously and carefully monitored and, in the case <strong>of</strong>suspected pancreatic injury, the imaging study should be repeated 12-24 hours after thetrauma. In case <strong>of</strong> doubt, ERCP provides detailed information on the condition <strong>of</strong> theWirsung duct and, in selected cases, may play a therapeutic role through the positioning <strong>of</strong>an intraductal prosthesis. The surgical management <strong>of</strong> blunt pancreatic trauma should beindividualised depending on the site and severity <strong>of</strong> the injury, the interval elapsing after thetrauma and the presence <strong>of</strong> associated injuries [657].Pancreatic trauma is rare and <strong>of</strong>ten missed during initial assessment <strong>of</strong> patients withabdominal trauma. One study <strong>review</strong>ed the experience <strong>of</strong> managing pancreatic trauma at atertiary referral center and discusses the diagnostic and therapeutic challenges. Aretrospective study <strong>of</strong> a prospectively maintained hepato-pancreatico-biliary database for 12years preceding 2007 revealed 28 patients (23 males, 10 children) with a median age <strong>of</strong> 12years (range, 6-16 years) in children and 28 years (range, 17-54 years) in adults. Nineteen <strong>of</strong>

the 28 had pancreatic duct injury <strong>of</strong> which 15 were missed on initial evaluation and referredafter conservative management (n=9) or laparotomy (n=6). Twenty-one patients developedcomplications including abdominal collections (n=10), pancreatic fistulae (n=9), andpseudocysts (n=2). There were 2 deaths (7 %), both <strong>of</strong> which were associated with multipleintra-abdominal injuries. At a median follow-up <strong>of</strong> 8 months (range, 3-44 months), 19 <strong>of</strong> 23patients were asymptomatic and had been discharged from follow-up. It was concluded thatpancreatic trauma in the United Kingdom is mainly the result <strong>of</strong> blunt trauma and mostcommonly affects young males. The presence <strong>of</strong> pancreatic duct disruption accounts formost <strong>of</strong> the complications, but in the absence <strong>of</strong> associated injuries, mortality is rare [658].In another study the diagnosis and treatment <strong>of</strong> blunt abdominal injury to the solid organswere examined, and the differences between children and adults were highlighted.Identification <strong>of</strong> injury to the solid organs in children depends on a high index <strong>of</strong> suspicion,abnormal physical examination findings, and the judicious use <strong>of</strong> laboratory and imagingstudies. Although abdominal and pelvic computed tomography with intravenous contrastremains the gold standard for imaging, it does expose children to a significant dose <strong>of</strong>radiation. Currently, more than 90 percent <strong>of</strong> solid organ injuries in children are treatednonoperatively. Abnormal hemodynamics, however, suggests active bleeding and requiresoperative intervention. Accurate diagnosis <strong>of</strong> the organ injured and degree <strong>of</strong> injury areimportant considerations for "return to play" decisions. The management <strong>of</strong> pancreatic ductalinjuries is somewhat controversial, although the distal spleen preserving pancreatectomy isfrequently the technique <strong>of</strong> choice. It was concluded that pediatric intra-abdominal solidorgan injury is relatively uncommon, but a potential source <strong>of</strong> significant morbidity. Nonoperativemanagement is the standard <strong>of</strong> care for the majority <strong>of</strong> these injuries, althoughcontinued hemodynamic instability mandates operative intervention [659].To evaluate the safety <strong>of</strong> nonoperative management (NOM), to examine the diagnosticsensitivity <strong>of</strong> computed tomography (CT), and to identify missed diagnoses and relatedoutcomes in patients with blunt pancreatoduodenal injury (BPDI). Eleven New Englandtrauma centers (7 academic and 4 nonacademic) with 230 patients (>15 years old) with BPDIadmitted to the hospital during 11 years were studied. Each BPDI was graded from 1(lowest) to 5 (highest) according to the American Association for the Surgery <strong>of</strong> Traumagrading system. Ninety-seven patients (42 %) with mostly grades 1 and 2 BPDI wereselected for nonoperative management: NOM failed in 10 (10 %), 10 (10 %) developedBPDI-related complications (3 in patients in whom nonoperative management failed), and 7(7 %) died (none related to failure <strong>of</strong> NOM). The remaining 133 patients were operated onurgently: 34 (26 %) developed BPDI-related complications and 20 (15 %) died. The initial CTmissed BPDI in 30 patients (13 %); 4 <strong>of</strong> them (13 %) died but not because <strong>of</strong> the BPDI. Themortality rate in patients without a missed diagnosis was 9 percent. There was no correlationbetween time to diagnosis and length <strong>of</strong> hospital stay. The sensitivity <strong>of</strong> CT for BPDI was 76percent (76 % for pancreatic and 70 % for duodenal injuries). It was concluded that thenonoperative management <strong>of</strong> low-grade BPDI is safe despite occasional failures. Misseddiagnosis <strong>of</strong> BPDI continues to occur despite advances in CT but does not seem to causeadverse outcomes in most patients [660].Trauma laparotomy is the most commonly performed procedure in the acute care setting. Ascurrent practice, removed specimens are sent for histological examination. A retrospective<strong>review</strong> <strong>of</strong> all trauma laparotomies with specimens removed and sent to pathology during a12-month period was performed in a Level I trauma center. One hundred five procedures <strong>of</strong>244 trauma laparotomies yielded specimens sent for examination. Eighty-six patients weremale and 19 patients were female with an average age <strong>of</strong> 34 + 14 years. Fifty-six percent <strong>of</strong>the injuries resulted from penetrating trauma and 44 percent were from blunt trauma.Gunshot wound and motor vehicle crash were the most common penetrating and bluntinjuries, respectively. One hundred thirteen specimens were sent to pathology. Forty-threeper cent <strong>of</strong> the specimens were spleen, 24 percent small bowel, 16 percent large bowel, 4

percent kidney, 2 percent omentum, 3 percent appendix, 3 pecent pancreas, and 1 percentfor gallbladder and lung. One hundred twelve <strong>of</strong> 113 grossly normal specimens had normalpathology. One grossly normal specimen exposed abnormal pathology revealing benignappendiceal mucocele. Therefore, 99 percent <strong>of</strong> grossly normal specimens sent forhistological examination after trauma laparotomy were normal. Based on this <strong>review</strong>, inselect patients routine histological examination <strong>of</strong> tissues removed for traumatic injury isunnecessary [661].

