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SurgicalstrategiesinMEN12

relatedpancreaticneuroendocrinetumors3

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Proefschrift9

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11terverkrijgingvandegraadvandoctoraandeUniversiteitvanUtrecht12

opgezagvanderectormagnificus,prof.dr.G.J.vanderZwaan,13ingevolgdehetbesluitvanhetcollegevoorpromoties14

inhetopenbaarteverdedingenop1529september201716

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door18

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SjoerdNell20geborenop20oktober198721

teNieuwkoop2223

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Promotoren Prof.dr.G.D.Valk29 Prof.dr.M.R.Vriens3031Copromotor Prof.dr.H.M.Verkooijen32333435363738394041424344454647484950515253545556575859606162636465666768697071727374

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Contents7576Chapter1: Introductionandthesisoutline7778Chapter2: ManagementofMEN1relatedNF-PNETs:ashiftingparadigm.Resultsfromthe 79 DutchMEN1StudyGroup.80 AnnalsofSurgery2017Mar2.8182Chapter3: NoAssociationoftype-ObloodwithNeuroendocrineTumorsinMultipleEndocrine 83 NeoplasiaType1.84 TheJournalofClinicalEndocrinology&Metabolism100.10(2015):3850-3855.85 86Chapter4: Robot-assistedspleenpreservingpancreaticsurgeryinMEN1patients.87 JournalofSurgicalOncology2016Sep;114(4):456-61.8889Chapter5: InsulinomainMultipleEndocrineNeoplasiaType1.90 Hypoglycemicdisorders,InPress9192Chapter6: MinimalrecurrencerateafterMEN1relatedinsulinomasurgery.Alargeinternationalcohort93

study94 Submitted9596Chapter7: Earlyandlatecomplicationsafternon-functioningpancreaticneuroendocrinetumorsurgeryin97

MEN1patients.98 AnnalsofSurgery2016Nov199100Chapter8: DuodenopancreaticneuroendocrinetumorsandtumorlivermetastasesinMultipleEndocrine101

Neoplasiatype1:survivalandprognosticfactors102 EndocrinePractice2017Feb22.doi:10.4158/EP161639.OR.103104Chapter9: GeneralDiscussion105106107

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ManagementofMEN1relatednon-functioningpancreaticNETs:a112

shiftingparadigm.ResultsfromtheDutchMEN1StudyGroup113

SjoerdNell,MD,DepartmentofEndocrineSurgicalOncologyandEndocrineOncology,UniversityMedicalCenter114

Utrecht,Utrecht,TheNetherlands115

HelenaM.Verkooijen,MD,Ph.D.,ImagingDivision,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands116

CarolinaR.C.Pieterman,MD,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,The117

Netherlands118

WouterW.deHerder,MD,Ph.D.DepartmentofInternalMedicine,ErasmusMedicalCenter,Rotterdam,The119

Netherlands120

AdR.Hermus,MD,Ph.D.,DepartmentofEndocrinology,RadboudUniversityMedicalCenter,Nijmegen,The121

Netherlands122

OlafM.Dekkers,MD,Ph.D.DepartmentsofEndocrinologyandMetabolismandClinicalEpidemiology,Leiden123

UniversityMedicalCenter,Leiden,TheNetherlands124

AnoukN.vanderHorst-Schrivers,MD,Ph.D.DepartmentofEndocrinology,UniversityofGroningen,University125

MedicalCenterGroningen,Groningen,TheNetherlands126

MadeleineL.Drent,MD,Ph.D.DepartmentofInternalMedicine,SectionofEndocrinology,VUUniversityMedical127

Center,Amsterdam,TheNetherlands128

PeterH.Bisschop,MD,Ph.D.DepartmentofEndocrinologyandMetabolism,AcademicMedicalCenter,129

Amsterdam,TheNetherlands130

BasHavekes,MD,Ph.D.DepartmentofInternalMedicine,DivisionofEndocrinology,MaastrichtUniversityMedical131

Center,Maastricht,TheNetherlands132

InneH.M.BorelRinkes,MD,Ph.D.,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenter133

Utrecht,Utrecht,TheNetherlands134

MennoR.Vriens,MD,Ph.D.,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,135

Utrecht,TheNetherlands136

GerlofD.Valk,MD,Ph.D.,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,The137

Netherlands 138

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Abstract139

Objective:ToassessifsurgeryforMultipleEndocrineNeoplasiatype1(MEN1)relatednon-functioningpancreatic140

neuroendocrinetumors(NF-pNETs)iseffectiveforimprovingoverallsurvivalandpreventinglivermetastasis.141

Background:MEN1leadstomultipleearly-onsetNF-pNETs.Theevidencebaseforguidingthedifficultdecision142

whoandwhentooperateismeager.143

Methods:MEN1PatientsdiagnosedwithNF-pNETsbetween1990-2014wereselectedfromtheDutchMEN1study144

groupdatabase,including>90%oftheDutchMEN1population.Theeffectofsurgerywasestimatedusingtime-145

dependentCoxanalysiswithpropensityscorerestrictionandadjustment.146

Results:Ofthe152patients,53underwentsurgeryand99weremanagedbywatchfulwaiting.Inthesurgery147

group,tumorswerelargerandfaster-growing,patientswereyounger,moreoftenmaleandweremoreoften148

treatedincentersthatoperatedmorefrequently.SurgeryforNF-pNETswasnotassociatedwithasignificantly149

lowerriskoflivermetastasesordeath,(adjustedHazardRatio(HR)=0.73(0.25-2.11).AdjustedHR'safter150

stratificationbytumorsizewere:NF-pNETs<2cm=2.04(0.31-13.59)andNF-pNETs2-3cm=1.38(0.09-20.31).151

FiveoutofthesixpatientswithNF-pNETs>3cmmanagedbywatchfulwaitingdevelopedlivermetastasesordied152

comparedwithsixoutofthe16patientswhounderwentsurgery.153

Conclusions:MEN1patientswithNF-pNETs<2cmcanbemanagedbywatchfulwaiting,herebyavoidingmajor154

surgerywithoutlossofoncologicalsafety.ThebeneficialeffectofasurgeryinNF-pNETs2-3cmrequiresfurther155

research.InpatientswithNF-pNETs>3cm,watchfulwaitingseemsnotadvisable.156

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NoAssociationofBloodTypeOwithNeuroendocrineTumorsin158

