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1、Paediatric Brainstem Tumours among brainstem gliomasAtectal gliomaBfocal midbrain tumorCfocal intrinsic pontine gliomaDdorsal/exophytic gliomaEdiffuse intrinsic pontine glioma*Ffocal medullary gliomaGcervicomedullary gliomaA Few Important Distinctions* a form of high grade glioma, akin toanaplastic
2、astrocytoma or glioblastoma multiformeBrainstem GliomasLow grade gliomasLow grade gliomasl lNot common!Not common!l lFocal exophyticFocal exophyticl lCervicomedullary tumoursCervicomedullary tumoursDiffuse Intrinsic Brainstem TumoursDiffuse Intrinsic Brainstem Tumoursl l10-15% of all brain tumours10
3、-15% of all brain tumoursl l25% of the mortality by brain tumour in children25% of the mortality by brain tumour in childrenAtypical brainstem tumoursAtypical brainstem tumoursAtypical brainstem lesionsAtypical brainstem lesionsBrainstem tumours in infantsBrainstem tumours in infantsLow grade glioma
4、 of the brainstemClinical symptomsl lOften long presenting historyOften long presenting historyl lProgressive motor deficit or ataxiaProgressive motor deficit or ataxial lCranial nerve deficits are infrequentCranial nerve deficits are infrequentRadiological characteristicsl lMajority are focal and e
5、xophiticMajority are focal and exophiticl lEnhancing tumoursEnhancing tumoursDiagnosis and management of LGGNeed a biopsy/resectionl lOften pilocyticOften pilocyticl lResult needs to be correlated with the clinical Result needs to be correlated with the clinical and radiological characteristicsand r
6、adiological characteristicsSurgical resection (even incomplete) can lead to sustained remission or cureAugust 2001August 2006October 2014August 2000December 2001Diagnosis and management of LGGPostoperative managementl lEither immediately after surgeryEither immediately after surgeryl lOr at the time
7、 of progressionOr at the time of progressionRadiation or chemotherapy?l lNo clear answerNo clear answerl lRadiation still standard treatmentRadiation still standard treatmentl lChemotherapy works Chemotherapy works December 2001December 2002Low grade glioma of the brainstem: chemotherapy with weekly
8、 vincristine and carboplatinDiagnosis (11/2013)1/2015 (one year of VBL)BRAF V600 mutated tumourThe diffuse intrinsic brainstem tumours15-20% of all paediatric brain tumours15-20% of all paediatric brain tumoursTypical clinical presentationTypical clinical presentationl lShort history (6 Short histor
9、y (6 3 3 1 month) 1 month)l lAt least 2 of the 3 signs/symptomsAt least 2 of the 3 signs/symptoms Cranial nerve deficitCranial nerve deficit Long tracts signsLong tracts signs AtaxiaAtaxial lNot often reported, but nearly always present: Not often reported, but nearly always present: behavioral chan
10、gesbehavioral changes Laughter (night)Laughter (night) School phobiaSchool phobia SadnessSadnessThe diffuse intrinsic brainstem tumoursCranial nerve deficitsCranial nerve deficitsl lOcular motor deficits (CN 6 the most common)Ocular motor deficits (CN 6 the most common)l lFacial weaknessFacial weakn
11、essl lUnilateral deafnessUnilateral deafnessl lSwallowing disordersSwallowing disordersl lNystagmus often presentNystagmus often presentThe diffuse intrinsic brainstem tumoursRadiologyRadiologyl lMore than 50% More than 50% of the ponsof the ponsl lHypodenseHypodensel lLittle/no Little/no enhancemen
12、tenhancementTypical DPGTypical BSG The atypical brainstem tumoursAtypical by clinical presentationAtypical by clinical presentationl lLong history and imaging suggesting diffuse pontine Long history and imaging suggesting diffuse pontine gliomagliomaAtypical by imagingAtypical by imagingl lFocal enh
13、ancing tumour and short symptomsFocal enhancing tumour and short symptomsAtypical by pathologyAtypical by pathologyl lShort symptoms and low grade pathologyShort symptoms and low grade pathologyDiscrepancy symptoms/radiology/pathologyDiscrepancy symptoms/radiology/pathology13 year old10 month histor