ENDOCRINE PANCREATIC TUMORSHistoryA search on PubMed using the keywords “neuroendocrine”, “pancreas” and “carcinoid” wasperformed to identify relevant <strong>literature</strong> over the last 30 years. The introduction <strong>of</strong> a revisedclassification <strong>of</strong> neuroendocrine tumours by the World Health Organisation (WHO) in 2000significantly changed our understanding <strong>of</strong> and approach to the management <strong>of</strong> thesetumours. Advances in laboratory and radiological techniques have also led to an increaseddetection <strong>of</strong> PNETs. Surgery remains the only treatment that <strong>of</strong>fers a chance <strong>of</strong> cure withincreasing number <strong>of</strong> non-surgical options serving as beneficial adjuncts. The betterunderstanding <strong>of</strong> the behaviours <strong>of</strong> PNETs together with improvements in tumour localisationhas resulted in a more aggressive management strategy with a concomitant improvement insymptom palliation and a prolongation <strong>of</strong> survival. Due to their complex nature and the widerange <strong>of</strong> therapeutic options, the involvement <strong>of</strong> specialists from all necessary disciplines in amultidisciplinary team setting is vital to provide optimal treatment <strong>of</strong> this disease [662].Reported cases <strong>of</strong> diffuse nesidioblastosis have had common clinical features: postprandialhyperinsulinemic hypoglycemia, no abnormal findings in radiological examinations, and thepresence <strong>of</strong> the ductulo-insular complex on histological examination. Surgical resection isrecommended, but the extent <strong>of</strong> surgery is controversial. Our case had some clinical features<strong>of</strong> insulinoma but was diagnosed as diffuse nesidioblastosis according to histopathologiccriteria. Because arterial stimulation and veneous sampling showed that the pancreatic bodyand tail had a lesion producing insulin abnormally, we performed a distal pancreatectomy tocure the hypoglycemia. Clinically, it is very difficult to distinguish diffuse nesidioblastosis frominsulinkoma [663].GeneticsPancreatic endocrine neoplasms (PENs) are diagnostically challenging tumors whose naturalhistory is largely unknown. Histopathology allows the distinction <strong>of</strong> two categories: poorlydifferentiated high-grade carcinomas and well-differentiated neoplasms. The latter includemore than 90percent <strong>of</strong> PENs whose clinical behavior varies from indolent to malignant andcannot be predicted by their morphology. The diagnosis <strong>of</strong> PEN is generally easy, butunusual features may induce misdiagnosis. Immunohistochemistry solves the issue, providedthat the possibility <strong>of</strong> a PEN has been considered. Morphology allows the distinction <strong>of</strong> poorlydifferentiated aggressive carcinomas from well-differentiated neoplasms. The World HealthOrganization classification criteria allow for the discernment <strong>of</strong> the latter into neoplasms andcarcinomas with either benign or uncertain behavior. The recently proposed staging andgrading systems hold great promise for permitting a stratification <strong>of</strong> carcinomas into clinicallysignificant risk categories. To date, inactivation <strong>of</strong> the MEN1 gene remains the onlyascertained genetic event involved in PEN genesis. It is inactivated in roughly one-third <strong>of</strong>PENs. The degree <strong>of</strong> genomic instability correlates with the aggressiveness <strong>of</strong> the neoplasm.Gene silencing by promoter methylation has been advocated, but a formal demonstration <strong>of</strong>the involvement <strong>of</strong> specific genes is still lacking. Expression pr<strong>of</strong>iling studies are furnishingvaluable lists <strong>of</strong> mRNAs and noncoding RNAs that may advance further the research todiscover novel markers and/or therapeutic targets [664].Gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs) originate from cells <strong>of</strong>the diffuse endocrine system. Most GEP-NETs are sporadic, however, some <strong>of</strong> them,especially pancreatic endocrine tumors, may occur as part <strong>of</strong> familial syndromes. Thegenetic and molecular pathology <strong>of</strong> neuroendocrine tumor development is incomplete andremains largely unknown. However, the WHO classification introduced in clinical practice will

give more insight into genetic and molecular changes related to tumor subtypes. In sporadicendocrine pancreatic tumors, losses <strong>of</strong> chromosome 1 and 11q as well as gain on 9q appearto be early invents in development <strong>of</strong> pancreatic tumors because they are already present insmall tumors. Multiple genetic defects may accumulate with time and result in pancreaticneuroendocrine tumor progression and malignancy. Gastrointestinal endocrine tumors(carcinoids) show predominantly genetic alterations concentrated on chromosome 18. Thereare losses <strong>of</strong> the entire chromosome as well as smaller deletions. The most frequentlyreported mutated gene in gastrointestinal neuroendocrine tumors is b-catenin.Overexpression <strong>of</strong> cyclin D1 and cMyc has also been reported. Recently, a set <strong>of</strong> genesNAP1L1, MAGE-2D and MTA1 has been correlated with malignant behavior <strong>of</strong> smallintestinal carcinoids. It was concluded that molecular pr<strong>of</strong>iling <strong>of</strong> GEP-NETs demonstratesthat pancreatic endocrine tumors and gastrointestinal neuroendocrine tumors (carcinoids)display different genetic changes and should, therefore, be considered to be different tumorentities; thereby, also differently managed clinically. Although the number <strong>of</strong> genetic changesis higher in malignant tumors, we are still far away from defining a malignant pr<strong>of</strong>ile in GEP-NETs [665].Familial endocrinopathiasThe development <strong>of</strong> genetic testing has given patients with familial endocrine diseases theopportunity to be identified earlier in life. The importance <strong>of</strong> this technological advancementcannot be underestimated, as some <strong>of</strong> these heritable diseases have significant potential formalignancy. One article focused on the identification and surgical management <strong>of</strong> familialendocrinopathies <strong>of</strong> the thyroid, parathyroid, adrenal glands, and pancreas. Familialendocrinopathies discussed include hereditary nonmedullary carcinoma <strong>of</strong> the thyroid,Cowden disease, familial adenomatous polyposis, Carney complex, Werner syndrome,familial medullary thyroid carcinoma, Pendred syndrome, hereditary hyperparathyroidismjaw-tumor syndrome, familial isolated hyperparathyroidism, Beckwith-Wiedemann syndrome,Li-Fraumeni syndrome, neur<strong>of</strong>ibromatosis I, von Hippel-Lindau disease, and tuberoussclerosis [666].Multiple endocrine neoplasiaMultiple endocrine neoplasia syndrome type 1 (MEN-1) consists <strong>of</strong> endocrine tumors <strong>of</strong> theparathyroid, the endocrine pancreas-duodenum, and the pituitary. Surveillance andscreening for the endocrinopathies is recommended in gene carriers. Surgery for MEN-1-related hyperparathyroidism is generally performed as radical subtotal parathyroidectomy,because less surgery is likely to result in persistent or recurrent disease. Multiple endocrineneoplasia syndrome type 2 (MEN-2) consists <strong>of</strong> medullary thyroid carcinoma,pheochromocytoma, and hyperparathyroidism. Prophylactic thyroidectomy based on DNAtesting in the MEN-2 syndrome is considered one <strong>of</strong> the greater achievements in cancertreatment, because it may be performed before thyroid carcinoma development and providescure for the patient [667].The purpose <strong>of</strong> one study was to describe outcomes <strong>of</strong> MEN-1 patients with recurrencerequiring completion pancreatectomy and duodenectomy after initial treatment <strong>of</strong> pancreaticendocrine neoplasms (PENs) and hypergastrinemia with distal pancreatectomy, enucleation<strong>of</strong> pancreatic head PENs, and duodenotomy. After undergoing this initial operation, 8 <strong>of</strong> 49patients (16 %) required completion pancreatectomy and duodenectomy for recurrent PENsand hypergastrinemia. Median age was 39 years (27-51) at completion pancreatectomycompared to 31 years (20-40) at initial operation. Pathology revealed multiple PENs in 100percent, duodenal neoplasms in 63 percent, and metastatic lymph nodes in 75 percent.There was no operative mortality and 88 percent <strong>of</strong> patients are currently alive. Preoperativegastrin levels were 934 + 847 pg/mL while postoperative levels were 93 + 79 pg/mL (normal

25-111 pg/mL). Mean Hemoglobin A1C levels are 8.3 + 3.3 percent (normal 3.8-6.4 %). Thisinitial operation may provide tumor control and prevent metastases but recurrent PENs aremultifocal and progressive. Completion pancreatectomy and duodenectomy is arduous butoutcomes are acceptable. Considering the radical nature <strong>of</strong> this treatment, individualconsideration should be given to MEN-1 patients amenable to initial alternative pancreaticresections that preserve pancreatic mass and allow future pancreas-preserving reoperations[668].Multiple endocrine neoplasia type 1 (MEN1) is an autosomal syndrome caused by mutationsin the MEN1 tumor suppressor gene. Whereas the protein product <strong>of</strong> MEN1, menin, isubiquitously expressed, somatic loss <strong>of</strong> the remaining wild-type MEN1 allele results in tumorsprimarily in parathyroid, pituitary, and endocrine pancreas. To understand the endocrinespecificity <strong>of</strong> the MEN1 syndrome, it was evaluated biallelic loss <strong>of</strong> Men1 by inactivatingMen1 in pancreatic progenitor cells using the Cre-lox system. Men1 deletion in progenitorcells that differentiate into exocrine and endocrine pancreas did not affect normal pancreasmorphogenesis and development. However, mice having homozygous inactivation <strong>of</strong> theMen1 in pancreas developed endocrine tumors with no exocrine tumor manifestation,recapitulating phenotypes seen in the MEN1 patients. In the absence <strong>of</strong> menin, theendocrine pancreas showed increase in cell proliferation, vascularity, and abnormal vascularstructures; such changes were lacking in exocrine pancreas. Further analysis revealed thatthese endocrine manifestations were associated with up-regulation in vascular endothelialgrowth factor expression in both human and mouse MEN1 pancreatic endocrine tumors.Together, these data suggest the presence <strong>of</strong> cell-specific factors for menin and a permissiveendocrine environment