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1、Paediatric Brainstem Tumours,among brainstem gliomas,Atectal gliomaBfocal midbrain tumorCfocal intrinsic pontine gliomaDdorsal/exophytic gliomaEdiffuse intrinsic pontine glioma*Ffocal medullary gliomaGcervicomedullary glioma,A Few Important Distinctions,*a form of high grade glioma,akin toanaplastic
2、 astrocytoma or glioblastoma multiforme,Brainstem Gliomas,Low grade gliomasNot common!Focal exophyticCervicomedullary tumoursDiffuse Intrinsic Brainstem Tumours10-15%of all brain tumours25%of the mortality by brain tumour in childrenAtypical brainstem tumoursAtypical brainstem lesionsBrainstem tumou
3、rs in infants,Low grade glioma of the brainstem,Clinical symptomsOften long presenting historyProgressive motor deficit or ataxiaCranial nerve deficits are infrequentRadiological characteristicsMajority are focal and exophiticEnhancing tumours,Diagnosis and management of LGG,Need a biopsy/resectionO
4、ften pilocyticResult needs to be correlated with the clinical and radiological characteristicsSurgical resection(even incomplete)can lead to sustained remission or cure,August 2001,August 2006,October 2014,August 2000,December 2001,Diagnosis and management of LGG,Postoperative managementEither immed
5、iately after surgeryOr at the time of progressionRadiation or chemotherapy?No clear answerRadiation still standard treatmentChemotherapy works,December 2001,December 2002,Low grade glioma of the brainstem:chemotherapy with weekly vincristine and carboplatin,Diagnosis(11/2013),1/2015(one year of VBL)
6、,BRAF V600 mutated tumour,The diffuse intrinsic brainstem tumours,15-20%of all paediatric brain tumoursTypical clinical presentationShort history(6 3 1 month)At least 2 of the 3 signs/symptomsCranial nerve deficitLong tracts signsAtaxiaNot often reported,but nearly always present:behavioral changesL
7、aughter(night)School phobiaSadness,The diffuse intrinsic brainstem tumours,Cranial nerve deficitsOcular motor deficits(CN 6 the most common)Facial weaknessUnilateral deafnessSwallowing disordersNystagmus often present,The diffuse intrinsic brainstem tumours,RadiologyMore than 50%of the ponsHypodense
8、Little/no enhancement,Typical DPG,Typical BSG,The atypical brainstem tumours,Atypical by clinical presentationLong history and imaging suggesting diffuse pontine gliomaAtypical by imagingFocal enhancing tumour and short symptomsAtypical by pathologyShort symptoms and low grade pathologyDiscrepancy s
9、ymptoms/radiology/pathology,13 year old10 month history 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 ataxia,The atypical brainstem tumours,Always treat as a diffuse intrinsic glioma
10、 with upfront focal radiationChemotherapy to discuss case by case,The atypical brainstem lesions,No correlation between clinical and radiological findingDo not treat unless evidence of progression,11 year-old,January 2004,2010(18 years old),January 2004,2010,Brainstem tumours in babies,Not good(exce
11、pt LGG)Not always gliomas,1 day oldPM:PNET,1 day oldNo PM,LGG of infancy,4 month oldPilocytic AstrocytomaOn chemo,How to distinguish?,Clinical contextClinical examRadiologySpectroscopyPathology,DPG,LGG,Focal HGG,DPG,LGG,2 year-old,5 months history of ataxia and gaze palsy,Biopsy:low grade astrocytom
12、a,3 years old,NF1,10/2012,7/2013,3 years old Mild hemiparesisBiopsy:infiltrative astrocytoma(grade 2),9/2012,10/2016,MALIGNANT GLIOMA OF PONSCANADIAN CASES BY YEAR,Management of DIPG,Role of surgeryNo role has been demonstratedDoes not affect treatmentDoes not influence survivalCan be misleadingRisk
13、s are significantOngoing discussionsBiology?,Short symptoms(1 month)Classical triadCranial nerve deficitsLong tract signsAtaxiaNO NEED FOR BIOPSY!TREATMENT SHOULD BE STARTED ASAP(within 48 hours),Management,RadiationThe standard treatmentAims:to improve symptoms(the best palliative treatment)Timing:
14、ASAP+(within 24-48 hours)Technique:focal,opposed parallel fields,standard fractionationDose:54 Gy in 30 fractions,Diffuse Pontine Glioma,Standard RT50-54 Gy in 1.8 GyDaily fractions,Current trend to move to conformal techniques,Management,RadiationRole of other techniques?Hyperfractionation:POG and
