多伦多病童医院脑干胶质瘤.ppt

,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Paediatric Brainstem Tumours,among brainstem gliomas,Atectal glioma,Bfocal midbrain tumor,Cfocal intrinsic pontine glioma,Ddorsal/exophytic glioma,E,diffuse 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 Gliomas,Low grade gliomas,Not common!,Focal exophytic,Cervicomedullary tumours,Diffuse Intrinsic Brainstem Tumours,10-15%of all brain tumours,25%of the mortality by brain tumour in children,Atypical brainstem tumours,Atypical brainstem lesions,Brainstem tumours in infants,Low grade glioma of the brainstem,Clinical symptoms,Often long presenting history,Progressive motor deficit or ataxia,Cranial nerve deficits are infrequent,Radiological characteristics,Majority are focal and exophitic,Enhancing tumours,August 2001,August 2006,October 2014,August 2000,December 2001,Diagnosis and management of LGG,Postoperative management,Either immediately after surgery,Or at the time of progression,Radiation or chemotherapy?,No clear answer,Radiation still standard treatment,Chemotherapy 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),BRAF V600 mutated tumour,The diffuse intrinsic brainstem tumours,15-20%of all paediatric brain tumours,Typical clinical presentation,Short history(6,3 1 month),At least 2 of the 3 signs/symptoms,Cranial nerve deficit,Long tracts signs,Ataxia,Not often reported,but nearly always present:behavioral changes,Laughter(night),School phobia,Sadness,The diffuse intrinsic brainstem tumours,Cranial nerve deficits,Ocular motor deficits(CN 6 the most common),Facial weakness,Unilateral deafness,Swallowing disorders,Nystagmus often present,The diffuse intrinsic brainstem tumours,Radiology,More than 50%of the pons,Hypodense,Little/no enhancement,Typical DPG,Typical BSG,The atypical brainstem tumours,Atypical by clinical presentation,Long history and imaging suggesting diffuse pontine glioma,Atypical by imaging,Focal enhancing tumour and short symptoms,Atypical by pathology,Short symptoms and low grade pathology,Discrepancy 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 tumours,Always treat as a diffuse intrinsic glioma with upfront focal radiation,Chemotherapy to discuss case by case,The atypical brainstem lesions,No correlation between clinical and radiological finding,Do not treat unless evidence of progression,11 year-old,January 2004,2010(18 years old),January 2004,2010,Brainstem tumours in babies,Not good(except LGG),Not always gliomas,1 day old,PM:PNET,1 day old,No PM,LGG of infancy,4 month old,Pilocytic Astrocytoma,On chemo,How to distinguish?,Clinical context,Clinical exam,Radiology,Spectroscopy,Pathology,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 DIPG,Role of surgery,No role has been demonstrated,Does not affect treatment,Does not influence survival,Can be misleading,Risks are significant,Ongoing discussions,Biology?,Short symptoms(1 month),Classical triad,Cranial nerve deficits,Long tract signs,Ataxia,NO NEED FOR BIOPSY!,TREATMENT SHOULD BE STARTED ASAP(within 48 hours),Management,Radiation,The standard treatment,Aims:to improve symptoms(the best palliative treatment),Timing:ASAP+(within 24-48 hours),Technique:focal,opposed parallel fields,standard fractionation,Dose:54 Gy in 30 fractions,Diffuse Pontine Glioma,Standard,RT,50-54 Gy in 1.8 Gy,Daily fractions,Current trend to move to conformal techniques,Management,Radiation,Role of other techniques?,Hyperfractionation:,POG and CCSG experience,Several studies have been conducted in the late 80s/early 90s,Doses up to 84 Gy,No evidence of survival benefit,Some evidence of increased toxicity,Hyperfractionation:results of prospective studies,Freeman et al,POG 9239,IJROBP1999,Management,Radiation,Role of other techniques?,Gamma knife:BSG often listed as one of the tumours eligible for gamma knife,No series reported,No rational for this technique(would cause brainstem necrosis),Management,Radiation,Role of other techniques?,Radiosensitising agents,Gadolinium texaphyrin:COG phase I ongoing,should be completed soon and followed by a phase II study,Topotecan: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 sessions,Higher dose per fraction(13 or 15 instead of 30),Usually offered as a palliative option,in particular in elderly patients,Has been suggested and tested in patients with DIPG,Randomised 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 al,Radiotherapy&Oncology 2014,Management,Steroids,A major role,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 progression,Single agent or combinations,Response rate low,0 to 20%,No drug or combination seems to have a significant activity,Diffuse brainstem GliomasRole of chemotherapy,One randomised study,CCG 943,Conducted in the pre-MRI era(all BSG),Radiation,+,Chemotherapy(vincristine-CCNU),Overall survival 22%at 2 years,No evidence of benefit with chemotherapy,Diffuse brainstem GliomasRole of chemotherapy,Other studies,Conventional chemotherapy,Cisplatin,Carboplatin before and/or during radiation,Etoposide oral,High dose chemotherapy,SFOP experience with high dose busulfan and thiotepa,Diffuse brainstem Gliomas:Other agents,Other studies,Interferon(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,Median survival,8-11 months,Survival at one year,30-40%,Survival at 2 years 