for MEN1 tumorigenesis in endocrine pancreas. Based on thisanalysis, it was proposed that menin's ability to maintain cellular and microenvironmentintegrity might explain the endocrine-restrictive nature <strong>of</strong> the MEN1 syndrome [669].To investigate if transcription factors involved in pancreatic differentiation and regenerationare present in pancreatic endocrine tumors and if they are differentially expressed in normalpancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreasthe expression <strong>of</strong> neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POUclass 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomalprotein L10 (RPL10), delta-like 1 homolog (DLK1), and menin was analyzed byimmunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patientswith MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens fromMen1 heterozygous and wild type mice. Quantitative polymerase chain reaction wasperformed in a subset <strong>of</strong> human tumors. Tumors and MEN1 nontumorous endocrine cellsshowed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factorswere significantly more expressed in the cytoplasm <strong>of</strong> Men1 heterozygous mouse islet cellscompared with wild type islets; the latter showed an exclusively nuclear reactivity. Thedegree <strong>of</strong> Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets <strong>of</strong>heterozygous and wild type mice. The expressions <strong>of</strong> RPL10 and NEUROD1 were prominentin the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas hadsignificantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types[670].DiagnosticsThe aim <strong>of</strong> one study was to characterize the ultrasonographic features <strong>of</strong> neuroendocrinetumors (NET) and their metastases with contrast-enhanced ultrasonography (CEUS) and tocompare this to clinical data. During a period <strong>of</strong> 5 years, 82 patients with 83 histologicallyproven NET were prospectively examined using conventional US and pulse inversion USwith a second generation contrast agent (SonoVue, Contrast Pulse Sequencing) focusing on

the arterial (10-20 sec p. i.), capillary (20-25 sec p.i.), portal venous (25-120 sec p.i.), andlate phases (>120 sec p.i.). 69 patients had metastases in the abdominal tract, includingeight patients with poorly differentiated neuroendocrine carcinomas with high-grade behavior.In 31 patients the proliferation index (MIB-1) <strong>of</strong> the NET was < 2 percent, in 46 patients > 2percent, and in 6 patients > 20 percent. Thirteen patients had one primary lesion withoutmetastases. In NET <strong>of</strong> the lung, stomach, and colon it was found only hypoechoic orisoechoic liver metastases. NET <strong>of</strong> the small intestine and pancreas represented hypoechoic,isoechoic, and/or hyperechoic liver lesions, sometimes combined. Insulin producing tumors(6) had hypoechoic metastases. Necrotic areas (25/83) were detected after interferontherapy, embolization, systemic chemotherapy, and radi<strong>of</strong>requency ablation <strong>of</strong> livermetastases, but did not develop after somatostatin receptor radionuclide therapy. In largeNET (> 3 cm) with a proliferation index <strong>of</strong> > 2 percent, necrotic areas appearedspontaneously. In 93 percent (77/83) <strong>of</strong> the cases the NET and their metastases showed anearly arterial influx <strong>of</strong> microbubbles. Rim-like contrast enhancement occurred during thecapillary phase in 78 percent (65/83) <strong>of</strong> all lesions, and hypervascularization occurred duringthe arterial phase and at the beginning <strong>of</strong> the capillary phase in 95 percent (79/83). Thehypervascularized tissue was found in the primary lesions, in liver, lymph node metastasesand any kind <strong>of</strong> abdominal metastases. In liver metastases with a proliferation index >2percent, tumor arteries showed a chaotic growth pattern. In 93 percent (77/83) the NETlesions appeared as dark "defects" at the beginning <strong>of</strong> the late phase. It was concluded thatCEUS with CPS demonstrates typical NET imaging characteristics. In most cases real-timeCEUS may replace other imaging techniques [671].Gastro-entero-pancreatic neuroendocrine tumours (GEP NET) represent a rare and highlyheterogeneous entity that <strong>of</strong>ten is revealed by vague and non-specific symptoms, leading toa delayed diagnosis. Here we will <strong>review</strong> some <strong>of</strong> the most regularly observed false positiveand false negative cases and provide clues to recognize and manage them properly.Particularly, the value <strong>of</strong> chromogranin-A as a serum tumour marker and Somatostatinreceptor scintigraphy as an imaging test, were <strong>review</strong>ed. Indeed, chromogranin-A and otherhormones, such as gastrin, as well as urinary 5-hydroxy-indolic acetic acid (5-HIAA) are<strong>of</strong>ten tested to diagnose NET without appraising the clinical situation, leading to extensivework-up on false bases. On the other hand, some tests are performed in situations wherethey do not add additional information (e.g. 5-HIAA in pancreatic or rectal NET) becauseinvariably negative. Somatostatin receptor scintigraphy is an expensive examination forwhich indications must be carefully assessed, knowing its specificity and sensitivity [672].Somatostatin analogsSomatostatin analogs (SSAs) have an important role in the management <strong>of</strong> patients withneuroendocrine tumours <strong>of</strong> the gastrointestinal tract and pancreas (GEP NETs). Thesecompounds can control the symptoms induced by the production <strong>of</strong> hormones and peptides.The antiproliferative effects <strong>of</strong> SSAs and especially tumour shrinkage are less obvious inpatients with GEP NETs than in those with acromegaly. However, based upon phase IIexperience there is a strong suggestion <strong>of</strong> a disease stabilizing effect <strong>of</strong> SSAs in selectedpatients. Those patients with a progressive, non-functional GEP NET, positive octreotidescintigraphy, a low proliferation index and in the absence <strong>of</strong> surgical options may benefit froma first-line medical therapy with SSAs. The exploration <strong>of</strong> the mechanisms <strong>of</strong> this effect isunclear and hampered by the lack <strong>of</strong> suitable preclinical models. The better understanding <strong>of</strong>the tumour biology <strong>of</strong> GEP NETs, together with the development <strong>of</strong> new SSAs with betteraffinity on all somatostatin receptors, represent an unmet medical need [673].SomatostatinomaSomatostatinoma is a rare somatostatin-producing endocrine tumor, probably malignant.Due to its nonspecific symptoms such as vague abdominal pain, weight loss, or occult

clinical features, misdiagnosis occurs. It was reported a case <strong>of</strong> pancreatic somatostatinomawith severe hypoglycemia. The patient had experienced severe hypoglycemic attacks for 11months periodically. Contrast computed tomography scan revealed an isodensity mass about2 cm in the head <strong>of</strong> the pancreas. Ultimately, a local excision was carried out as the tumorwas located exactly on the surface <strong>of</strong> the pancreas. Somatostatinoma was established afterimmunohistochemical technique. The patient led a normal life without any complaint at 1 yearfollow-up [674].VIPomaClinical manifestations, laboratory examination, imaging features, surgical findings, andpathological findings <strong>of</strong> four patients with VIPoma admitted from 1991 to the present werediscussed. Watery diarrhea and hypokalemia were the main clinical manifestations. Hepaticmetastasis occurred in 2 patients. The pancreatic body and tail were the main locations <strong>of</strong>lesions. Two tumors were shown in the pancreatic body and tail in 1 patient. Two patientswith hepatic metastases received a combination therapy <strong>of</strong> octreotide, surgery, andchemotherapy, which resulted in symptom improvement and normalization <strong>of</strong> the serumpotassium values. Distal pancreatic resection and second resection <strong>of</strong> hepatic metastaticlesions were performed in 1 patient. Resection <strong>of</strong> the pancreatic body and tail was done in 1patient, and pancreatoduodenectomy was performed in another patient. Laparotomy wasdone in 1 patient because <strong>of</strong> invasion <strong>of</strong> the superior mesenteric vein and duodenum [675].Zollinger-Ellison syndromeMost patients with Zollinger-Ellison Syndrome (ZES), even those in whom gastrinoma isfound and resected at initial operation, will suffer from persistent or recurrent disease inlongterm followup. There is currently no consensus about managing patients with recurrentor persistent ZES. It was performed a <strong>review</strong> <strong>of</strong> a consecutive series <strong>of</strong> patients evaluatedand managed at our institution between 1970 and 2007 for ZES. "Biochemical cure" wasdefined as normal serum gastrin assays and negative imaging studies. Reoperations wereperformed for elevations in serum gastrin assays and positive findings on imaging studies.Fifty-two patients with sporadic ZES were analyzed. Median followup was 14 years. Amongpatients with sporadic ZES, 37 patients underwent operative management. The mostcommon operations were resection <strong>of</strong> duodenal gastrinoma (n=8) and total gastrectomy(n=7). Nine patients underwent 15 reoperations for recurrent or persistent disease."Biochemical cure" was obtained in four patients (44 %) undergoing reoperation for ZES.Three <strong>of</strong> these patients remained without evidence <strong>of</strong> recurrence at 4, 9, and 12 years aftertheir curative re-resection. Only one <strong>of</strong> nine patients who underwent reoperation died <strong>of</strong>metastatic gastrinoma. It was concluded that primary and reoperative surgery in patients withsporadic ZES results in a significant rate <strong>of</strong> "biochemical cure." In selected patients withrecurrent or persistent disease, reoperation for resection <strong>of</strong> gastrinoma is associated withexcellent longterm survival and is warranted [676].InsulinomasInsulinoma is a rare neuroendocrine tumor with an incidence <strong>of</strong> 4 per 1 million persons peryear, which may occur as a unifocal sporadic event in patients without an inherited syndromeor as a part <strong>of</strong> multiple endocrine neoplasia type 1. Key neuroglycopenic and hypoglycemicsymptoms in conjunction with biochemical pro<strong>of</strong> establish the diagnosis. Once the diagnosisis established, the insulinoma is preoperatively localized within the pancreas with the goal <strong>of</strong>surgical excision for cure [677].