14、y of progressive right sided weakness, (R) CN 7 and 8Grade 2 on histolology 17 year old12 month history of dizziness when lying downNo CN deficit, no Long tract sign, no ataxiaThe atypical brainstem tumoursAlways treat as a diffuse intrinsic glioma with upfront focal radiationChemotherapy to discuss
15、 case by caseThe atypical brainstem lesionsNo correlation between clinical and radiological findingDo not treat unless evidence of progression11 year-oldJanuary 20042010 (18 years old)January 20042010Brainstem tumours in babiesNot good (except LGG)Not always gliomas1 day oldPM: PNET1 day oldNo PMLGG
16、 of infancy4 month oldPilocytic AstrocytomaOn chemoHow to distinguish?Clinical contextClinical examRadiologySpectroscopyPathologyDPGLGGFocal HGGDPGLGG2 year-old, 5 months history of ataxia and gaze palsyBiopsy: low grade astrocytoma3 years old, NF110/20127/20133 years old Mild hemiparesisBiopsy: inf
17、iltrative astrocytoma (grade 2)9/201210/2016MALIGNANT GLIOMA OF PONSCANADIAN CASES BY YEARManagement of DIPGRole of surgeryl lNo role has been demonstratedNo role has been demonstrated Does not affect treatmentDoes not affect treatment Does not influence survivalDoes not influence survival Can be mi
18、sleadingCan be misleadingl lRisks are significantRisks are significantl lOngoing discussionsOngoing discussions Biology?Biology?Short symptoms Short symptoms ( 1 month)( 1 month)Classical triadClassical triadl lCranial nerve Cranial nerve deficitsdeficitsl lLong tract Long tract signssignsl lAtaxiaA
19、taxiaNO NEED FOR NO NEED FOR BIOPSY!BIOPSY!TREATMENT TREATMENT SHOULD BE SHOULD BE STARTED ASAP STARTED ASAP (within 48 hours)(within 48 hours)ManagementRadiationl lThe standard treatmentThe standard treatmentl lAims: to improve symptoms (the best Aims: to improve symptoms (the best palliative treat
20、ment)palliative treatment)l lTiming: ASAP + (within 24-48 hours)Timing: ASAP + (within 24-48 hours)l lTechnique: focal, opposed parallel fields, Technique: focal, opposed parallel fields, standard fractionationstandard fractionationl lDose: 54 Gy in 30 fractionsDose: 54 Gy in 30 fractionsDiffuse Pon
21、tine GliomaStandard RT50-54 Gy in 1.8 GyDaily fractionsCurrent trend to move to conformal techniquesManagementRadiationl lRole of other techniques?Role of other techniques?l lHyperfractionation: Hyperfractionation: POG and CCSG experiencePOG and CCSG experience Several studies have been conducted in
22、 the late Several studies have been conducted in the late 80s/early 90s 80s/early 90s Doses up to 84 GyDoses up to 84 Gy No evidence of survival benefitNo evidence of survival benefit Some evidence of increased toxicitySome evidence of increased toxicityHyperfractionation: results of prospective stu
23、diesFreeman et al, POG 9239, IJROBP1999ManagementRadiationl lRole of other techniques?Role of other techniques?l lGamma knife: BSG often listed as one of the Gamma knife: BSG often listed as one of the tumours eligible for gamma knifetumours eligible for gamma knifel lNo series reportedNo series rep
24、ortedl lNo rational for this technique (would cause No rational for this technique (would cause brainstem necrosis)brainstem necrosis)ManagementRadiationl lRole of other techniques?Role of other techniques?l lRadiosensitising agentsRadiosensitising agents Gadolinium texaphyrin: COG phase I ongoing,
25、Gadolinium texaphyrin: COG phase I ongoing, should be completed soon and followed by a should be completed soon and followed by a phase II studyphase II study Topotecan: phase I POG study completed 4 years Topotecan: phase I POG study completed 4 years ago, published in 2003 in Neuro-oncology. Sugge
26、st ago, published in 2003 in Neuro-oncology. Suggest improvement in median survival. Phase II study improvement in median survival. Phase II study plannedplannedHypofractionationLess sessionsLess sessionsHigher dose per fraction (13 or 15 instead of 30)Higher dose per fraction (13 or 15 instead of 3
27、0)Usually offered as a palliative option, in Usually offered as a palliative option, in particular in elderly patientsparticular in elderly patientsHas been suggested and tested in patients with Has been suggested and tested in patients with DIPGDIPGRandomised study published in 2014 (Cairo)Randomis
