多倫多病童醫(yī)院腦干膠質(zhì)瘤

PaediatricBrainstemTumours

精選課件精選課件amongbrainstemgliomasA tectalgliomaB focalmidbraintumorC focalintrinsicpontinegliomaD dorsal/exophyticgliomaE diffuseintrinsicpontineglioma*F focalmedullarygliomaG cervicomedullarygliomaAFewImportantDistinctions*aformofhighgradeglioma,akintoanaplasticastrocytomaorglioblastomamultiforme精選課件BrainstemGliomasLowgradegliomasNotcommon!FocalexophyticCervicomedullarytumoursDiffuseIntrinsicBrainstemTumours10-15%ofallbraintumours25%ofthemortalitybybraintumourinchildrenAtypicalbrainstemtumoursAtypicalbrainstemlesionsBrainstemtumoursininfants精選課件LowgradegliomaofthebrainstemClinicalsymptomsOftenlongpresentinghistoryProgressivemotordeficitorataxiaCranialnervedeficitsareinfrequentRadiologicalcharacteristicsMajorityarefocalandexophiticEnhancingtumours精選課件精選課件精選課件DiagnosisandmanagementofLGGNeedabiopsy/resectionOftenpilocyticResultneedstobecorrelatedwiththeclinicalandradiologicalcharacteristicsSurgicalresection(evenincomplete)canleadtosustainedremissionorcure精選課件August2001August2006October2014精選課件August2000December2001精選課件DiagnosisandmanagementofLGGPostoperativemanagementEitherimmediatelyaftersurgeryOratthetimeofprogressionRadiationorchemotherapy?NoclearanswerRadiationstillstandardtreatmentChemotherapyworks精選課件December2001December2002Lowgradegliomaofthebrainstem:chemotherapywithweeklyvincristineandcarboplatin精選課件Diagnosis(11/2013)1/2015(oneyearofVBL))BRAFV600mutatedtumour精選課件Thediffuseintrinsicbrainstemtumours15-20%ofallpaediatricbraintumoursTypicalclinicalpresentationShorthistory(631month)Atleast2ofthe3signs/symptomsCranialnervedeficitLongtractssignsAtaxiaNotoftenreported,butnearlyalwayspresent:behavioralchangesLaughter(night)SchoolphobiaSadness精選課件ThediffuseintrinsicbrainstemtumoursCranialnervedeficitsOcularmotordeficits(CN6themostcommon)FacialweaknessUnilateraldeafnessSwallowingdisordersNystagmusoftenpresent精選課件ThediffuseintrinsicbrainstemtumoursRadiologyMorethan50%oftheponsHypodenseLittle/noenhancement精選課件TypicalDPG精選課件TypicalBSG精選課件TheatypicalbrainstemtumoursAtypicalbyclinicalpresentationLonghistoryandimagingsuggestingdiffusepontinegliomaAtypicalbyimagingFocalenhancingtumourandshortsymptomsAtypicalbypathologyShortsymptomsandlowgradepathologyDiscrepancysymptoms/radiology/pathology精選課件13yearold10monthhistoryofprogressiverightsidedweakness,(R)CN7and8Grade2onhistolology精選課件17yearold12monthhistoryofdizzinesswhenlyingdownNoCNdeficit,noLongtractsign,noataxia精選課件精選課件TheatypicalbrainstemtumoursAlwaystreatasadiffuseintrinsicgliomawithupfrontfocalradiationChemotherapytodiscusscasebycase精選課件TheatypicalbrainstemlesionsNocorrelationbetweenclinicalandradiologicalfindingDonottreatunlessevidenceofprogression精選課件11year-oldJanuary20042010(18yearsold)精選課件January20042010精選課件精選課件BrainstemtumoursinbabiesNotgood(exceptLGG)Notalwaysgliomas精選課件1dayoldPM:PNET1dayoldNoPM精選課件LGGofinfancy4montholdPilocyticAstrocytomaOnchemo精選課件Howtodistinguish?ClinicalcontextClinicalexamRadiologySpectroscopyPathology精選課件DPGLGG精選課件FocalHGGDPGLGG精選課件2?year-old,5monthshistoryofataxiaandgazepalsyBiopsy:lowgradeastrocytoma精選課件3yearsold,NF110/20127/2013精選課件3yearsold–MildhemiparesisBiopsy:infiltrativeastrocytoma(grade2)9/201210/2016精選課件MALIGNANTGLIOMAOFPONSCANADIANCASESBYYEAR精選課件ManagementofDIPGRoleofsurgeryNorolehasbeendemonstratedDoesnotaffecttreatmentDoesnotinfluencesurvivalCanbemisleadingRisksaresignificantOngoingdiscussionsBiology?精選課件Shortsymptoms(<1month)ClassicaltriadCranialnervedeficitsLongtractsignsAtaxiaNONEEDFORBIOPSY!TREATMENTSHOULDBESTARTEDASAP(within48hours)精選課件ManagementRadiationThestandardtreatmentAims:toimprovesymptoms(thebestpalliativetreatment)Timing:ASAP+++(within24-48hours)Technique:focal,opposedparallelfields,standardfractionationDose:54Gyin30fractions精選課件DiffusePontineGlioma‘Standard’RT50-54Gyin1.8GyDailyfractionsCurrenttrendtomovetoconformaltechniques精選課件ManagementRadiationRoleofothertechniques?Hyperfractionation:POGandCCSGexperienceSeveralstudieshavebeenconductedinthelate80s/early90sDosesupto84GyNoevidenceofsurvivalbenefitSomeevidenceofincreasedtoxicity精選課件Hyperfractionation:resultsofprospectivestudies精選課件Freemanetal,POG9239,IJROBP1999精選課件ManagementRadiationRoleofothertechniques?Gammaknife:BSGoftenlistedasoneofthetumourseligibleforgammaknifeNoseriesreportedNorationalforthistechnique(wouldcausebrainstemnecrosis)精選課件ManagementRadiationRoleofothertechniques?RadiosensitisingagentsGadoliniumtexaphyrin:COGphaseIongoing,shouldbecompletedsoonandfollowedbyaphaseIIstudyTopotecan:phaseIPOGstudycompleted4yearsago,publishedin2003inNeuro-oncology.Suggestimprovementinmediansurvival.PhaseIIstudyplanned精選課件HypofractionationLesssessionsHigherdoseperfraction(13or15insteadof30)Usuallyofferedasapalliativeoption,inparticularinelderlypatientsHasbeensuggestedandtestedinpatientswithDIPGRandomisedstudypublishedin2014(Cairo)Nosignificantdifferencewithconventionalradiation精選課件Hypofractionaltion54Gyin30fractionsversus39Gyin13fractionsZhaglouletalRadiotherapy&Oncology2014精選課件精選課件ManagementSteroidsAmajorroleAlwaysthelowestpossibledosetolimitthesideeffects(qualityoflife)Becarefulduringthefirstweek(significantreactionstothefirstsessionsofradiation)Withcautionatthetimeofprogression精選課件DiffusebrainstemGliomas