MultipleEndocrineNeoplasiaType1159

SjoerdNell1,MD,DepartmentofEndocrineSurgery,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands160RachelS.vanLeeuwaarde1,MD,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,161TheNetherlands162CarolinaR.C.Pieterman,MD,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,The163Netherlands164JoanneM.deLaat,MD,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,The165Netherlands166AdR.Hermus,MD,Ph.D.,DepartmentofEndocrinology,RadboudUniversityMedicalCenter,Nijmegen,The167Netherlands168OlafM.Dekkers,MD,Ph.D.DepartmentsofEndocrinologyandMetabolismandClinicalEpidemiology,Leiden169UniversityMedicalCenter,Leiden,TheNetherlands.DepartmentofClinicalEpidemiology,AarhusUniversity170Hospital,Aarhus,Denmark171WouterW.deHerder,MD,Ph.D.DepartmentofInternalMedicine,ErasmusMedicalCenter,Rotterdam,The172Netherlands173AnoukN.vanderHorst-Schrivers,MD,Ph.D.DepartmentofEndocrinology,UniversityofGroningen,University174MedicalCenterGroningen,Groningen,TheNetherlands175MadeleineL.,MD,Ph.D.DepartmentofInternalMedicine,SectionofEndocrinology,VUUniversityMedicalCenter,176Amsterdam,TheNetherlands177PeterH.Bisschop,MD,Ph.D.DepartmentofEndocrinologyandMetabolism,AcademicMedicalCenter,178Amsterdam,TheNetherlands179BasHavekes,MD,Ph.D.DepartmentofInternalMedicine,DivisionofEndocrinology,MaastrichtUniversityMedical180Center,Maastricht,TheNetherlands181InneH.M.BorelRinkes,MD,Ph.D.,DepartmentofEndocrineSurgery,UniversityMedicalCenterUtrecht,The182Netherlands183MennoR.Vriens,MD,Ph.D.,DepartmentofEndocrineSurgery,UniversityMedicalCenterUtrecht,The184Netherlands185GerlofD.Valk,MD,Ph.D.,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,TheNetherlands1861871bothauthorscontributedequallytothismanuscript 188

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Abstract189

Context:AnassociationbetweenABObloodtypeandthedevelopmentofcancer,inparticular,pancreaticcancer,190

hasbeenreportedintheliterature.AnassociationbetweenbloodtypeOandneuroendocrinetumorsinmultiple191

endocrineneoplasiatype1(MEN1)patientswasrecentlysuggested.Therefore,bloodtypeOwasproposedasan192

additionalfactortopersonalizescreeningcriteriaforneuroendocrinetumorsinMEN1patients.193

Objective:TheaimofthisstudywastoassesstheassociationbetweenbloodtypeOandtheoccurrenceof194

neuroendocrinetumorsinthenationalDutchMEN1cohort.195

Design:CohortstudyusingtheDutchNationalMEN1database,whichincludes>90%oftheDutchMEN1196

population.Demographicandclinicaldatawereanalyzedbybloodtype.Chi-squaretestsandFisherexacttests197

wereusedtodeterminetheassociationbetweenbloodtypeOandoccurrenceofneuroendocrinetumors.A198

cumulativeincidenceanalysis(Gray’stest)wasperformedtoassesstheequalityofcumulativeincidenceof199

neuroendocrinetumorsinbloodtypegroups,takingdeathasacompetingriskintoaccount.200

Results:ABObloodtypeof200of322MEN1patientswasknown.Demographicandclinicalcharacteristicswere201

similaramongstbloodtypeOandnon-Otypecohorts.Theoccurrenceofneuroendocrinetumorsofthelung,202

thymus,pancreasandthegastrointestinaltractwasequallydistributedacrossthebloodtypeOandnon-Otype203

cohorts(Grays’stestforequality;P=0.72).Furthermore,wefoundnoassociationbetweenbloodtypeOandthe204

occurrenceofmetastaticdiseaseorsurvival.205

Conclusions:AnassociationbetweenbloodtypeOandtheoccurrenceofneuroendocrinetumorsinMEN1206

patientswasnotconfirmed.Additionofthebloodtypetoscreeningandsurveillancepracticeseemsforthisreason207

notofadditionalvalueforidentifyingMEN1patientsatriskforthedevelopmentofneuroendocrinetumors,208

metastaticdiseaseorashortenedsurvival. 209

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Robot-assistedspleenpreservingpancreaticsurgeryinMEN1patients210

SjoerdNell,MD,DepartmentofEndocrineSurgicalOncologyandEndocrineOncology,UniversityMedicalCenter211

Utrecht,theNetherlands212

LaurentBrunaud,MD,Ph.D.,DepartmentofDigestive,HepatobiliaryandEndocrineSurgery,UniversitédeLorraine,213

HôpitalBraboisAdultes,CHUNancy,France214

AhmetAyav,MD,Ph.D.,DepartmentofDigestive,HepatobiliaryandEndocrineSurgery,UniversitédeLorraine,215

HôpitalBraboisAdultes,CHUNancy,France216

BertA.Bonsing,MD,Ph.D.,DepartmentofSurgery,LeidenUniversityMedicalCenter,Leiden,TheNetherlands217

BasGrootKoerkamp,MD,Ph.D.,DepartmentofSurgery,ErasmusMedicalCenter,Rotterdam,TheNetherlands218

ElsJ.NieveenvanDijkum,MD,Ph.D.,DepartmentofSurgery,AcademicMedicalCenter,Amsterdam,The219

Netherlands220

GeertKazemier,MD,Ph.D.,DepartmentofSurgery,VUUniversityMedicalCenter,Amsterdam,theNetherlands221

RubenH.J.deKleine,MD,DepartmentofHepatobiliarySurgeryandLiverTransplantation,UniversityofGroningen,222

UniversityMedicalCenterGroningen,Groningen,theNetherlands223

JeroenHagendoorn,MD,Ph.D.,DepartmentofSurgicalOncologyandHepato-Pancreato-BiliarySurgery,University224

MedicalCenterUtrecht,theNetherlands225

I.QuintusMolenaar,MD,Ph.D.,DepartmentofSurgicalOncologyandHepato-Pancreato-BiliarySurgery,University226

MedicalCenterUtrecht,theNetherlands227

GerlofD.ValkonbehalfoftheDMSG,MD,Ph.D.,DepartmentofEndocrineOncology,UniversityMedicalCenter228

Utrecht,theNetherlands229

InneH.M.BorelRinkes,MD,Ph.D.,DepartmentofSurgicalOncologyandEndocrineSurgicalOncology,University230

MedicalCenterUtrecht,theNetherlands231

MennoR.Vriens,MD,Ph.D.,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,the232

Netherlands233

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Abstract236

Background:MultipleEndocrineNeoplasiatype1(MEN1)patientsoftenundergomultiplepancreaticoperationsat237

ayoungage.238

Objective:Todescriberobot-assistedandlaparoscopicspleen-preservingpancreaticsurgeryinMEN1patients,and239

tocomparebothtechniques.240

Methods:Robot-assistedpancreatectomiesoftheDutchMEN1studygroupandtheUniversitédeLorraine,Nancy,241

FrancewerecomparedtoahistoricalcohortoflaparoscopictreatedMEN1patients.Perioperativeoutcomeswere242

compared.243

Results:Atotaloftwenty-oneMEN1patientsunderwentminimallyinvasivepancreaticsurgeryforpancreatic244

neuroendocrinetumors,sevenpatientsweresubjectedtorobot-assistedsurgery,andfourteenpatientsunderwent245

laparoscopicsurgery.Demographicsandclinicalcharacteristicsdidnotdifferbetweenthecohortsandno246

significantdifferencesinoperativeoutcomeswerefound.AhighnumberofISGPSgradeB/Cpancreaticfistulas247

wereobservedinbothcohorts(38%),andnoconversionswereseenintherobot-assistedcohort(respectively0%248

versus43%,P=0.06).Inonelaparoscopicandonerobot-assistedcasetheprimarytumorwasnotresected.249