15、CCSG experienceSeveral studies have been conducted in the late 80s/early 90s Doses up to 84 GyNo evidence of survival benefitSome evidence of increased toxicity,Hyperfractionation:results of prospective studies,Freeman et al,POG 9239,IJROBP1999,Management,RadiationRole of other techniques?Gamma knif
16、e:BSG often listed as one of the tumours eligible for gamma knifeNo series reportedNo rational for this technique(would cause brainstem necrosis),Management,RadiationRole of other techniques?Radiosensitising agentsGadolinium texaphyrin:COG phase I ongoing,should be completed soon and followed by a p
17、hase II studyTopotecan:phase I POG study completed 4 years ago,published in 2003 in Neuro-oncology.Suggest improvement in median survival.Phase II study planned,Hypofractionation,Less sessionsHigher dose per fraction(13 or 15 instead of 30)Usually offered as a palliative option,in particular in elde
18、rly patientsHas been suggested and tested in patients with DIPGRandomised study published in 2014(Cairo)No significant difference with conventional radiation,Hypofractionaltion,54 Gy in 30 fractions versus 39 Gy in 13 fractions,Zhagloul et alRadiotherapy&Oncology 2014,Management,SteroidsA major role
19、Always the lowest possible dose to limit the side effects(quality of life)Be careful during the first week(significant reactions to the first sessions of radiation)With caution at the time of progression,Diffuse brainstem GliomasRole of chemotherapy,Numerous studies Upfront or at the time of progres
20、sionSingle agent or combinationsResponse rate low0 to 20%No drug or combination seems to have a significant activity,Diffuse brainstem GliomasRole of chemotherapy,One randomised study CCG 943Conducted in the pre-MRI era(all BSG)Radiation+Chemotherapy(vincristine-CCNU)Overall survival 22%at 2 yearsNo
21、 evidence of benefit with chemotherapy,Diffuse brainstem GliomasRole of chemotherapy,Other studiesConventional chemotherapyCisplatinCarboplatin before and/or during radiationEtoposide oralHigh dose chemotherapySFOP experience with high dose busulfan and thiotepa,Diffuse brainstem Gliomas:Other agent
22、s,Other studiesInterferon(CCG study)Tamoxifen(Brazilian study)Thalidomide(Boston)Small molecules(PBTC)Imatinib(TK inhibitor)Gefitinib(EGFR inhibitor)Vandetanib(inhibitor of VEGFR2&EGFR),Correlative studies,UK/French study of erlotinib(EGFR inhibitor)Biopsy driven,Diffuse brainstem GliomasResults,Med
23、ian survival8-11 monthsSurvival at one year 30-40%Survival at 2 years 10%Progression-free survival6-8 months,Examples,Excellent Response to Radiotherapy?,PATIENT DIED AT 11 MONTHS POST DIAGNOSIS,LONG TERM SURVIVORS,Clinical HistoryFemale 3.5 yrs3 week Hx headache right sided VI N palsyMRI-T2 hyperde
24、nse intrinsic pontine gliomaNo biopsyRadiotherapy 54GyReceived ICE chemotherapy x 5MRI post radiotherapy showed some improvement,6 months post diagnosis recurrence of symptomsNo further conventional therapy/-alternative healerNo further MRI-refused,but clinical follow upAlive age 18 yrsNormal statur
25、e 50th centile,premature pubertyNeuro-psychometric testing.Difficulties in:Verbal processing,language acquisition Attention poor,CLINICAL CHARACTERISTICS,TREATMENT AND OUTCOME OF SURVIVING PATIENTS,MRI IMAGING OF LONG TERM SURVIVORS,Are they true DIPG?,Are they true DIPG?,October 2011,January 2012,J
26、anuary 2017,Long term survivor,Diffuse brainstem GliomasNorth American studies,Few studies openFuture studies,Brainstem Gliomas,Recently closed ACNS 0927:phase II study of SAHA(vorinostat)during and after radiationOpenADVL 1217(A phase I study of MK-1775 concurrent with local radiation therapy for t
27、he treatment of newly diagnosed children with diffuse intrinsic pontine gliomas(DIPG)Soon?Arsenic trioxyde(antivascular effect,radiosensitizer),Brainstem Gliomas,PBTC studies:PARP inhibitor+Temozolomide+radiation(closed for futility)Pembrolizumab(closed for toxicity)Panabinostat(HDAC inhibitor)curre
28、ntly recruiting,Biospy for DIPG:Why?How?,Frame-basedFrame lessNo indication for DIPG,How is it done?,Limitations,No direct benefit for the patient yetClear explanation&Parents informed consentRisk of neurological deteriorationSmall&few samples,Necker series,65 stereotactic biopsies of DIPG4 patients