10%,Progression-free survival,6-8 months,Examples,Excellent Response to Radiotherapy?,PATIENT DIED AT 11 MONTHS POST DIAGNOSIS,LONG TERM SURVIVORS,Clinical History,Female 3.5 yrs,3 week Hx,headache right sided VI N palsy,MRI-T2 hyperdense intrinsic pontine glioma,No biopsy,Radiotherapy 54Gy,Received,ICE chemotherapy,x 5,MRI post radiotherapy showed some improvement,6 months post diagnosis recurrence of symptoms,No further conventional therapy/-alternative healer,No further MRI-refused,but clinical follow up,Alive age 18 yrs,Normal stature 50,th,centile,premature puberty,Neuro-psychometric testing.Difficulties in:,Verbal processing,language acquisition,Attention poor,Age at,Diagnosis,(MONTHS),Sex,Neurological Signs at Presentation,Interval Between Onset of Symptoms and Diagnosis,(Weeks),Initial Treatment,Survival(Years),Cranial Nerve,Palsy,Pyramidal Deficits,Cerebellar Signs,20,Male,Yes,Yes,Yes,24,RT+,Temozolomide,+5,22,Male,Yes,Yes,No,12-24,RT,+4,CLINICAL CHARACTERISTICS,TREATMENT AND OUTCOME OF SURVIVING PATIENTS,MRI IMAGING OF LONG TERM SURVIVORS,Are they true DIPG?,Are they true DIPG?,October 2011,January 2012,January 2017,Long term survivor,Diffuse brainstem GliomasNorth American studies,Few studies open,Future studies,Brainstem Gliomas,Recently closed,ACNS 0927:,phase II study of SAHA(vorinostat)during and after radiation,Open,ADVL 1217,(A phase I study of MK-1775 concurrent with local radiation therapy for the 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)currently recruiting,Biospy for DIPG:Why?How?,Frame-based,Frame less,No indication for DIPG,How is it done?,Limitations,No direct benefit for the patient yet,Clear explanation&Parents informed consent,Risk of neurological deterioration,Small&few samples,Necker series,65 stereotactic biopsies of DIPG,4 patients refused,Number of samples increased with time(up to 8),Histological diag,Frozen samples,Stem cell cultures,No mortality,No permanent morbidity,3 transient morbidity(facial nerve palsy associated with increased motor deficit in 1 case),2 tumoral dissemination along the trajectory,Biopsy,Cohort 1,MGMT-,EGFR-,Cohort 2,MGMT-,EGFR+,Cohort 3,MGMT+,EGFR-,Cohort 4,MGMT+,EGFR+,RT,Bevacizumab,RT,Bevacizumab,Erlotinib,RT,Bevacizumab,Temozolomide,RT,Bevacizumab,Erlotinib,Temozolomide,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,(Lonser,J Child Neurol 2008),Brainstem glioma,Patient 3-year,10-month-old female,History,Diagnosed(May 2005),Headaches and falling,Radiation therapy(June 2005),Chemotherapy(January 2006),MR-imaging evidence of progression(January 2006),Examination,Left facial nerve weakness,Disconjugate gaze,Weakness bilateral 6th nerves(left greater than right),Gait discoordination,Convective delivery,Brainstem glioma,Perfuse the hypointense region of tumor,IL13-PE(0.125 mcg/ml),Gadolinium-DTPA(1 mM),Intraoperative MR-imaging,T1 and FLAIR-imaging,Convective delivery,Brainstem glioma,Results,Intraoperative MR-imaging,Rate of infusion of 0.5 to 5 microliters/minute,Perfusion of 1.4 ml,Convective delivery,Brainstem glioma,Results,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 patients,Linked to DIPG clinical trial at SickKids Drs.Bouffet and Bartels,Performing high-resolution DNA microarray analysis(whole-genome single 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,1,2,3,4,5,6,7,8,9,10,11,1,2,3,4,5,6,7,8,9,10,11,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,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,DIPGs are genetically distinct from supratentorial high grade astrocytomas,RESULTSSpecific Genes,TP53,One copy deleted in 7 of 11 DIPGs,TP53,mutations present in 6/6 DIPGs tested,EGFR,Not amplified in any case,gained in one,Protein strongly expressed in 3 tumors,weak in a further 4,?therapeutic target,RESULTSSpecific Genes,MGMT,One copy deleted in 2 tumors,Protein not expressed in any case,?Methylation status,PTEN,Hemizygous loss of 10q,including,PTEN,in 2 tumors,RESULTSSpecific Genes,PDGFRA,Gained in 4/11 DIPGs,FISH,Q-PCR,RESULTSSpecific Genes,PARP-1,Gained in 3 cases,Protein expressed in 6 cases,PARP,RESULTSSpecific Genes,PARP-1,PARP-1,encodes a chromatin-associated enzyme which modifies nuclear proteins and is involved in the regulation of differentiation,proliferation,tumor transformation and recovery of cells from DNA damage,PARP inhibitors have been shown to induce growth inhibition in malignant glioma cells,RESULTSSpecific Genes,PARP-1,PARP possible therapeutic target for a subset of pediatric DIPGs?,Aurora Kinase,ACVR1(FOP:fibrodysplasia ossifians progressive),Other Genes,Pediatric High Grade Astrocytoma and Histone Mutations,Me,H3F3A,replication-independent histone 3 variant 3.3,two critical positions within the histone tail-K27M,G34R,HIST1H3B/C,Replication-dependent histone 3 variant 3.1,K27M only,Location and frequency of Histone 3 mutations in pediatric HGG,H3K27M is a midline disease,H3G34R/V is a hemispheric disease,Hemispheric,Thalamic,Pontine(DIPG),20%,H3.3K27M,H3.3G34R/V,65%,50%,15%,H3.1K27M,50%,Spinal cord,CONCLUSIONS,Pediatric DIPGs are one of the main causes of brain tumor death in children,After decades of clinical trials,largely based on protocols for adult brain tumors,no effective treatment has yet been found,Ongoing 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,