Conclusions:Minimallyinvasivespleen-preservingsurgeryinMEN1patientsissafeandfeasible.Patientswho250

underwentrobot-assistedsurgerydidnotrequireconversiontoopensurgery. 251

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InsulinomainMultipleEndocrineNeoplasiaType1252

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CliveS.Grant,M.D.,DepartmentofSurgery,MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica254

SjoerdNell,MD,DepartmentofEndocrineSurgicalOncologyandEndocrineOncology,UniversityMedicalCenter255

Utrecht,Utrecht,theNetherlands256

MennoR.Vriens,MD,PhD,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,257Utrecht,theNetherlands258

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Noabstractavailable 260

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MinimalriskofpersistentorrecurrenthypoglycemiaafterMEN1-261

relatedinsulinomasurgery.Alargeinternationalcohortstudy.262

SjoerdNell,MD,DepartmentofEndocrineSurgicalOncologyandEndocrineOncology,UniversityMedicalCenter263Utrecht,Utrecht,theNetherlands264PierreGoudet,MD,PhD,onbehalfoftheFrenchEndocrineTumorStudyGroup(GTE),CenterHospitalier265UniversitairedeDijon,DepartmentofDigestiveandEndocrineSurgery,Dijon,France266AdrianVella,MD,PhD,DivisionofEndocrinology,Diabetes,Metabolism,andNutrition,MayoClinic,Rochester,267Minnesota,UnitedStatesofAmerica268DianeDonegan,MD,DivisionofEndocrinology,Diabetes,Metabolism,andNutrition,MayoClinic,Rochester,269Minnesota,UnitedStatesofAmerica270DetlefK.Bartsch,MD,PhD,DepartmentofVisceral,ThoracicandVascularSurgery,PhilippsUniversityMarburg,271Baldingerstrasse,Marburg,Germany272JerenaManoharan,MD,DepartmentofVisceral,ThoracicandVascularSurgery,PhilippsUniversityMarburg,273Baldingerstrasse,Marburg,Germany274NancyD.Perrier,MD,DepartmentofSurgicalOncology,TheUniversityofTexas,MD275AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica276IoannisChristakis,MD,PhD,DepartmentofSurgicalOncology,TheUniversityofTexasMD277AndersonCancerCenter,Houston,Texas,UnitedStatesofAmerica278MariaLuisaBrandi,MD,PhD,DepartmentofSurgeryandTranslationalMedicine,UniversityofFlorence,Florence,279Italy280RasaZarnegar,MD,DepartmentofSurgery,NewYorkPresbyterianHospitalWeillCornellMedicalCenter,New281York,NewYork,UnitedStatesofAmerica282EmilyL.Postma,MD,PhD,DepartmentofSurgery,NewYorkPresbyterianHospitalWeillCornellMedicalCenter,283NewYork,NewYork,UnitedStatesofAmerica284ElectronKebebew,MD,EndocrineOncologyBranch,NationalCancerInstitute,NationalInstitutesofHealth,285Bethesda,Maryland,UnitedStatesofAmerica286PavelNockel,MD,EndocrineOncologyBranch,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,287Maryland,UnitedStatesofAmerica288LaurentBrunaud,MD,PhD,DepartmentofDigestive,HepatobiliaryandEndocrineSurgery,UniversitédeLorraine,289HôpitalBraboisAdultes,CHUNancy,France290JesseD.Pasternak,MD,DepartmentofSurgery,UniversityHealthNetwork,Toronto,ON,Canada291WouterP.Kluijfhout,MD,DepartmentofSurgery,UniversityHealthNetwork,Toronto,ON,Canada292CordSturgeon,MD,DepartmentofSurgery,NorthwesternUniversity,Chicago,Illinois,UnitedStatesofAmerica293SnehaGoswami,BA,DepartmentofSurgery,NorthwesternUniversity,Chicago,Illinois,UnitedStatesofAmerica294BertA.Bonsing,MD,PhD,DepartmentofSurgery,LeidenUniversityMedicalCenter,Leiden,theNetherlands295CasperH.vanEijck,MD,PhD,DepartmentofSurgery,ErasmusMedicalCenter,Rotterdam,theNetherlands296HarryvanGoor,MD,PhD,DepartmentofSurgery,RadboudUniversityMedicalCenter,Nijmegen,theNetherlands297RubenH.J.deKleine,MD,DepartmentofHepato-Pancreatico-BiliaryandLiverTransplantation,Universityof298Groningen,UniversityMedicalCenterGroningen,Groningen,theNetherlands299ElisabethJ.NieveenvanDijkum,MD,PhD,DepartmentofSurgery,AcademicMedicalCenter,Amsterdam,the300Netherlands301CornelisH.C.Dejong,MD,PhD,DepartmentofSurgery,MaastrichtUniversityMedicalCenter,NUTRIMSchoolfor302NutritionandTranslationalResearchinMetabolism,Maastricht,theNetherlandsandDepartmentofSurgery,303UniversitätsklinikumAachen,Germany.304

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HelenaM.Verkooijen,MD,PhD,ImagingDivision,UniversityMedicalCenterUtrecht,Utrecht,the305Netherlands306InneH.M.BorelRinkes,MD,PhD,DepartmentofSurgicalOncologyandEndocrineSurgicalOncology,University307MedicalCenterUtrecht,Utrecht,theNetherlands308GerlofD.Valk,MD,PhD.,onbehalfoftheDutchMEN1studygroup(DMSG),DepartmentofEndocrineOncology,309UniversityMedicalCenterUtrecht,Utrecht,theNetherlands310MennoR.Vriens,MD,PhD,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,311

Utrecht,theNetherlands312

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Abstract341

ObjectiveTodeterminetheoptimalsurgicalstrategyintreatingpatientswithMultipleEndocrineNeoplasiatype1342

(MEN1)-relatedinsulinomas.343

BackgroundCurrentliteraturestatesthat15-30%ofMEN1patientshavepersistentorrecurrenthypoglycemia344

afterinsulinomasurgery,dependingonthesurgicalprocedure.ThecurrentEuropeanNeuroendocrineTumor345

Society(ENETS)andtheMEN1clinicalpracticeguidelineslackwell-groundedrecommendationswithregardsto346

whichsurgicalstrategyispreferredduetolimitedevidence.347

MethodsAtotalof96MEN1patientswithinsulinomasunderwentsurgerybetween1990-2015atoneofthe46348

participatinghospitalsfromEuropeandNorthAmerica.Post-operativehypoglycemia,complications,and349

pancreaticinsufficiencywerecaptured.350

ResultsSevenpercentofthepatientshadpersistentorrecurrenthypoglycemia.Noneoftheninepatientswho351

wereoperatedforasolitaryproximalinsulinomadevelopedhypoglycemia.Ofthe54patientswithasolitarydistal352

insulinoma,onepatienthadpersistentdiseaseafteradistalpancreatectomy(1/41),andonepatientdevelopeda353

newinsulinomaafteradistalenucleation(1/13).Ofthe33patientsoperatedformultipleinsulinomas,1/26354

patientsdevelopedaninsulinproducinglivermetastasisafteradistalpancreatectomycombinedwithsurgeryof355

thepancreatichead.Fouroutofsevenpatientsdevelopedrecurrentdiseaseafterothersurgicalapproachesfor356

multipleinsulinomas.Patientswhounderwentanenucleationdidnotdeveloppancreaticinsufficiency.357

