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1、Paediatric Brainstem Tumours,among brainstem gliomas,A tectal glioma B focal midbrain tumor C focal intrinsic pontine glioma D dorsal/exophytic glioma E diffuse intrinsic pontine glioma* F focal medullary glioma G cervicomedullary glioma,A Few Important Distinctions,* a form of high grade glioma, ak
2、in 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 brains
3、tem 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,Diagnosis and managemen
4、t of LGG,Need a biopsy/resection Often pilocytic Result needs to be correlated with the clinical and radiological characteristics Surgical resection (even incomplete) can lead to sustained remission or cure,August 2001,August 2006,October 2014,August 2000,December 2001,Diagnosis and management of LG
5、G,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 carboplat
6、in,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 ofte
7、n 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 in
8、trinsic 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 sympt
9、oms 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 sig
10、n, 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,Jan
11、uary 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,LG
12、G,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 su
13、rgery 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
14、 (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.
15、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 tox
16、icity,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),
17、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
18、. 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 differenc
19、e 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 r
20、eactions to the first sessions of radiation) With caution at the time of progression,Diffuse brainstem Gliomas Role 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 activi
21、ty,Diffuse brainstem Gliomas Role 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 Gliomas Role of chemotherapy,Other studies Conv
22、entional 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 mo
23、lecules (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 Gliomas Results,Median survival 8-11 months Survival at one year 30-40% Survival at 2 years 10%
24、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 I
25、CE 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 50th centile, premature puberty Neuro-psychometric tes
26、ting. 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,January 2017,Long term survivor,Diffuse brainstem G
27、liomas North 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 w
28、ith 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
29、 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 Numbe
30、r 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-,Coh
31、ort 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,Maintenanc
32、e 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 Histor
33、y 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 de
34、livery,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,Conv
35、ective 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
36、 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 astrocytom
37、as,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
38、.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 supratento
39、rial high grade astrocytomas,RESULTS Specific 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,RESULTS Specific Genes,MGMT One copy de
40、leted in 2 tumors Protein not expressed in any case ?Methylation status PTEN Hemizygous loss of 10q, including PTEN, in 2 tumors,RESULTS Specific Genes,PDGFRA Gained in 4/11 DIPGs,FISH,Q-PCR,RESULTS Specific Genes PARP-1,Gained in 3 cases Protein expressed in 6 cases,PARP,RESULTS Specific Genes PARP
41、-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,RESULT
42、S Specific 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 w
43、ithin 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,50%,Spinal cord,CONCLUSIONS,Pediatric DIPGs are one of the main causes of b
44、rain 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,