28、ed study published in 2014 (Cairo)No significant difference with conventional No significant difference with conventional radiationradiationHypofractionaltion 54 Gy in 30 fractions versus 39 Gy in 13 fractionsZhagloul et alRadiotherapy & Oncology 2014ManagementSteroidsl lA major roleA major rolel lA
29、lways the lowest possible dose to limit the Always the lowest possible dose to limit the side effects (quality of life)side effects (quality of life)l lBe careful during the first week (significant Be careful during the first week (significant reactions to the first sessions of radiation)reactions t
30、o the first sessions of radiation)l lWith caution at the time of progressionWith caution at the time of progressionDiffuse brainstem GliomasRole of chemotherapyNumerous studies l lUpfront or at the time of progressionUpfront or at the time of progressionl lSingle agent or combinationsSingle agent or
31、 combinationsResponse rate lowl l0 to 20%0 to 20%l lNo drug or combination seems to have a No drug or combination seems to have a significant activitysignificant activityDiffuse brainstem GliomasRole of chemotherapyOne randomised study l lCCG 943CCG 943l lConducted in the pre-MRI era (all BSG)Conduc
32、ted in the pre-MRI era (all BSG)l lRadiation Radiation + + Chemotherapy (vincristine- Chemotherapy (vincristine-CCNU)CCNU)l lOverall survival 22% at 2 yearsOverall survival 22% at 2 yearsl lNo evidence of benefit with chemotherapyNo evidence of benefit with chemotherapyDiffuse brainstem GliomasRole
33、of chemotherapyOther studiesl lConventional chemotherapyConventional chemotherapy CisplatinCisplatin Carboplatin before and/or during radiationCarboplatin before and/or during radiation Etoposide oralEtoposide orall lHigh dose chemotherapyHigh dose chemotherapy SFOP experience with high dose busulfa
34、n and SFOP experience with high dose busulfan and thiotepa thiotepa Diffuse brainstem Gliomas:Other agentsOther studiesl lInterferon (CCG study)Interferon (CCG study)l lTamoxifen (Brazilian study)Tamoxifen (Brazilian study)l lThalidomide (Boston)Thalidomide (Boston)l lSmall molecules (PBTC)Small mol
35、ecules (PBTC) Imatinib (TK inhibitor)Imatinib (TK inhibitor) Gefitinib (EGFR inhibitor)Gefitinib (EGFR inhibitor) Vandetanib (inhibitor of VEGFR2 & EGFR)Vandetanib (inhibitor of VEGFR2 & EGFR)Correlative studiesUK/French study of erlotinib (EGFR inhibitor)l lBiopsy drivenBiopsy drivenDiffuse brainst
36、em GliomasResultsMedian survivall l8-11 months8-11 monthsl lSurvival at one year Survival at one year 30-40% 30-40%l lSurvival at 2 years 10%Survival at 2 years 10%Progression-free survivall l6-8 months6-8 monthsExamplesExcellent Response to Radiotherapy?Excellent Response to Radiotherapy?PATIENT DI
37、ED AT 11 MONTHS POST DIAGNOSISLONG TERM SURVIVORSClinical HistoryClinical Historyl lFemale 3.5 yrsFemale 3.5 yrsl l3 week Hx 3 week Hx headache headache right sided VI N palsyright sided VI N palsyl lMRI - T2 hyperdense MRI - T2 hyperdense intrinsic pontine gliomaintrinsic pontine gliomal lNo biopsy
38、No biopsyl lRadiotherapy 54GyRadiotherapy 54Gyl lReceived Received ICE ICE chemotherapychemotherapy x 5 x 5l lMRI post radiotherapy MRI post radiotherapy showed some showed some improvementimprovement6 months post diagnosis recurrence of symptoms6 months post diagnosis recurrence of symptomsl lNo fu
39、rther conventional therapy/ -alternative healerNo further conventional therapy/ -alternative healerl lNo further MRI- refused, but clinical follow upNo further MRI- refused, but clinical follow upAlive age 18 yrsAlive age 18 yrsl lNormal stature 50Normal stature 50thth centile, premature puberty cen
40、tile, premature pubertyl lNeuro-psychometric testing. Difficulties in:Neuro-psychometric testing. Difficulties in: Verbal processing, language acquisition Verbal processing, language acquisition Attention poorAttention poorAge at Diagnosis(MONTHS)SexNeurological Signs at PresentationInterval Between