ConclusionsMEN1-relatedinsulinomasurgeryismoresuccessfulthanpreviouslythought.InMEN1patientswitha358

solitaryinsulinoma,enucleationisrecommended,ifsurgicallyfeasible.Adistalpancreatectomycombinedwith359

enucleationofthepancreaticheadlesionsisfavorableforMEN1patientswithmultipleinsulinomas.360

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EarlyandlatecomplicationsaftersurgeryforMEN1relatednon-368

functioningpancreaticneuroendocrinetumors369

SjoerdNell,MD,DepartmentofEndocrineSurgicalOncologyandEndocrineOncology,UniversityMedicalCenter370

Utrecht,Utrecht,theNetherlands371

InneH.M.BorelRinkes,MD,Ph.D.,DepartmentofSurgicalOncologyandEndocrineSurgicalOncology,University372

MedicalCenterUtrecht,Utrecht,theNetherlands373

HelenaM.Verkooijen,MD,Ph.D.,ImagingDivision,UniversityMedicalCenterUtrecht,Utrecht,theNetherlands374

BertA.Bonsing,MD,Ph.D.,DepartmentofSurgery,LeidenUniversityMedicalCenter,Leiden,theNetherlands375

CasperH.vanEijck,MD,Ph.D.,DepartmentofSurgery,ErasmusMedicalCenter,Rotterdam,theNetherlands376

HarryvanGoor,MD,Ph.D.,DepartmentofSurgery,RadboudUniversityMedicalCenter,Nijmegen,the377

Netherlands.378

RubenH.J.deKleine,MD,DepartmentofHepato-Pancreatico-BiliaryandLiverTransplantation,Universityof379

Groningen,UniversityMedicalCenterGroningen,Groningen,theNetherlands380

GeertKazemier,MD,Ph.D.,DepartmentofSurgery,VUUniversityMedicalCenter,Amsterdam,theNetherlands381

ElisabethJ.NieveenvanDijkum,MD,Ph.D.,DepartmentofSurgery,AcademicMedicalCenter,Amsterdam,the382

Netherlands383

CornelisH.C.Dejong,MD,Ph.D.,DepartmentofSurgery,MaastrichtUniversityMedicalCenter,Maastricht,the384

Netherlands385

GerlofD.ValkonbehalfoftheDMSG,MD,Ph.D.,DepartmentofEndocrineOncology,UniversityMedicalCenter386

Utrecht,Utrecht,theNetherlands387

MennoR.Vriens,MD,Ph.D.,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,388

Utrecht,theNetherlands389

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Abstract392

Objective:Toestimateshort-andlong-termmorbidityafterpancreaticsurgeryforMultipleEndocrineNeoplasia393

type1(MEN1)relatednon-functioningpancreaticneuroendocrinetumors(NF-pNETs).394

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Background:FiftypercentoftheMEN1patientsharbormultipleNF-pNETs.ThedecisiontoproceedtoNF-pNET396

surgeryisabalancebetweentheriskofdiseaseprogressionversustheriskofsurgery-relatedmorbidity.Currently,397

thereareinsufficientdataonthesurgicalcomplicationsafterMEN1NF-pNETsurgery.398

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Methods:MEN1PatientsdiagnosedwithaNF-pNETwhounderwentsurgerywereselectedfromtheDutchMEN1400

studygroupdatabase,including>90%oftheDutchMEN1population.Earlypostoperativecomplications,new-401

onsetdiabetesmellitus,andexocrinepancreaticinsufficiencywerecaptured.402

403

Results:Sixty-onepatientsunderwentNF-pNETsurgeryatoneoftheeightDutchacademiccenters.Patientswere404

young(medianage;41years)withlowASAscores.MedianNF-pNETsizeonimagingwas22mm[3-157].Thirty-405

threepercent(19/58)ofthepatientsdevelopedmajorearly-Clavien-DindogradeIII-IV–complicationsmainly406

consistingISGPSgradeB/Cpancreaticfistulas.Twenty-threepercentofthepatients(14/61)developedendo-or407

exocrinepancreasinsufficiency.Thedevelopmentofmajorearlypostoperativecomplicationswasindependentof408

theNF-pNETtumorsize.Twenty-onepercentofthepatients(12/58)developedmultiplemajorearly409

complications.410

411

Conclusions:MEN1NF-pNETsurgeryisassociatedwithhighratesofmajorshort-andlong-termcomplications.412

Currentfindingsshouldbetakenintoaccountintheshareddecision-makingprocesswhenMEN1NF-pNETsurgery413

isconsidered.414

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PrognosticfactorsforsurvivalofMEN1patientswith416

duodenopancreatictumorsmetastatictotheliver:resultsfromthe417

DMSG418

419SjoerdNell*,MD,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,Utrecht,420

DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands421

ElfiB.Conemans*,MD,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,Utrecht,422

DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands423

CarolinaR.C.Pieterman,MD,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,The424

Netherlands425

WouterW.deHerder,MD,PhD,DepartmentofInternalMedicine,ErasmusMedicalCenter,Rotterdam,The426

Netherlands427

OlafM.Dekkers,MD,PhD,DepartmentsofEndocrinologyandMetabolismandClinicalEpidemiology,Leiden428

UniversityMedicalCenter,Leiden,TheNetherlands429

AdR.Hermus,MD,PhD,DepartmentofEndocrinology,RadboudUniversityMedicalCenter,Nijmegen,The430

Netherlands431

AnoukN.vanderHorst-Schrivers,MD,PhD,DepartmentofEndocrinology,UniversityofGroningen,University432

MedicalCenterGroningen,Groningen,TheNetherlands433

PeterH.Bisschop,MD,PhD,partmentofEndocrinologyandMetabolism,AcademicMedicalCenter,Amsterdam,434

TheNetherlands435

BasHavekesMD,PhD,DepartmentofInternalMedicine,DivisionofEndocrinology,MaastrichtUniversityMedical436

Center,Maastricht,TheNetherlands437

MadeleineL.DrentMD,PhD,DepartmentofInternalMedicine,SectionofEndocrinology,VUUniversityMedical438

Center,Amsterdam,TheNetherlands439

MennoR.VriensMD,PhD,DepartmentofEndocrineSurgicalOncology,UniversityMedicalCenterUtrecht,440

Utrecht,TheNetherlands441

GerlofD.Valk,MD,PhD,DepartmentofEndocrineOncology,UniversityMedicalCenterUtrecht,Utrecht,The442

