多伦多病童医院脑干胶质瘤课件

Paediatric Brainstem Paediatric Brainstem TumoursTumours among brainstem gliomas Atectal glioma Bfocal midbrain tumor Cfocal intrinsic pontine glioma Ddorsal/exophytic glioma Ediffuse intrinsic pontine glioma* Ffocal medullary glioma Gcervicomedullary glioma A Few Important Distinctions * a form of high grade glioma, akin to anaplastic astrocytoma or glioblastoma multiforme Brainstem GliomasBrainstem Gliomas Low grade gliomasLow grade gliomas l l Not common!Not common! l l Focal exophyticFocal exophytic l l Cervicomedullary tumoursCervicomedullary tumours Diffuse Intrinsic Brainstem TumoursDiffuse Intrinsic Brainstem Tumours l l 10-15% of all brain tumours10-15% of all brain tumours l l 25% of the mortality by brain tumour in children25% of the mortality by brain tumour in children Atypical brainstem tumoursAtypical brainstem tumours Atypical brainstem lesionsAtypical brainstem lesions Brainstem tumours in infantsBrainstem tumours in infants Low grade glioma of the brainstemLow grade glioma of the brainstem Clinical symptomsClinical symptoms l l Often long presenting historyOften long presenting history l l Progressive motor deficit or ataxiaProgressive motor deficit or ataxia l l Cranial nerve deficits are infrequentCranial nerve deficits are infrequent Radiological characteristicsRadiological characteristics l l Majority are focal and exophiticMajority are focal and exophitic l l Enhancing tumoursEnhancing tumours Diagnosis and management of Diagnosis and management of LGGLGG Need a biopsy/resectionNeed a biopsy/resection l l Often pilocyticOften pilocytic l l Result needs to be correlated with the clinical Result needs to be correlated with the clinical and radiological characteristicsand radiological characteristics Surgical resection (even incomplete) can Surgical resection (even incomplete) can lead to sustained remission or curelead to sustained remission or cure August 2001 August 2006 October 2014 August 2000 December 2001 Diagnosis and management of Diagnosis and management of LGGLGG Postoperative managementPostoperative management l l Either immediately after surgeryEither immediately after surgery l l Or at the time of progressionOr at the time of progression Radiation or chemotherapy?Radiation or chemotherapy? l l No clear answerNo clear answer l l Radiation still standard treatmentRadiation still standard treatment l l Chemotherapy works Chemotherapy works December 2001December 2002 Low grade glioma of the brainstem: chemotherapy with weekly vincristine and carboplatin Diagnosis (11/2013) 1/2015 (one year of VBL) BRAF V600 mutated tumour The diffuse intrinsic brainstem The diffuse intrinsic brainstem tumourstumours 15-20% of all paediatric brain tumours15-20% of all paediatric brain tumours Typical clinical presentationTypical clinical presentation l l Short history (6 Short history (6 3 3 1 month) 1 month) l l At least 2 of the 3 signs/symptomsAt least 2 of the 3 signs/symptoms Cranial nerve deficitCranial nerve deficit Long tracts signsLong tracts signs AtaxiaAtaxia l l Not often reported, but nearly always present: Not often reported, but nearly always present: behavioral changesbehavioral changes Laughter (night)Laughter (night) School phobiaSchool phobia SadnessSadness The diffuse intrinsic brainstem The diffuse intrinsic brainstem tumourstumours Cranial nerve deficitsCranial nerve deficits l l Ocular motor deficits (CN 6 the most common)Ocular motor deficits (CN 6 the most common) l l Facial weaknessFacial weakness l l Unilateral deafnessUnilateral deafness l l Swallowing disordersSwallowing disorders l l Nystagmus often presentNystagmus often present The diffuse intrinsic brainstem The diffuse intrinsic brainstem tumourstumours RadiologyRadiology l l More than 50% More than 50% of the ponsof the pons l l HypodenseHypodense l l Little/no Little/no enhancementenhancement Typical DPG Typical BSG The atypical brainstem tumoursThe atypical brainstem tumours Atypical by clinical presentationAtypical by clinical presentation l l Long history and imaging suggesting diffuse pontine Long history and imaging suggesting diffuse pontine gliomaglioma Atypical by imagingAtypical by imaging l l Focal enhancing tumour and short symptomsFocal enhancing tumour and short symptoms Atypical by pathologyAtypical by pathology l l Short symptoms and low grade pathologyShort symptoms and low grade pathology Discrepancy symptoms/radiology/pathologyDiscrepancy symptoms/radiology/pathology 13 year old 10 month history of progressive right sided weakness, (R) CN 7 and 8 Grade 2 on histolology 17 year old 12 month history of