41、 Onset of Symptoms and Diagnosis(Weeks)Initial TreatmentSurvival (Years)Cranial Nerve PalsyPyramidal DeficitsCerebellar Signs20MaleYesYesYes24 RT +Temozolomide+522MaleYesYesNo12-24 RT+4CLINICAL CHARACTERISTICS, TREATMENT AND OUTCOME OF SURVIVING PATIENTSMRI IMAGING OF LONG TERM SURVIVORSAre they tru
42、e DIPG?Are they true DIPG?October 2011January 2012January 2017Long term survivorDiffuse brainstem GliomasNorth American studiesFew studies openFuture studiesBrainstem GliomasRecently closedl l ACNS 0927:ACNS 0927: phase II study of SAHA (vorinostat) during phase II study of SAHA (vorinostat) during
43、and after radiationand after radiationOpenl lADVL 1217 ADVL 1217 (A phase I study of MK-1775 concurrent with (A phase I study of MK-1775 concurrent with local radiation therapy for the treatment of newly diagnosed local radiation therapy for the treatment of newly diagnosed children with diffuse int
44、rinsic pontine gliomas (DIPG)children with diffuse intrinsic pontine gliomas (DIPG)Soon?l lArsenic trioxyde Arsenic trioxyde (antivascular effect, radiosensitizer)(antivascular effect, radiosensitizer)Brainstem Gliomas PBTC studies: PBTC studies: PARP inhibitor + Temozolomide + radiation PARP inhibi
45、tor + Temozolomide + radiation (closed for futility)(closed for futility)Pembrolizumab (closed for toxicity)Pembrolizumab (closed for toxicity)Panabinostat (HDAC inhibitor) currently Panabinostat (HDAC inhibitor) currently recruitingrecruitingBiospy for DIPG: Why? How?Frame-basedFrame-basedFrame les
46、sFrame lessl lNo indication for DIPGNo indication for DIPGHow is it done?LimitationsNo direct benefit for the patient yetNo direct benefit for the patient yetl lClear explanation & Parents informed consentClear explanation & Parents informed consentRisk of neurological deteriorationRisk of neurologi
47、cal deteriorationSmall & few samplesSmall & few samplesNecker series65 stereotactic biopsies of DIPG65 stereotactic biopsies of DIPG4 patients refused 4 patients refused Number of samples increased with time (up to 8)Number of samples increased with time (up to 8)l lHistological diagHistological dia
48、gl lFrozen samplesFrozen samplesl lStem cell culturesStem cell culturesNo mortalityNo mortalityNo permanent morbidityNo permanent morbidity3 transient morbidity (facial nerve palsy associated with increased 3 transient morbidity (facial nerve palsy associated with increased motor deficit in 1 case)m
49、otor deficit in 1 case)2 tumoral dissemination along the trajectory2 tumoral dissemination along the trajectoryBiopsyCohort 1 MGMT- EGFR-Cohort 2 MGMT- EGFR+Cohort 3 MGMT+ EGFR-Cohort 4 MGMT+EGFR+RT BevacizumabRTBevacizumab ErlotinibRTBevacizumabTemozolomideRTBevacizumab ErlotinibTemozolomide4 Weeks
50、 Bevacizumab4 Weeks Bevacizumab Erlotinib4 Weeks Bevacizumab4 Weeks Bevacizumab ErlotinibMaintenance BevacizumabMaintenance Bevacizumab ErlotinibMaintenanceBevacizumab TemozolomideMaintenance Bevacizumab ErlotinibTemozolomideMRI Diagnosis DIPGTREATMENT SCHEMAEnrollmentTissue AnalysesBoston/UCSF prot
51、ocolConvection delivery (Lonser (Lonser J Child Neurol 2008)J Child Neurol 2008) Brainstem gliomal lPatient 3-year, 10-month-old femalePatient 3-year, 10-month-old female HistoryHistoryl lDiagnosed (May 2005) Diagnosed (May 2005) Headaches and fallingHeadaches and fallingl lRadiation therapy (June 2
52、005)Radiation therapy (June 2005)l lChemotherapy (January 2006)Chemotherapy (January 2006)l lMR-imaging evidence of progression (January 2006)MR-imaging evidence of progression (January 2006) ExaminationExaminationl lLeft facial nerve weaknessLeft facial nerve weaknessl lDisconjugate gazeDisconjugat
53、e gaze Weakness bilateral 6th nerves (left greater than right)Weakness bilateral 6th nerves (left greater than right)l lGait discoordinationGait discoordinationConvective deliveryBrainstem glioma Perfuse the hypointense region of tumorPerfuse the hypointense region of tumorl lIL13-PE (0.125 mcg/ml)I
54、L13-PE (0.125 mcg/ml)l lGadolinium-DTPA (1 mM)Gadolinium-DTPA (1 mM) Intraoperative MR-imagingIntraoperative MR-imagingl lT1 and FLAIR-imagingT1 and FLAIR-imagingConvective deliveryBrainstem gliomal lResultsResults Intraoperative MR-imagingIntraoperative MR-imagingl lRate of infusion of 0.5 to 5 mic