Netherlands,TheNetherlands443

444

*Bothauthorscontributedequallytothemanuscript445

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17

Abstract447

ObjectiveDuodenopancreaticneuroendocrinetumors(DP-NETs)developinamajorityofpatientswithMultiple448

EndocrineNeoplasiaType1(MEN1)andaretheleadingcauseofdeath.Overallsurvival(OS)andprognostic449

factorsforpatientswithlivermetastasesfromDP-NETsarenotknown.450

DesignandMethodsCohortstudyusingtheDutchNationalMEN1database,whichincludes>90%oftheDutch451

MEN1populationbetween1990-2014.OSwasassessedwithtimetoeventanalysis,andprognosticfactorswere452

evaluated.453

ResultsAtotalof56%oftheMEN1patients(n=220)werediagnosedwithaDP-NETofwhom34(15%)developed454

DP-NETlivermetastases.Medianageatlivermetastasesdiagnosiswas53years[range31-74].Ofthosepatients,455

afteramedianfollow-upof4years[range0.3-12.3]16patients(47%)haddied.After2,5,10yearsOSwas456

respectively91%,65%,and50%.Atrendtowardsworsesurvivalwasseeninmalescomparedtofemales(5-year457

OS58%versus75%,p=0.07)andalsoinpatientswithmultiplelivermetastasescomparedtopatientswithsolitary458

livermetastasis(59versus83%,p=0.09).459

ConclusionsDespitethefairlyindolentcourseofDP-NETlivermetastasesinMEN1patients,halfofthepopulation460

wasdeceasedafter10years.Genderandtumorloadatdiagnosisoflivermetastasesarepossibleprognostic461

factorsforworsesurvival.462

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GeneralDiscussion469470

ThisthesisinvestigatedtheoptimalstrategyforMEN1relatedpNETsinwhichthebenefitsofsurgerytoprevent471

metastasisandprematuredeathisweighedagainsttheriskofunintendedpotentialharm.Identifyingpatientsat472

highestriskforanadversecourseofthediseaseintermsofmetastasiscouldleadtoclearersurgicalindications473

andevenhelptoindicatetheextentofduodenopancreaticsurgery.Consequently,evidence-based474

recommendationscanbemadetoimprovemorbidityandmortalityinthispatientgroup.Thiswillresultin475

improvementofpersonalizedcancercareandlifeexpectancyamongMEN1patients.476

477

WhentooperateaMEN1patientwithanon-functioningpancreaticneuroendocrinetumor?478

Inchapter2weassessifsurgeryforMEN1relatednonfunctioningpancreaticneuroendocrinetumors(NF-pNETs)479

iseffectiveforimprovingoverallsurvivalandpreventinglivermetastasis.Evidence-basedtreatmentguidelinesare480

lacking,andclinicianarefacedwiththedifficultdecisionofwhoandwhentooperateMEN1patientswithNF-481

pNET.Westudied152MEN1patientswithNF-pNETsandestimatedtheeffectofsurgeryonthedevelopmentof482

livermetastasesandoverallsurvival.Theoutcomesofthisstudyresultssuggestthatthemajorityofpatientscan483

safelybemanagedbywatchfulwaiting,herebyavoidingmajorsurgerywithoutincreasingtheriskofmetastasesor484

death.Furthermore,thedecisiontooperatepatientswithNF-pNETsbetween2to3cmisdebatableonthebasis485

ofourresults.486

Uptonow,basedontheavailablestudies,clinicaldecisionmakingforMEN1patientswithNF-pNETswas487

hamperedbynon-comparablestudygroupsbecauseofissuesofconfoundingbyindicationandpossiblyselected488

populations.CurrentevidenceismainlybasedontwoimportantpapersfromtheGrouped’EtudedesTumeurs489

EndocrinesinFrance.4,5Inthefirststudy,50MEN1patientswithNF-pNETsof≤2cmmanagednon-operatively490

werecomparedto15surgicallytreatedpatientsanditappearedthatsurgerydidnotdecreasemortalityordisease491

progressionsincemorepatientsdiedinthesurgicallytreatedgroup.4Inthesecondstudyof108MEN1patients492

withNF-pNETs,theimportanceoftumorsize,asitcorrelatedwithmetastasis,washighlighted.5Inbothstudies493

19

(timedependent)confounderswerenottakenintoaccount.Furthermore,althoughbothstudieswerethelargest494

yetavailableMEN1studies,selectionbiascannotberuledout.Basedonthesefindingstheauthorsrecommended495

nottoperformroutinesurgeryforNF-pNETsof<2cm.4,5Giventhepaucityofevidence,currentMEN1clinical496

practiceguidelinesaremoreconservativeandadvisetoconsidersurgeryforNF-pNETs>1cmbasedonthesame497

studies.6Toadjustforknownconfounders,weusedapropensityscoreforthedifferencesbetweenpatients.7,8498

Propensityscoreanalysisisacceptedasavalidalternativewhenarandomizedcontrolledtrialisnotfeasible.9499

ChangingthesurgicalstrategyfromoperatingpatientswithNF-pNETs≥1cmtooperatingpatientswithNF-pNETs≥500

2cmwouldleadtoareductionof59%ofthepancreaticproceduresinourpopulation.Shiftingthecut-offpoint501

from≥2cmto>3cmwouldfurtherreducethenumberofpancreaticsurgicalprocedureswith37%.Indicating502

thatchangingthecut-offpointforsurgicalresectionoftheNF-pNEThasasubstantialimpactontheMEN1503

population.504

BasedontheoutcomesofthisstudyitcanbeconcludedthatMEN1patientswithNF-pNETs<2cmcanbe505

managedbywatchfulwaitingandthegroupofMEN1patientswithNF-pNETs2to3cmrequiresfurtherresearch.506

Basedontheoutcomesofotherstudiesandourstudy,settinguparandomizedcontrolledtrialonsurgical507

resectionofNF-pNETsbetween2and3cmseemsjustifiedatthispoint.Althoughthepropensityscoremethod508

accountsfortheknownconfoundersmeasuredinthestudy,unknownconfounders(residualconfounding)may509

stillhaveoccurred.Arandomizedcontrolledtrialcouldovercometheissueofpotentialresidualconfounding.This510

trialwouldhavetotakeplaceinthecontextofabroadinternationalcollaborationandneedsalong-termfollow-511

up,becauseoftherarityandfairlyindolentcourseofthedisease.Alternatively,awell-designedinternationallarge512

long-termprospectivecohortstudycouldbethesubsequentsteptoinvestigatethesurgicalindicationsforMEN1513

relatedNF-pNETs.Aprospectivecohortstudyiseasiertosetup,comparedtoarandomizedcontrolledtrial.514

Selectionbiasisapotentialdisadvantageofsuchastudysinceitwouldbeimpossibletosetupaprospective515

internationalpopulation-basedcohortstudy.516

Untilawell-designedrandomizedcontrolledtrialisavailable,thedecisiontoproceedtosurgeryinMEN1patients517

withNF-pNETsbetween2-3cmshouldbeabalancebetweentheriskofdiseaseprogressionversustheriskof518

surgery-relatedmorbidity.Wesupposethattheclinician,shouldinformMEN1patientswithNF-pNETsbetween2-519