dizziness when lying down No CN deficit, no Long tract sign, no ataxia The atypical brainstem tumoursThe atypical brainstem tumours Always treat as a diffuse intrinsic glioma Always treat as a diffuse intrinsic glioma with upfront focal radiationwith upfront focal radiation Chemotherapy to discuss case by caseChemotherapy to discuss case by case The atypical brainstem lesionsThe atypical brainstem lesions No correlation between clinical and No correlation between clinical and radiological findingradiological finding Do not treat unless evidence of Do not treat unless evidence of progressionprogression 11 year-old January 2004 2010 (18 years old) January 2004 2010 Brainstem tumours in babiesBrainstem tumours in babies Not good (except LGG)Not good (except LGG) Not always gliomasNot always gliomas 1 day old PM: PNET 1 day old No PM LGG of infancyLGG of infancy 4 month old Pilocytic Astrocytoma On chemo How to distinguish?How to distinguish? Clinical contextClinical context Clinical examClinical exam RadiologyRadiology SpectroscopySpectroscopy PathologyPathology DPG LGG Focal HGG DPG LGG 2 year-old, 5 months history of ataxia and gaze palsy Biopsy: low grade astrocytoma 3 years old, NF1 10/2012 7/2013 3 years old Mild hemiparesis Biopsy: infiltrative astrocytoma (grade 2) 9/2012 10/2016 MALIGNANT GLIOMA OF PONS CANADIAN CASES BY YEAR Management of DIPGManagement of DIPG Role of surgeryRole of surgery l l No role has been demonstratedNo role has been demonstrated Does not affect treatmentDoes not affect treatment Does not influence survivalDoes not influence survival Can be misleadingCan be misleading l l Risks are significantRisks are significant l l Ongoing discussionsOngoing discussions Biology?Biology? Short symptoms Short symptoms (24 RT + Temozolomide +5 22MaleYesYesNo12-24 RT+4 CLINICAL CHARACTERISTICS, TREATMENT AND OUTCOME OF SURVIVING PATIENTS MRI IMAGING OF LONG TERM SURVIVORS Are they true DIPG?Are they true DIPG? Are they true DIPG?Are they true DIPG? October 2011 January 2012January 2017 Long term survivor Diffuse brainstem GliomasDiffuse brainstem Gliomas North American studiesNorth American studies Few studies openFew studies open Future studiesFuture studies Brainstem GliomasBrainstem Gliomas Recently closedRecently closed l l ACNSACNS 0927: 0927: phase II study of phase II study of SAHASAHA ( (vorinostatvorinostat) during ) during and after radiationand after radiation OpenOpen l l ADVLADVL 1217 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 intrinsic children with diffuse intrinsic pontinepontine gliomas (DIPG) gliomas (DIPG) Soon?Soon? l l Arsenic Arsenic trioxydetrioxyde ( (antivascularantivascular effect, effect, radiosensitizerradiosensitizer) ) Brainstem GliomasBrainstem Gliomas PBTCPBTC studies: studies: PARP inhibitor + Temozolomide + radiation PARP inhibitor + Temozolomide + radiation (closed for futility)(closed for futility) PembrolizumabPembrolizumab (closed for toxicity) (closed for toxicity) PanabinostatPanabinostat (HDAC inhibitor) currently (HDAC inhibitor) currently recruitingrecruiting Biospy for DIPG: Why? How?Biospy for DIPG: Why? How? Frame-basedFrame-based Frame lessFrame less l l No indication for DIPGNo indication for DIPG How is it done?How is it done? LimitationsLimitations No direct benefit for the patient yetNo direct benefit for the patient yet l l Clear explanation & Parents informed consentClear explanation & Parents informed consent Risk of neurological deteriorationRisk of neurological deterioration Small & few samplesSmall & few samples Necker seriesNecker series 65 stereotactic biopsies of DIPG65 stereotactic biopsies of DIPG 4 patients refused 4 patients refused Number of samples increased with time (up to 8)Number of samples increased with time (up to 8) l l Histological diagHistological diag l l Frozen samplesFrozen samples l l Stem cell culturesStem cell cultures No mortalityNo mortality No permanent morbidityNo permanent morbidity 3 transient morbidity (facial nerve palsy associated with increased 3 transient morbidity (facial nerve palsy associated with increased motor deficit in 1 case)motor deficit in 1 case) 2 tumoral dissemination along the trajectory2 tumoral dissemination along the trajectory Biopsy Cohort 1 MGMT- EGFR- Cohort 2 MGMT- EGFR+ Cohort 3 MGMT+ EGFR- Cohort 4 MGMT+ EGFR+ RT Bevacizuma b RT Bevacizumab Erlotinib RT Bevacizumab Temozolomide RT Bevacizumab Erlotinib Temozolomid e 4 Weeks Bevacizumab 4 Weeks Bevacizumab Erlotinib 4 Weeks Bevacizumab 4 Weeks Bevacizumab Erlotinib Maintenance Bevacizumab Maintenance Bevacizumab Erlotinib Maintenance Bevacizumab