55、roliters/minuteRate of infusion of 0.5 to 5 microliters/minutel lPerfusion of 1.4 mlPerfusion of 1.4 mlConvective deliveryBrainstem gliomal lResultsResultsDec 2013Oct 201330 Gy in 17 sessions Oct 2012: 54 Gy in 30 sessions DIPG STUDYCollecting post-mortem tumor and matched normal brain samples from
56、DIPG patientsl lLinked to DIPG clinical trial at SickKids Drs. Linked to DIPG clinical trial at SickKids Drs. Bouffet and BartelsBouffet and BartelsPerforming high-resolution DNA microarray analysis (whole-genome single nucleotide polymorphism arrays (Affymetrix 500K and 6.0)DIPGsHGAs135791124681013
57、15171921X12141618202213579111315171921X246810121416182022DIPGs are genetically distinct from supratentorial high grade astrocytomasDIPGHGA12345678910111234567891011Chromosome 14Chromosome 17p13p12q12p12q12q22p13p12q12p12q12q22DIPGs are genetically distinct from supratentorial high grade astrocytomas
58、RESULTSSpecific GenesTP53TP53l lOne copy deleted in 7 of 11 DIPGs One copy deleted in 7 of 11 DIPGs l lTP53TP53 mutations present in 6/6 DIPGs tested mutations present in 6/6 DIPGs testedEGFREGFRl lNot amplified in any case, gained in one Not amplified in any case, gained in one l lProtein strongly
59、expressed in 3 tumors, weak in a Protein strongly expressed in 3 tumors, weak in a further 4further 4l l? therapeutic target? therapeutic targetRESULTSSpecific GenesMGMTl lOne copy deleted in 2 tumorsOne copy deleted in 2 tumorsl lProtein not expressed in any caseProtein not expressed in any casel l
60、?Methylation status ?Methylation status PTENl lHemizygous loss of 10q, including Hemizygous loss of 10q, including PTENPTEN, in 2 , in 2 tumorstumorsRESULTSSpecific GenesPDGFRAGained in 4/11 DIPGs FISHQ-PCRRESULTSSpecific Genes PARP-1l lGained in 3 casesGained in 3 casesl lProtein expressed in 6 cas
61、es Protein expressed in 6 cases PARPRESULTSSpecific Genes PARP-1l lPARP-1PARP-1 encodes a chromatin-associated encodes a chromatin-associated enzyme which modifies nuclear proteins and enzyme which modifies nuclear proteins and is involved in the regulation of differentiation, is involved in the reg
62、ulation of differentiation, proliferation, tumor transformation and proliferation, tumor transformation and recovery of cells from DNA damagerecovery of cells from DNA damagel lPARP inhibitors have been shown to induce PARP inhibitors have been shown to induce growth inhibition in malignant glioma c
63、ellsgrowth inhibition in malignant glioma cellsRESULTSSpecific Genes PARP-1PARP possible therapeutic target for a subset of pediatric DIPGs? Aurora KinaseACVR1 (FOP: fibrodysplasia ossifians progressive)Other GenesPediatric High Grade Astrocytoma and Histone MutationsMeH3F3A l lreplication-independe
64、nt replication-independent histonehistonel ltwo critical positions within two critical positions within the histone tail -K27M, the histone tail -K27M, G34RG34RHIST1H3B/Cl lReplication-dependent Replication-dependent histonehistonel lK27M onlyK27M onlyLocation and frequency of Histone 3 mutations in
65、 pediatric HGGH3K27M is a midline diseaseH3K27M is a midline diseaseH3G34R/V is a hemispheric diseaseH3G34R/V is a hemispheric diseaseHemisphericThalamicPontine (DIPG)20%H3.3K27MH3.3G34R/V65%50%15%H3.1K27M50%Spinal cordCONCLUSIONSPediatric DIPGs are one of the main causes of Pediatric DIPGs are one
66、of the main causes of brain tumor death in childrenbrain tumor death in childrenAfter decades of clinical trials, largely based on After decades of clinical trials, largely based on protocols for adult brain tumors, no effective protocols for adult brain tumors, no effective treatment has yet been f
67、oundtreatment has yet been foundOngoing studies are now based on the results of Ongoing studies are now based on the results of genomic studies that have identified potential genomic studies that have identified potential target.target.Still radiation is the mainstay of treatment and Still radiation is the mainstay of treatment and re-irradiations offer benefit in some childrenre-irradiations offer benefit in some children