20

3cmabouttheriskofdevelopmentoflivermetastases,andthedebatableeffectofsurgeryonoverallsurvivaland520

developmentoflivermetastases.Further,tumorsizeandgrowthrateshouldbetakenintoaccountinthedecision521

toproceedtosurgeryinthissubgroupsincelargerandfaster-growingtumorshaveagreaterpotentialto522

metastasizetotheliver.Additionally,theage,overallconditionofthepatient,tumorrelationtothepancreatic523

duct,theriskofpostoperativecomplications,andthepatient’spreferenceshouldbetakenintoaccountwhen524

decidingtooperateMEN1relatedNF-pNETsbetween2-3cm.525

526

WhichMEN1patientgetsaneuroendocrinetumor?527

AnassociationbetweenABObloodtypeandthedevelopmentofcancer,inparticular,pancreaticcancer,was528

recentlyreportedintheliterature.TheadditionofotherprognosticfactorstothecurrentMEN1neuroendocrine529

screeningprogramareimportantbecauseprognosticfactorsforneuroendocrinetumordevelopmentinMEN1530

patientsremainlargelyunknown.IntheAmericanNationalInstituteofHealth(NIH)cohortof105MEN1patients,531

asignificantassociationwasfoundbetweenbloodtypeOandneuroendocrinetumorsofthelung,thymus,532

pancreas,andGItract;therefore,thepossibleadditionofbloodtypecriteriontothecurrentscreeningand533

surveillancepracticesofMEN1patientswasproposed.6534

Inthestudydescribedinchapter3,thepreviousfoundassociationwasvalidatedin200DutchMEN1patients.In535

ourcohorttheoccurrenceofneuroendocrinetumorsofthelung,thymus,pancreas,andgastrointestinaltractwas536

equallydistributedacrossthebloodtypeOandnon-Otypecohorts(Grays’stestforequality;P=0.72).537

Furthermore,wedidn’tfindanassociationbetweenbloodtypeOandtheoccurrenceofmetastaticdiseaseor538

survival.10IntheinitialNIHstudy,noneuroendocrinetumorsinbloodtypeABpatientswerefound,further539

supportingtheassumptionthatbloodtypeOwasassociatedwiththeoccurrenceofneuroendocrinetumors.11540

However,inourpopulation6outof10patientswithbloodtypeABdevelopedaneuroendocrinetumor.541

Differencesinthestudypopulationsmightbeanexplanationforthecontradictoryresults.Intheinitialreport,the542

bloodtypedistributionofthestudiedpopulationwasnotcorrespondingtothegeneralpopulationoftheUnited543

States.11Inourpopulation-basedcohort,therewasnoselectionofaparticularbloodtypesincetheallocationof544

21

bloodtypesdidnotdifferfromthedistributionofthegeneralDutchpopulation.Thisdifferencecouldexplainthe545

contradictoryresults,andunderpinstheessenceofindependentvalidationofscreeningcriteriabeforeusingthem546

indailyclinicalpractice.Basedonourstudy,bloodtypescreeningseemsofnoadditionalvalueforidentifying547

patientsathigherriskforthedevelopmentofneuroendocrinetumorsandmetastaticdiseaseinclinicalpractice.548

ThereforebloodtypeisnoadditionaltoolforMEN1livermetastasesriskstratificationanddoesnotcontributeto549

themaingoalofthisthesis.FurtherresearchshouldfocusonnewfactorsforidentifyingMEN1patientsathigher550

riskforthedevelopmentofneuroendocrinetumorsandmetastaticdisease.551

552

MinimallyinvasivepancreaticsurgerytotreatMEN1relatedpancreaticneuroendocrinetumors.553

MEN1patientsoftenundergomultiplepancreaticoperationsatayoungage,withahighriskofsurgery-related554

morbidity.MinimallyinvasivepancreaticsurgerycouldreducesurgicalmorbidityinMEN1patients,since,555

minimallyinvasivepancreaticsurgeryisassociatedwithashorterhospitalstay,lessbloodloss,andlesspain556

comparedtoopenpancreaticsurgery.12-14Possibleadvantagesanddisadvantagesofrobot-assistedand557

laparoscopicspleen-preservingpancreaticsurgeryremainlargelyunknowninMEN1patients.Inchapter4we558

showedourfirstexperienceofminimallyinvasive,spleen-preserving,pancreaticsurgeryinMEN1patientsand559

comparedtheoutcomesoftechniquesinMEN1patients.AsubstantialpartoftheMEN1patientsunderwent560

minimallyinvasivepancreaticsurgeryintheNetherlandsandNancy,Francebetween1990–2014.Wedemonstrate561

thesafetyandfeasibilityofbothtechniquesinasmallnumberofselectedpatients.Patientswhounderwent562

robot-assistedsurgerydidnotrequireconversiontoopensurgery.563

BenefitsofminimallyinvasivepancreaticMEN1surgerywerealsoobservedinarecentGermanseriescomparing564

21patientswhounderwentopenpancreaticsurgerytopatientswhounderwentlaparoscopically(n=8)orrobot-565

assisted(n=4)surgery.15Thisstudyshowedashorteroperationtime,lessintraoperativebloodlossandshorter566

hospitalstayintheminimallyinvasivetreatedgroup.Surprisinglymorespleenpreservationswereseeninthe567

openlytreatedgroup,afindingthatisinconsistentwithcurrentliteratureonminimallyinvasivepancreatic.14568

Challengesfindingtheprimarytumorwerenotreported.15Pancreasfistulasareamajorcomplicationofminimally569

22

invasivepancreaticsurgery12,13,andseemstobeasignificantcomplicationinMEN1relatedpancreaticsurgery.570

Aminimallyinvasiveapproachcouldpotentiallyleadtoimprovedaccessibilityinthefuture,asignificantadvantage571

forthesepatientswhohaveasubstantialchanceofbeingoperatedagain.16572

AsignificantdisadvantageofminimallyinvasivepancreaticsurgerycomparedtoopensurgeryinMEN1patientsis573

theimpossibilityofdigitalpalpationofthepancreas.Incontrasttopancreaticsurgeryforadenocarcinomasor574

sporadicpNETs,MEN1relatedpNETsaremultipleanddifficulttolocalize.Inourstudy,infourpatientsitwas575

challengingtolocalizetheprimarytumor,andintwopatientstheprimarytumorwasnotresected.Weconsider576

thelackofdigitalpalpationastheprimarycauseforunsuccessfulprocedures.Theprobabilityofnotresectingthe577

primarytumorisessentialtotakeintoaccountwhenplanningminimallyinvasivesurgeryinMEN1patients.The578

useofintraoperativepancreaticultrasound,frozensectionofthespecimen,carefulpostoperativeexaminationof579

thepathologicspecimenandimagingare,therefore,inouropinion,essentialinminimallyinvasiveMEN1surgery580

inclinicalpractice.581

Settingupaprospectivecohortcomparingrobot-assistedspleen-preservingpancreaticsurgerytolaparoscopic582

pancreaticsurgeryinMEN1patientscouldbethenextsteptoevaluatetheeffectofminimallyinvasivepancreatic583

surgeryonshort-termpostoperativecomplications.Datacollectionandcorrectionforpotentialconfounders,such584

astumorsize,locationandtheoverallconditionofthepatient,wouldbeimportantwhensettingupsuchastudy.585