RoleofchemotherapyNumerousstudiesUpfrontoratthetimeofprogressionSingleagentorcombinationsResponseratelow0to20%Nodrugorcombinationseemstohaveasignificantactivity精選課件DiffusebrainstemGliomas

RoleofchemotherapyOnerandomisedstudyCCG943Conductedinthepre-MRIera(allBSG)Radiation+Chemotherapy(vincristine-CCNU)Overallsurvival22%at2yearsNoevidenceofbenefitwithchemotherapy精選課件DiffusebrainstemGliomas

RoleofchemotherapyOtherstudiesConventionalchemotherapyCisplatinCarboplatinbeforeand/orduringradiationEtoposideoralHighdosechemotherapySFOPexperiencewithhighdosebusulfanandthiotepa精選課件DiffusebrainstemGliomas:

OtheragentsOtherstudiesInterferon(CCGstudy)Tamoxifen(Brazilianstudy)Thalidomide(Boston)Smallmolecules(PBTC)Imatinib(TKinhibitor)Gefitinib(EGFRinhibitor)Vandetanib(inhibitorofVEGFR2&EGFR)精選課件CorrelativestudiesUK/Frenchstudyoferlotinib(EGFRinhibitor)Biopsydriven精選課件DiffusebrainstemGliomas

ResultsMediansurvival8-11monthsSurvivalatoneyear~30-40%Survivalat2years~10%Progression-freesurvival6-8months精選課件ExamplesExcellentResponsetoRadiotherapy?PATIENTDIEDAT11MONTHSPOSTDIAGNOSIS精選課件LONGTERMSURVIVORSClinicalHistoryFemale3.5yrs3weekHx↑headacherightsidedVINpalsyMRI-T2hyperdenseintrinsicpontinegliomaNobiopsyRadiotherapy54GyReceivedICEchemotherapyx5MRIpostradiotherapyshowedsomeimprovement6monthspostdiagnosisrecurrenceofsymptomsNofurtherconventionaltherapy/-alternativehealerNofurtherMRI-refused,butclinicalfollowupAliveage18yrsNormalstature50thcentile,prematurepubertyNeuro-psychometrictesting.Difficultiesin:Verbalprocessing,languageacquisitionAttentionpoor精選課件AgeatDiagnosis(MONTHS)SexNeurologicalSignsatPresentationIntervalBetweenOnsetofSymptomsandDiagnosis(Weeks)InitialTreatmentSurvival(Years)CranialNervePalsyPyramidalDeficitsCerebellarSigns20MaleYesYesYes<6RT+99703+866FemaleYesNoYes>24RT+Temozolomide+522MaleYesYesNo>12-24RT+4CLINICALCHARACTERISTICS,TREATMENTANDOUTCOMEOFSURVIVINGPATIENTS精選課件MRIIMAGINGOFLONGTERMSURVIVORS精選課件AretheytrueDIPG?精選課件精選課件AretheytrueDIPG?精選課件October2011January2012January2017Longtermsurvivor精選課件DiffusebrainstemGliomas