Insulinomas are rare neuroendocrine tumours with an incidence <strong>of</strong> four cases per million ayear. Only few cases <strong>of</strong> insulinoma in patients with preexisting diabetes mellitus have beenreported. It was presented a 50-year-old male with type 2 diabetes mellitus who sufferedfrom recurring hypoglycemia. He had gained 20 kilograms <strong>of</strong> weight in five years. 72-hourfast revealed hypoglycaemia in the presence <strong>of</strong> inadequately high C-peptide and insulinlevels. Magnetic resonance imaging and selective arterial calcium stimulation test confirmeda mass in the body <strong>of</strong> the pancreas. The tumor was removed surgically. Pathologicalexamination demonstrated a benign insulinoma. Postoperatively, blood glucose levels werewithin the therapeutic range. The HbA (1c) value was 6.8 percent three months after theintervention. Clinicians should be alert to insulinoma as a, though rare, differential diagnosis<strong>of</strong> hypoglycaemia in diabetes, in particular in patients with recurrent, otherwise unexplainedhypoglycaemia [678].Non-functioning tumorA 52-year-old man was admitted for detailed examination <strong>of</strong> a mass with extensivecalcification in the tail <strong>of</strong> the pancreas by fluoro-deoxy glucose-positron emissiontomography/computed tomography (FDG-PET/CT). Abdominal CT and magnetic resonanceimaging (MRI) findings showed a calcified tumor 5 cm in diameter with a smooth surface. Thetumor mainly showed calcification at it center and a partially solid element around it marginwhich was enhanced in the early phase. Pathological and immunohistochemical studiesrevealed a nonfunctioning islet cell tumor with calcification. A nonfunctioning islet cell tumorwith central calcification formation as it grew to a maximum diameter <strong>of</strong> 7 cm is rare. Whendiagnosing pancreatic tumors it must be kept in mind that some nonfunctioning islet celltumors <strong>of</strong> the pancreas can show nontypical features such as calcification formation [679].Tumors <strong>of</strong> the papilla <strong>of</strong> VaterEndocrine tumors <strong>of</strong> the ampullary region are rare, and accurate indications for theirmanagement are lacking. It was <strong>review</strong>ed all patients who 1982-2003 were submitted to apancreaticoduodenectomy for ampullary endocrine tumors. Eight patients, 3 men and 5women, with a mean age <strong>of</strong> 48 years were included. Two patients presented with Zollinger-Ellison syndrome, and 1 had neur<strong>of</strong>ibromatosis. Operative mortality was nil. The mean size<strong>of</strong> the tumors was 17 mm (range, 5-40 mm). There were 7 well-differentiated and 1 poorlydifferentiated endocrine carcinomas. Seven patients had satellite lymph node metastases,and 1 had diffuse liver metastases. Median follow-up was 131 months (range, 17-315months). At the end <strong>of</strong> the follow-up period, 5 patients were alive and disease-free; 1 patientwas alive with stable liver metastases. Two patients died 17 months and 13 years aftersurgery, respectively, from metastasis and an unrelated cause. This study demonstrates thehigh frequency <strong>of</strong> lymph node invasion in these uncommon tumors, even at an early clinicalstage. Pancreaticoduodenectomy may result in prolonged survival <strong>of</strong> patients with welldifferentiatedtumors [680].SurgerySurgery represents the only chance <strong>of</strong> cure for a patient with a neuroendocrine tumour(NET). The main indications for surgery lie in the risk <strong>of</strong> developing metastatic disease withincreasing tumour diameter and for a functioning NET also in control <strong>of</strong> the hormonalsyndrome. However, only a small minority <strong>of</strong> patients presents with a potentially resectableprimary NET without metastatic disease. An R0-resection is mandatory, which may be

achieved in selected cases by tissue sparing surgical techniques. Most patients unfortunatelypresent with a locally advanced or metastatic disease. For patients with an advancedfunctioning NET, control <strong>of</strong> the hormonal syndrome may also represent a surgical indication.Various cytoreductive techniques or, in highly selected cases, liver transplantation can beapplied. For locally advanced non-functioning tumours, there is an indication for surgery inlarge tumours which tend to create local complications because <strong>of</strong> bleeding or bowelobstruction. Especially in ileal NETs aggressive surgical therapy is recommended because <strong>of</strong>prevention <strong>of</strong> long-term complications, which may improve survival [681].Medical treatmentThe incidence <strong>of</strong> pancreatic endocrine tumor (PET) accounts for approximately 2 percent <strong>of</strong>total pancreatic tumors and for approximately 1.5 pecent <strong>of</strong> autopsy cases, reflecting therecently increasing trend. According to WHO criteria (2004), PET is classified by the type <strong>of</strong>hormone produced by the tumor and its biological behavior. Together with the classical clinicalimages and hormone markers, 11 C-5-HTP-Positron emission tomography, OctreoScan ( 111 In-DTPA0-octreotide)scintigram, SACI-test and IOUS are used for diagnosis. Surgery is thetreatment <strong>of</strong> choice, if supposed to be curative and tolerable. In case <strong>of</strong> a well-differentiatedendocrine tumor, with no indication <strong>of</strong> resection or IVR, somatostatin analog is another therapyshowing stable disease status for a long period. Systemic chemotherapy, including 5-FU+streptozotocin, and streptozotocin+doxorubicin, are used in cases <strong>of</strong> well -differentiatedendocrine carcinoma, and cisplatin+etoposide are applied for poorly-differentiated endocrinecarcinoma (or small cell carcinoma). Recent studies focus on molecular target therapyincluding small molecules and monoclonal antibody, such as tyrosine kinase inhibitor, anti-VEGF antibody and moor inhibitor [682].Cytotoxic treatmentGastroenteropancreatic neuroendocrine tumours (GEP NET) are