Inconclusion,minimallyinvasivespleen-preservingpancreaticsurgeryinMEN1patientsissafeandfeasible.586

Furtherresearchisneededtoassesswhetherminimallyinvasivepancreaticsurgerycouldreducesurgery-related587

morbidityinMEN1patients.588

589

HowtooperateaMEN1patientwithaninsulinoma?590

About10%-15%ofMEN1patientsdevelopinsulin-producingpNETs.6,17Insulinomasoriginatefrompancreatic591

islets,resultinginanoverproductionofinsulinthatcanleadtosymptomsofhypoglycemia.18Aminorityofthe592

insulinomasmetastasizetotheliver.Inchapter5&6weinvestigatedtheoptimalsurgicalstrategytoreduce593

23

surgery-relatedmorbidityforthisseparateandsymptomaticgroupofMEN1relatedpNETs.Inchapter5we594

reviewedtheliteratureandgaveanoverviewofcurrentstrategiesandevidencefordifferentsurgicalapproaches595

totreatMEN1relatedinsulinomas.WefoundthattheliteratureabouttheextentofpancreaticsurgeryforMEN1596

relatedinsulinomasislimited,andnoparticularprocedureisrecommendedintheMEN1guidelines.6,19To597

provideascientificsurgicaltreatmentguidelineforMEN1patientswithaninsulinomawesetupalarge598

internationalcohortstudy.Theresultsofthisstudyaredescribedinchapter6.Thisstudywasaninternational599

collaborationbetween40hospitalsfromEuropeandsixhospitalsfromNorthAmerica,includingtheMayoClinic,600

MDAnderson,WeillCornellMedicalCenter,theNationalInstitutesofHealth,andtheFrenchEndocrineTumor601

StudyGroup.Thisstudyshowsthatonly7%ofMEN1patientswhounderwentsurgeryforaninsulinomahad602

postoperativehypoglycemia,duetothedevelopmentofdenovoinsulinomasorinsulin-producinglivermetastases603

ratherthanpersistentdisease.Thispercentagewasmuchlowerthanweexpectedtofindbasedoncurrent604

literature.20-23Duetotheabsenceoflong-termcomplicationsandhighrateofsymptomresolution,enucleation605

appearstobethefavorablesurgicalstrategytotreatsolitaryMEN1-relatedinsulinoma.Inpatientswithmultifocal606

disease,distalpancreatectomycombinedwithenucleationoftumorsintheheadofthepancreasispreferable.607

Duetohighdiseaserecurrence,enucleationoftheheadandbody/tailseemsnotrecommendabletotreat608

multifocalpancreaticinsulinomas.609

Thelackofdetailedinformationaboutthediagnostictoolstolocalizetheinsulinomaisadisadvantageofthe610

currentstudy.Settingupaprospectivecohortstudycouldbethenextstepinevaluatingtheoptimalsurgical611

strategyfortreatingMEN1relatedinsulinomas.Thisstudyshouldcollectdetailedinformationonthepreoperative612

diagnosticworkupoftheinsulinoma,tumorlocation,relationtothepancreaticductandtheconsiderationsofthe613

surgeontooptforanenucleationoralargerpancreasresection.614

615

ComplicationsaftersurgeryforMEN1relatednon-functioningpancreaticneuroendocrinetumors616

AlthoughweperformedasmallstudyonminimallyinvasivepancreaticsurgeryinMEN1patients,nolarge617

comprehensiveseriesonsurgicalmorbidityafterMEN1NF-pNETsurgeryexistedwhenwritingthisthesis.Most618

24

MEN1NF-pNETstudiesfocusontheoncologicaloutcomeafterMEN1relatedNF-pNETsurgerywithoutdescribing619

postoperativecomplications.4,5,24Othersdodescribepostoperativecomplicationsbutonlyreportsmalland620

selectedstudypopulations(<20NF-pNETprocedures),emphasizingtherarityofthedisorder.4,25,26621

FewstudiesdescribecomplicationsafterMEN1NF-pNETsurgerybutwereonlyabletorepresentasmallnumbers622

ofpatients.ArecentseriesaboutminimallyinvasiveandopenpancreaticsurgeryinMEN1patientsdescribes33623

pancreaticresectionsforeitherinsulinomas(n=9)orNF-pNETs(n=24).Thisstudyobservedahighnumberof624

pancreaticfistulasaswell.Sixty-threepercentofthepatientsdevelopedanISGPSgradeB/Cpancreaticfistula.The625

highratesofpancreaticfistulaswereexplainedbytheverysofttextureoftheMEN1pancreas.15626

Toimprovecurrentevidenceandtofacilitatethedecision-makingprocessweinvestigatedtheshort-andlong-627

termcomplicationsofsurgicalresectionofMEN1relatedNF-pNETsinchapter7.Wefoundthat33%ofthe628

patientsdevelopedmajorearly-Clavien-DindogradeIII-IV–complications,meaningthat33%ofthepatientsneed629

atleastonesurgicalorradiologicalinterventiontotreatpostoperativecomplications.Mostcomplicationswere630

InternationalStudyGroupofPancreaticSurgerygradeB/Cpancreaticfistulas.Twenty-threepercentofthe631

patients(14/61)developedendo-orexocrinepancreasinsufficiency.Thedevelopmentofmajorearly632

postoperativecomplicationswasindependentoftheNF-pNETtumorsize.Twenty-onepercentofthepatients633

(12/58)developedmultiplemajorearlycomplications,onepatientdied30daysaftersurgeryand2patients634

becamepermanentlydisabled.CurrentfindingsprovideinsightintothecomplicationrateafterMEN1pNET635

surgeryandcould,therefore,supportashareddecision-makingprocesswhenMEN1NF-pNETsurgeryis636

considered.WecouldnotdeterminefromcurrentdataifthehighincidenceoffistulasweredirectlyMEN1related637

oriftheyaresecondarytotheMEN1relatedsoftpancreas.Weexpectedtofindmoreearlycomplicationsin638

operationsforlargertumors(i.e.NF-pNETs>2cm)ormoreextendedoperationssuchasliverresections,butcould639

notidentifysuchfactors.Therelativelylowpowercouldbethereasonwedidnotfindanassociation.Themajor640

earlycomplicationrateappearedhigherinpatientswhounderwentsecondarypancreaticsurgery(45%)andlower641

inpatientswhounderwenttertiarypancreaticsurgery(0%)comparedtoMEN1patientswhounderwentprimary642

pancreaticsurgery(33%).Thesegroupsweretoosmalltocometoreliableconclusionsaboutearlycomplication643