29、 refused Number of samples increased with time(up to 8)Histological diagFrozen samplesStem cell culturesNo mortalityNo permanent morbidity3 transient morbidity(facial nerve palsy associated with increased motor deficit in 1 case)2 tumoral dissemination along the trajectory,Biopsy,Cohort 1 MGMT-EGFR-
30、,Cohort 2 MGMT-EGFR+,Cohort 3 MGMT+EGFR-,Cohort 4 MGMT+EGFR+,RT Bevacizumab,RTBevacizumab Erlotinib,RTBevacizumabTemozolomide,RTBevacizumab ErlotinibTemozolomide,4 Weeks Bevacizumab,4 Weeks Bevacizumab Erlotinib,4 Weeks Bevacizumab,4 Weeks Bevacizumab Erlotinib,Maintenance Bevacizumab,Maintenance Be
31、vacizumab Erlotinib,MaintenanceBevacizumab Temozolomide,Maintenance Bevacizumab ErlotinibTemozolomide,MRI Diagnosis DIPG,TREATMENT SCHEMA,Enrollment,Tissue Analyses,Boston/UCSF protocol,Convection delivery(Lonser J Child Neurol 2008),Brainstem gliomaPatient 3-year,10-month-old femaleHistoryDiagnosed
32、(May 2005)Headaches and fallingRadiation therapy(June 2005)Chemotherapy(January 2006)MR-imaging evidence of progression(January 2006)ExaminationLeft facial nerve weaknessDisconjugate gazeWeakness bilateral 6th nerves(left greater than right)Gait discoordination,Convective delivery,Brainstem gliomaPe
33、rfuse the hypointense region of tumorIL13-PE(0.125 mcg/ml)Gadolinium-DTPA(1 mM)Intraoperative MR-imagingT1 and FLAIR-imaging,Convective delivery,Brainstem gliomaResultsIntraoperative MR-imagingRate of infusion of 0.5 to 5 microliters/minutePerfusion of 1.4 ml,Convective delivery,Brainstem gliomaResu
34、lts,Dec 2013,Oct 2013,30 Gy in 17 sessions,Oct 2012:54 Gy in 30 sessions,DIPG STUDY,Collecting post-mortem tumor and matched normal brain samples from DIPG patientsLinked to DIPG clinical trial at SickKids Drs.Bouffet and BartelsPerforming high-resolution DNA microarray analysis(whole-genome single
35、nucleotide polymorphism arrays(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
36、,5,6,7,8,9,10,11,Chromosome 14,Chromosome 17,p13,p12,p11.2,q11.1,q11.2,q12,q13.1,q21.1,q21.2,q21.3,q23.1,q22.1,q23.2,q23.3,q24.1,q24.2,q24.3,q31.1,q31.3,q32.13,q32.2,q32.33,p13.3,p13.2,p13.1,p11.2,p12,q11.2,q12,q21.2,q21.31,q21.32,q21.33,q22,q23.2,q24.1,q24.2,q24.3,q25.1,q25.3,p13,p12,p11.2,q11.1,q1
37、1.2,q12,q13.1,q21.1,q21.2,q21.3,q23.1,q22.1,q23.2,q23.3,q24.1,q24.2,q24.3,q31.1,q31.3,q32.13,q32.2,q32.33,p13.3,p13.2,p13.1,p11.2,p12,q11.2,q12,q21.2,q21.31,q21.32,q21.33,q22,q23.2,q24.1,q24.2,q24.3,q25.1,q25.3,DIPGs are genetically distinct from supratentorial high grade astrocytomas,RESULTSSpecifi
38、c Genes,TP53One copy deleted in 7 of 11 DIPGs TP53 mutations present in 6/6 DIPGs testedEGFRNot amplified in any case,gained in one Protein strongly expressed in 3 tumors,weak in a further 4?therapeutic target,RESULTSSpecific Genes,MGMTOne copy deleted in 2 tumorsProtein not expressed in any case?Me
39、thylation status PTENHemizygous loss of 10q,including PTEN,in 2 tumors,RESULTSSpecific Genes,PDGFRAGained in 4/11 DIPGs,FISH,Q-PCR,RESULTSSpecific Genes PARP-1,Gained in 3 casesProtein expressed in 6 cases,PARP,RESULTSSpecific Genes PARP-1,PARP-1 encodes a chromatin-associated enzyme which modifies
40、nuclear proteins and is involved in the regulation of differentiation,proliferation,tumor transformation and recovery of cells from DNA damagePARP inhibitors have been shown to induce growth inhibition in malignant glioma cells,RESULTSSpecific Genes PARP-1,PARP possible therapeutic target for a subs
41、et of pediatric DIPGs?Aurora KinaseACVR1(FOP:fibrodysplasia ossifians progressive),Other Genes,Pediatric High Grade Astrocytoma and Histone Mutations,Me,H3F3A replication-independent histone 3 variant 3.3two critical positions within the histone tail-K27M,G34RHIST1H3B/CReplication-dependent histone
42、3 variant 3.1K27M only,Location and frequency of Histone 3 mutations in pediatric HGG,H3K27M is a midline diseaseH3G34R/V is a hemispheric disease,50%,Spinal cord,CONCLUSIONS,Pediatric DIPGs are one of the main causes of brain tumor death in childrenAfter decades of clinical trials,largely based on protocols for adult brain tumors,no effective treatment has yet been foundOngoing studies are now based on the results of genomic studies that have identified potential target.Still radiation is the mainstay of treatment and re-irradiations offer benefit in some children,