heterogeneous and raremalignancies although their prevalence is increasing. Multiple therapeutic approaches areavailable to date for their management, including surgery, hormonal and immuneradionucleide therapies and chemotherapy. The purpose <strong>of</strong> one <strong>review</strong> was to collect,examine, and analyze data available regarding contemporary chemotherapeuticmanagement <strong>of</strong> GEP NET in order to determine whether or not chemotherapy still takesplace in the therapeutic arsenal <strong>of</strong> GEP NET. Anthracyclins, 5-fluorouracil (5-FU), DTIC andstreptozotocin are amongst the most commonly used chemotherapeutic agents, usuallyprescribed in combination. Their efficiency in reducing tumor burden is not always associatedwith better survival, perhaps due to severe toxicity. Chemotherapy in GEP NET is mainlydevoted to poorly differentiated tumours, but also in well differentiated carcinomas either noteligible or resistant to other therapies. Chemotherapy remains therefore useful in specificcases <strong>of</strong> GEP NET management. However, a new era <strong>of</strong> antitumoral agents, such astargeted therapies, could eventually replace these old recipes in the near future [683].Radiolabeled targeted therapiesGastro-entero-pancreatic neuroendocrine tumours (GEP NET) are a heterogeneous group <strong>of</strong>proliferative disorders whose management dramatically relies on tumour biology. For welldifferentiated,low-proliferative index tumours, locoregional treatment and targetedradioisotopic therapies <strong>of</strong>fer an attractive and seemingly efficient alternative to palliativesurgical resections. Lack <strong>of</strong> well-designed, prospective, randomized multicentric studieshinders a balanced evaluation <strong>of</strong> available locoregional treatment methods: embolization,chemo-embolization, radio-embolization. According to available datas, all techniques achievea 50-60 percent radiological response rate and almost 80 percent <strong>of</strong> symptomatic relieve forthe patients, while their impact on progression-free and overall survival remains not

assessable. Same conclusions can be drawn for radiolabeled targeted therapies likeMetaiodoBenzylGuanidine (MIBG) and Peptide Receptor Radionuclide Therapy (PRRT),which, provided that their target is expressed by tumour cells, can deliver therapeutic doses<strong>of</strong> radiation to neoplastic tissues. 131 I-MIBG has been associated with a 50 percentsymptomatic response rate and mainly haematological toxicities. PRRT with111 In-DiethyleneTriamineentaacetic Acid-Octreotide, [90Y-DOTA0-Tyr3]-Octreotide, or [177Lu-DOTA0-Tyr3]-Octreotate seem to alleviate symptoms in 50 percent <strong>of</strong> patients and obtain aradiological response in 30-38 percent. Renal toxicity, partially preventable, is more frequentthan previously thought and result in an annual decrease in glomerular function by 4 to 8percent per year. Forthcoming research in GEP NET should by a majority be designed inrandomized, prospective and multicentric fashion. Locoregional disease trials must focus onclinical outcome differences between embolization techniques (embolization,chemoembolization and radioembolization) and surgery. In disseminated disease, studiesshould assess radiolabeled targeted therapies efficiency when administered along with andcompared to new biological and older chemotherapeutic agents [684].Metastatic endocrine cancersPancreatic endocrine carcinomas (PECAs) are uncommon, with an incidence <strong>of</strong> 1 per100,000. Past studies <strong>of</strong> chemotherapy and hepatic arterial embolization have describedmedian survival durations <strong>of</strong> approximately 2 to 3 years. Overall survival from time <strong>of</strong>diagnosis <strong>of</strong> metastases has never been reported in a large cohort <strong>of</strong> patients. The objective<strong>of</strong> one study was to evaluate the stage-specific prognosis <strong>of</strong> patients with metastatic PECAsand to assess the impact <strong>of</strong> clinical and pathologic prognostic factors. It was evaluated allcases <strong>of</strong> differentiated, metastatic PECAs seen at a cancer center between the years 1999and 2003, measuring survival from time <strong>of</strong> diagnosis <strong>of</strong> metastases. Ninety cases <strong>of</strong>metastatic PECAs were identified. Median overall survival was 70 months, and the 5-yearsurvival rate was 56 percent. Age, sex, and tumor type (functional vs nonfunctional) did notimpact prognosis. Tumor grade, however, was highly prognostic for survival. The prolongedsurvival duration may reflect the impact <strong>of</strong> multimodality treatments. Tumor grade (low vsintermediate grade) represents a highly significant prognostic factor [685].PanniculitisThe association between pancreatic panniculitis and pancreatic disease is well described,but differentiation among the neoplastic causes <strong>of</strong> the syndrome remains difficult due tosubstantial overlap in histological and immunohistochemical features. It was reported a case<strong>of</strong> subcutaneous fat necrosis as the presenting feature in a 61-year-old man with metastaticcarcinoma <strong>of</strong> pancreatic origin. Previous pathological evaluation <strong>of</strong> the patient's liver biopsyled to an initial diagnosis <strong>of</strong> adenocarcinoma <strong>of</strong> unknown primary site. One month later, thepatient presented with pancreatic panniculitis, prompting further investigation. Immunohistochemistrywas consistent with neuroendocrine differentiation, but the patient rapidlydecompensated and died before the evaluation was complete, leaving the definitivediagnosis in question. In a <strong>review</strong> <strong>of</strong> the published reports <strong>of</strong> tumor types associated withpancreatic panniculitis, it was found that immunohistochemical staining and electronmicroscopy can and should be used in conjunction with clinical correlation to accuratelydifferentiate neuroendocrine tumors from carcinomas with acinar cell features [686].