Temozolomide Maintenance Bevacizumab Erlotinib Temozolomide MRI Diagnosis DIPG TREATMENT SCHEMA Enrollment Tissue Analyses Boston/UCSF protocol Convection delivery Convection delivery (Lonser (Lonser J Child Neurol 2008)J Child Neurol 2008) Brainstem gliomaBrainstem glioma l l Patient 3-year, 10-month-old femalePatient 3-year, 10-month-old female HistoryHistory l l Diagnosed (May 2005) Diagnosed (May 2005) Headaches and fallingHeadaches and falling l l Radiation therapy (June 2005)Radiation therapy (June 2005) l l Chemotherapy (January 2006)Chemotherapy (January 2006) l l MR-imaging evidence of progression (January 2006)MR-imaging evidence of progression (January 2006) ExaminationExamination l l Left facial nerve weaknessLeft facial nerve weakness l l Disconjugate gazeDisconjugate gaze Weakness bilateral 6th nerves (left greater than right)Weakness bilateral 6th nerves (left greater than right) l l Gait discoordinationGait discoordination Convective deliveryConvective delivery Brainstem gliomaBrainstem glioma Perfuse the Perfuse the hypointensehypointense region of tumor region of tumor l l IL13IL13-PE (0.125 mcg/ml)-PE (0.125 mcg/ml) l l Gadolinium-Gadolinium-DTPADTPA (1 (1 mMmM) ) IntraoperativeIntraoperative MRMR-imaging-imaging l l T1 and FLAIR-imagingT1 and FLAIR-imaging Convective deliveryConvective delivery Brainstem gliomaBrainstem glioma l l ResultsResults Intraoperative MR-imagingIntraoperative MR-imaging l l Rate of infusion of 0.5 to 5 microliters/minuteRate of infusion of 0.5 to 5 microliters/minute l l Perfusion of 1.4 mlPerfusion of 1.4 ml Convective deliveryConvective delivery Brainstem gliomaBrainstem glioma l l ResultsResults Dec 2013Oct 201330 Gy in 17 sessions Oct 2012: 54 Gy in 30 sessions DIPG STUDYDIPG STUDY Collecting post-mortem tumor and Collecting post-mortem tumor and matched normal brain samplesmatched normal brain samples from DIPG from DIPG patientspatients l l Linked to DIPG clinical trial at SickKids Drs. Linked to DIPG clinical trial at SickKids Drs. Bouffet and BartelsBouffet and Bartels Performing high-resolution DNA Performing high-resolution DNA microarray analysismicroarray analysis ( (whole-genome single whole-genome single nucleotide polymorphism arrays nucleotide polymorphism arrays (Affymetrix 500K and 6.0)(Affymetrix 500K and 6.0) DIPGs HGAs 1 3 5 7 9 11 2 4 6 8 10 13 15 17 19 21 X 12 14 16 18 20 22 1 3 5 7 9 11 13 15 17 19 21 X 2 4 6 8 10 12 14 16 18 20 22 DIPGs are genetically distinct from supratentorial high grade astrocytomas DIPG HGA 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 Chromosome 14Chromosome 17 DIPGs are genetically distinct from supratentorial high grade astrocytomas RESULTSRESULTS Specific GenesSpecific Genes TP53TP53 l l One copy deleted in 7 of 11 DIPGs One copy deleted in 7 of 11 DIPGs l l TP53TP53 mutations present in 6/6 DIPGs tested mutations present in 6/6 DIPGs tested EGFREGFR l l Not amplified in any case, gained in one Not amplified in any case, gained in one l l Protein strongly expressed in 3 tumors, weak in a Protein strongly expressed in 3 tumors, weak in a further 4further 4 l l ? therapeutic target? therapeutic target RESULTSRESULTS Specific GenesSpecific Genes MGMTMGMT l l One copy deleted in 2 tumorsOne copy deleted in 2 tumors l l Protein not expressed in any caseProtein not expressed in any case l l ?Methylation status ?Methylation status PTENPTEN l l Hemizygous loss of 10q, including Hemizygous loss of 10q, including PTENPTEN, in 2 , in 2 tumorstumors RESULTSRESULTS Specific GenesSpecific Genes PDGFRA Gained in 4/11 DIPGs FISHQ-PCR RESULTSRESULTS Specific Genes Specific Genes PARP-1PARP-1 l l Gained in 3 casesGained in 3 cases l l Protein expressed in 6 cases Protein expressed in 6 cases PARP RESULTSRESULTS Specific Genes Specific Genes PARP-1PARP-1 l l PARP-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 regulation of differentiation, proliferation, tumor transformation and proliferation, tumor transformation and recovery of cells from DNA damagerecovery of cells from DNA damage l l PARP inhibitors have been shown to induce PARP inhibitors have been shown to induce growth inhibition in malignant glioma cellsgrowth inhibition in malignant glioma cells RESULTSRESULTS Specific Genes Specific Genes PARP-1PARP-1 PARP possible therapeutic target for a PARP possible therapeutic target for a subset of pediatric DIPGs? subset of pediatric DIPGs? Aurora KinaseAurora Kinase ACVR1 (FOP: fibrodysplasia ossifians ACVR1 (FOP: fibrodysplasia ossifians progressive)progressive) Other Genes Pediatric High Grade Pediatric High Grade AstrocytomaAstrocytom