NorthAmericanstudiesFewstudiesopenFuturestudies精選課件BrainstemGliomasRecentlyclosed

ACNS0927:

phaseIIstudyofSAHA(vorinostat)duringandafterradiationOpenADVL1217(AphaseIstudyofMK-1775concurrentwithlocalradiationtherapyforthetreatmentofnewlydiagnosedchildrenwithdiffuseintrinsicpontinegliomas(DIPG))Soon?Arsenictrioxyde(antivasculareffect,radiosensitizer)精選課件BrainstemGliomasPBTCstudies:PARPinhibitor+Temozolomide+radiation(closedforfutility)Pembrolizumab(closedfortoxicity)Panabinostat(HDACinhibitor)currentlyrecruiting精選課件BiospyforDIPG:Why?How?Frame-basedFramelessNoindicationforDIPG精選課件Howisitdone?精選課件精選課件精選課件精選課件精選課件LimitationsNodirectbenefitforthepatientyetClearexplanation&ParentsinformedconsentRiskofneurologicaldeteriorationSmall&fewsamples精選課件Neckerseries65stereotacticbiopsiesofDIPG4patientsrefusedNumberofsamplesincreasedwithtime(upto8)HistologicaldiagFrozensamplesStemcellculturesNomortalityNopermanentmorbidity3transientmorbidity(facialnervepalsyassociatedwithincreasedmotordeficitin1case)2tumoraldisseminationalongthetrajectory精選課件BiopsyCohort1MGMT-

EGFR-Cohort2MGMT-

EGFR+Cohort3MGMT+

EGFR-Cohort4MGMT+EGFR+RTBevacizumabRTBevacizumab

ErlotinibRTBevacizumabTemozolomideRTBevacizumab

ErlotinibTemozolomide4WeeksBevacizumab4WeeksBevacizumab

Erlotinib4WeeksBevacizumab4WeeksBevacizumab

ErlotinibMaintenanceBevacizumabMaintenanceBevacizumab

ErlotinibMaintenanceBevacizumab

TemozolomideMaintenanceBevacizumab

ErlotinibTemozolomideMRIDiagnosisDIPGTREATMENTSCHEMAEnrollmentTissueAnalysesBoston/UCSFprotocol精選課件Convectiondelivery

(LonserJChildNeurol2008)

BrainstemgliomaPatient3-year,10-month-oldfemaleHistoryDiagnosed(May2005)HeadachesandfallingRadiationtherapy(June2005)Chemotherapy(January2006)MR-imagingevidenceofprogression(January2006)ExaminationLeftfacialnerveweaknessDisconjugategazeWeaknessbilateral6thnerves(leftgreaterthanright)Gaitdiscoordination精選課件ConvectivedeliveryBrainstemgliomaPerfusethehypointenseregionoftumorIL13-PE(0.125mcg/ml)Gadolinium-DTPA(1mM)IntraoperativeMR-imagingT1andFLAIR-imaging精選課件ConvectivedeliveryBrainstemgliomaResultsIntraoperativeMR-imagingRateofinfusionof0.5to5microliters/minutePerfusionof1.4ml精選課件ConvectivedeliveryBrainstemglioma Results精選課件精選課件精選課件Dec2013Oct201330Gyin17sessionsOct2012:54Gyin30sessions精選課件精選課件DIPGSTUDYCollectingpost-mortemtumorandmatchednormalbrainsamplesfromDIPGpatientsLinkedtoDIPGclinicaltrialatSickKids–Drs.BouffetandBartelsPerforminghigh-resolutionDNAmicroarrayanalysis(whole-genomesinglenucleotidepolymorphismarrays(Affymetrix500Kand6.0))精選課件精選課件DIPGsHGAs13579112468101315171921X12141618202213579111315171921X246810121416182022DIPGsaregeneticallydistinctfromsupratentorialhighgradeastrocytomas精選課件DIPGHGA12345678910111234567891011Chromosome14Chromosome17p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3DIPGsaregeneticallydistinctfromsupratentorialhighgradeastrocytomas精選課件RESULTS

SpecificGenesTP53Onecopydeletedin7of11DIPGsTP53mutationspresentin6/6DIPGstestedEGFRNotamplifiedinanycase,gainedinoneProteinstronglyexpressedin3tumors,weakinafurther4?therapeutictarget精選課件RESULTS

SpecificGenesMGMTOnecopydeletedin2tumorsProteinnotexpressedinanycase?MethylationstatusPTENHemizygouslossof10q,includingPTEN,in2tumors精選課件RESULTS

SpecificGenesPDGFRAGainedin4/11DIPGsFISHQ-PCR精選課件RESULTS

SpecificGenes–PARP-1Gainedin3casesProteinexp