Overall survivalPancreatic neuroendocrine tumors (pNETs) are an uncommon pancreatic neoplasm. It was<strong>review</strong>ed the presentation, management, and outcome <strong>of</strong> patients with pNETs treated at asingle center by a multidisciplinary approach between 2004 and 2008. Over this time period,154 patients with carcinoid and neuroendocrine tumors were treated, which included 46patients (30 % <strong>of</strong> total) with pNETs. The most common presentations included abdominalpain (43 %), systemic symptoms such as hypoglycemia (33 %), and incidental mass (15 %).Fourteen patients had functional tumors. At the time <strong>of</strong> diagnosis, 22 patients (48 %)presented without metastases and 24 (52 %) had metastatic disease. Median follow up forthe entire group was 42 months. All patients with nonmetastatic pNET underwent pancreaticresection with 95 percent postoperative survival. Overall survival in this group at 3 years was86 percent and disease-free survival was 81 percent. In patients presenting with metastaticpNET, multiple treatment modalities were used, including liver resection or ablation (n=15),hepatic chemoembolization (n=17), pancreatic resection (n=12), and systemic treatments(n=7). Three-year survival was 70 percent. Pancreatic resection results in greater than 80 percent 3-year survival in nonmetastatic pNET. In patients presenting with metastatic pNET,excellent survival rates are also achievable using a multidisciplinary multimodal approach[687].Pancreatic endocrine tumors (PETs) are infrequent, which makes large experiences unlikely.The aim was to describe a large single-center experience with PETs and the use <strong>of</strong>endoscopic ultrasound (EUS) and a cancer staging system (TNM). This study involves aretrospective analysis <strong>of</strong> 86 patients (44 men) who underwent EUS-fine needle aspiration(EUS-FNA). Immunohistochemistry was used. Typical EUS features were well-demarcated,hypoechoic, solid, homogeneous lesions. Ninety percent had the diagnosis obtained by EUS-FNA. Twelve PETs (14 %) were functioning, 8 (9 %) were cystic, and 14 (16 %) were 10 mmor smaller. Nonfunctional PETs and larger lesions were more advanced. The TNM stage wasI in 24, II in 10, III in 18, and IV in 34 patients. Sixteen patients (27 %) died, and 30 patients(52 %) had progression or recurrence during the follow-up (34 + 27 months). TNM stage andsurgery with curative intent were related to progression. The overall 5-year survival was 60percent. The mean survival time was 94 + 12 months for stage I, 52 + 12 months for stageIII, and 54 + 7 months for stage IV. It was concluded that nonfunctional PETs were morecommon and advanced. The EUS-FNA has a high accuracy for diagnosing PETs.Progression and poorer survival were associated with TNM stage [688].To identify potential preoperative prognostic factors in resected pancreatic and periampullaryneuroendocrine tumours clinico-pathological data for 54 consecutive patients with pancreaticor periampullary neuroendocrine tumors referred over a 10-year period were identified from aprospective database. Thirty-four patients underwent pancreatic resection (12 males, medianage 54 years). There was a single 30-day mortality (3 %). Nodal status, microscopicresection margin involvement, and tumor size failed to exhibit any prognostic value. Only thepresence <strong>of</strong> malignant tumor characteristics was significantly associated with poorer overallsurvival. Analysis <strong>of</strong> preoperative parameters showed that age >60 years, plateletlymphocyteratio >300, alkaline phosphatase levels >125 U/l, and alanine aminotransferase>35 U/l were adverse prognostic factors. A risk stratification score was generated whereeach adverse preoperative parameter was allocated a score <strong>of</strong> 1. A cumulative score <strong>of</strong> < 1was defined as low risk, while a score <strong>of</strong> > 2 was defined as high risk. Median overall survivalin the high-risk group was 10 months, while the median survival in the low-risk group was>60 months. It was concluded that significant prognostic information can be gained fromroutine preoperative biochemistry and haematology results in resected pancreatic andperiampullary neuroendocrine tumours [689].

Quality <strong>of</strong> lifeTo develop a disease-specific questionnaire for identifying domains having the greatestimpact on the quality <strong>of</strong> life (QOL) <strong>of</strong> patients with neuroendocrine tumors (NETS) patientresponses to clinical interviews provided an 80-item initial pool for the development <strong>of</strong> theQOL-NET. The Delphi panel <strong>review</strong>ed the items for content validity; the patient focus group<strong>review</strong>ed the items for content/readability. Domains were derived from analysis <strong>of</strong>224questionnaire responses. After principal components analysis, a scree plot suggested 7domains. Exploratory factor analysis with forced 7-factor varimax rotation determined anideal structure. Reliability/reproducibility was determined by test/retest 4 to 6 weeks apart.Logistic regression determined each domain score. All 7 domains exhibited strong internalconsistency. Physical functioning contributed 40 percent <strong>of</strong> the total QOL score, followed byflushing, gastrointestinal symptoms, respiratory, cardiovascular, depression, and attitudedomains. Most items loaded 0.40 or higher. No significant differences in test and retestscores. The mean values for the total QOL and 4 <strong>of</strong> 7 factor scores were significantly higherfor NETS than controls: sensitivity was 71 percent and specificity was 70 percent todiscriminate the NETS from the controls. Thus, though the QOL-NET is reliable andreproducible it only weakly identifies NETS [690].

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