25

ratesaftersecondaryortertiarypancreaticsurgeryinMEN1patients.Fifteenpercentofthepatientsinourcohort644

developednew-onsetdiabetes,and20%developedexocrinepancreaticinsufficiency.645

Thehighrateofmajorshortandlong-termcomplicationsdescribedinchapter7underpinstherecommendation646

tomanageNF-pNETs<2cmbywatchfulwaitingasproposedinchapter2.Inthe2-3cmgroup,cliniciansshouldbe647

reluctanttooperate,sincesurgerydoesnotseemtopreventlivermetastasesnoritimprovesthesurvival648

however,itcouldharmthepatient.InpatientswithNF-pNETs>3cm,surgeryseemsindicated,theclinicianand649

thepatientshould,therefore,beinformedbynumberandkindofpostoperativecomplicationsinpreparationfor650

surgery.Wesupposethatfurtherresearchonthistopicshouldexamineriskfactorsforthedevelopmentofshort-651

andlong-termcomplicationsafterMEN1relatedNF-pNETsurgerytoultimatelyimprovethepostoperativecourse.652

Also,evidenceonhowtodiagnoseandmanagepostoperativepancreaticfistulaislacking.Furtherresearchis653

neededtoevaluatethedetectionandmanagementofpostoperativepancreaticfistulatoreducemajor654

complicationsanddeathafterpancreaticresection.655

Newtechniquessuchasrobot-assistedpancreaticsurgery,theuseofintra-andpostoperativesomatostatin656

treatmentorfurthercentralizationofMEN1relatedpancreaticsurgerycouldpotentiallydecreasethenumberof657

postoperativecomplications.Furtherresearchisneededtotestthesehypotheses.658

659

660

WhichprognosishasaMEN1patientwhodevelopesduodenopancreaticneuroendocrinelivermetastases?661

AreliableprognosisandprognosticfactorsforMEN1patientsdiagnosedwithpancreaticneuroendocrinetumor662

metastasesremainedunknown.Weinvestigated34MEN1patientswithduodenopancreaticneuroendocrine663

tumor(dp-NET)metastasesandaimedtodeterminesurvivalandprognosticfactorsforsurvivalinchapter8.This664

studyshowedaprevalenceof15%dp-NETlivermetastasesinMEN1patients.Althoughprogressionofliver665

metastasesfromDP-NETsinMEN1canbefairlyslow,lifeexpectancyofthisrelativelyyoungpatientgroupis666

clearlyreducedasthe10-yearoverallsurvivalrateisonly50%.Asfarasweknow,thisisthefirststudyshowing667

26

overallsurvivalfromthemomentoflivermetastasesdiagnosisinapopulation-basedstudyofMEN1patients.668

Genderandtumorloadatdiagnosisoflivermetastaseswerepossibleprognosticfactorsforworsesurvival.669

CurrentfindingscouldbeusedinthecounselingprocesswhenanMEN1patientisdiagnosedwithdp-NETliver670

metastases.Prospectiveclinicalstudiesarewarrantedtoseewhethergenderandtumorloadstatusareof671

prognosticvalueinMEN1screeningandsurveillancepractices.TheapparentsurvivalbenefitforMEN1patients672

withasolitarylivermetastasiscomparedtopatientswithmultiplelesionsisalsoanimportantfinding.Thisbenefit673

doesnotseemtobeinfluencedbylocoregionaltreatmentofthesolitarylesion(eithersurgery,radiofrequent674

ablationorembolization),asonlyonepatientunderwentlocoregionaltherapyandsevenothersdidnot.However,675

itisreasonabletoarguethatresectionorotherlocoregionaltherapiesofthesolitarylesionsmightimprovethe676

prognosisofpatientswithsolitarylivermetastases.Insummary,showsChapter8ashortenedsurvivalforMEN1677

patientswithlivermetastases,andunderpinstheimportanceofpreventionoflivermetastases.678

679

680

Conclusions681

WiththisthesisweinvestigatedMEN1pNETlivermetastasesriskstratificationtopreventshortenedsurvival,to682

reducesurgicalmorbidity,andtoultimatelyimprovepersonalizedcancercareforMEN1patientswithapNET.683

Theoutcomesofchapter2indicatethatthemajorityofMEN1patients(ie,thosewithtumors<2cm)cansafelybe684

managedbywatchfulwaiting;herebyavoidingmajorsurgerywithoutincreasingtheriskformetastasesordeath.685

ThepreferredstrategyinMEN1patientswithNF-pNETsrangingfrom2to3cmisdebatable,asthesubgroup686

analysisofthispatientgroupshowedasmallereffectsizecomparedwiththe<2cmsubgroupandanevenlarger687

confidenceinterval.ThesubgroupofpatientswithNF-pNETs>3cmwatchfulwaitingappearstobenot688

recommendableonthebasisoftherelativelyhighnumberofeventsinthisgroup.Basedontheresultsofchapter689

3theadditionofthebloodtypetoscreeningandsurveillancepracticeseemsnottobeofadditionalvaluefor690

27

identifyingMEN1patientsatriskforthedevelopmentofneuroendocrinetumors,metastaticdisease,ora691

shortenedsurvival.692

Inchapter4weintroducedtheutilityofminimallyinvasivepancreaticsurgerytotreatMEN1relatedpNETs,and693

foundthatpatientswhounderwentrobot-assistedsurgerydidnotrequireconversiontoopensurgery.Inchapter694

5&6weinvestigatedtheoptimalsurgicalstrategytoreducesurgery-relatedmorbidityinaseparateand695

symptomaticgroupofMEN1relatedpNETs;insulinomas.WefoundthatMEN1-relatedinsulinomasurgeryismore696

successfulthanpreviouslythought,andinMEN1patientswithasolitaryinsulinoma,enucleationisrecommended,697

ifsurgicallyfeasible.Adistalpancreatectomycombinedwithenucleationofthepancreaticheadlesionsis698

favorableforpatientswithmultipleinsulinomas.699

Surgerycouldalsoharmthepatient.Inchapter7weinvestigatedtheshortandlong-termmorbidityafter700

pancreaticsurgeryforMEN1-relatedNF-pNETsandfoundthatMEN1NF-pNETsurgeryisassociatedwithhighrates701

ofmajorshortandlong-termcomplications.Webelievethatcurrentfindingsshouldbetakenintoaccountinthe702

shareddecision-makingprocesswhenMEN1NF-pNETsurgeryisconsidered.Inchapter8investigatedoverall703

survivalandprognosticfactorsforpatientswithlivermetastases,andfoundthatdespitethefairlyindolentcourse704

ofdp-NETlivermetastasesinMEN1patients,halfofthepopulationwasdeceasedafter10years.Genderand705

tumorloadatdiagnosisoflivermetastasesarepossibleprognosticfactorsforworsesurvival.706

Inconclusion,weimprovedMEN1livermetastasesriskstratification.Theoutcomesofthisthesiscouldpotentially707

reduceprematuredeathandsurgicalmorbidityforMEN1patientswithapNETinthefuture.708

709