Transcript Slide 1
MEDULLOBLASTOMA: Current Treatment and Future Directions • James T Rutka, MD, PhD, FRCSC, FACS • Division of Neurosurgery • The Hospital for Sick Children • The University of Toronto The Past Cushing and Pediatric Neurosurgery Cushing and Pediatric Brain Tumours Acta Pathologica, Microbiologica Surgery, et Gynecology and Obstetrics Immunologica Scandinavica52: 7:1-86, 129-204, 19301931 Clinical Presentation of the Child with a Medulloblastoma • “A preadolescent child previously in good health begins to complain of headaches or of suboccipital discomfort and to have occasional attacks of vomiting without preliminary nausea, usually on first arising in the morning…The family doctor, who has previously suspected some gastro-intestinal disorder, may then have the eyegrounds examined and to the surprise of everyone a choked disk is found…” Clinical Presentation of the Child with a Medulloblastoma • “If not recognized so soon…the clumsiness increases, vomiting grows more frequent, the child begins to lose weight, the muscles become wasted and atonic; there may be a slight facial palsy; the internal squint may become bilateral; finally…extensor rigidities occur, ere this child becomes bedridden. The whole story if uninterrupted by operation may cover a period from 8-9 months” Acta Path Microbiol Immunol Scandinavica 7: 1-86, 1930 MEDULLOBLASTOMA • Contributions of Cushing and Bailey – Coined term “medulloblastoma” 1925 – Described patient presentations – 61 operative cases by 1930 – Aware of tendency to invade brainstem and to disseminate along CSF pathways Operative sketch of Medulloblastoma from Cushing’s Collection MEDULLOBLASTOMA • HISTORICAL LANDMARKS – 1925 – Described by Cushing and Bailey – 1953 – Patterson and Farr describe efficacy of craniospinal irradiation – 1991 – Packer et al. describe efficacy of pre-irradiation chemotherapy KG McKenzie Canada’s first neurosurgeon Medulloblastoma - The Evolution of Pediatric Neuro-radiology • • • • • • • • • • Skull Xrays Angiography Ventriculography Pneumoencephalography Myelography CT Scan PET MRI MEG DTI Early CT Imaging of Pediatric Brain Tumors Early CT scans Circa 1976 Air encephalography MEDULLOBLASTOMA • HSC EXPERIENCE (1980 – 1990) – NUMBER OF PATIENTS = 50 – LOW RISK = 26; HIGH RISK = 24 – LOW RISK 5 YR SURVIVAL = 70% – HIGH RISK 5 YR SURVIVAL = 40% MEDULLOBLASTOMA • IMPROVING PATIENT SURVIVAL – – – – 63 high risk children; cis-plat, VCR, CCNU PFS @ 5 yrs = 85% for entire group PFS @ 5 yrs = 67% for children with metastases PFS @ 5 yrs = 90% for children with local disease – Packer et al, J Neurosurg 81: 690, 1994 The Present MEDULLOBLASTOMA • Most common malignant neoplasm of the CNS in children (15-20% of childhood brain tumors) • Peak incidence between 3 and 8 years • Slight male predominance MEDULLOBLASTOMA • BIOLOGICAL BEHAVIOUR – 40% infiltrate the brainstem – 20-50% CSF dissemination along the neuraxis The Harold J Hoffman Slide Collection – 10% systemic metastases (lung, lymph node, bone) www.surg.med.utoronto.ca/neuro/slides.html Diffuse bone mets CSF spread Met along shunt tubing MEDULLOBLASTOMA RISK SEGREGATION Low Risk > 3 yrs No residual tumor No distant metastases High Risk < 3 yrs > 1.5 cm2 residual Metastases All patients with medulloblastoma are high risk Kintomo Takakura MEDULLOBLASTOMA • IMAGING STUDIES – Hyperdense lesion on CT before contrast – Heterogeneous enhancement after contrast Pre-contrast Post-contrast MEDULLOBLASTOMA TUMOR LOCATION Midline, vermian Hemispheric CP angle Brainstem (rare) Supratentorial (PNET) Pre-operative MRI Spine!! MEDULLOBLASTOMA: Spine MRI Pre-operative spinal imaging is mandatory! MEDULLOBLASTOMA: Imaging Diagnosis of leptomeningeal disease Medulloblastoma Lessons learned • TO SHUNT OR NOT TO SHUNT? – Do not shunt unless the child is moribund from acute obstructive hydrocephalus – Most children will be symptomatically controlled by steroids MEDULLOBLASTOMA • OPERATIVE APPROACH – Midline, vermian split – Lateral hemispheric – Inferior medullary velum - telovelar – CP angle MEDULLOBLASTOMA INTRA-OPERATIVE NUANCES Removing tumor from Floor of IVth Inspecting anatomical Structures with tumor removed Intra-operative video MEDULLOBLASTOMA Surgery, XRT And Chemo 5 years Surgery, XRT And Chemo 4 years With Medulloblastoma, the More Tumor You Remove, the Better! MEDULLOBLASTOMA • POST-OPERATIVE COMPLICATIONS – Cerebellar, cranial nerve deficits – Hydrocephalus requiring shunt or ETV – Meningitis – Pseudomeningocele – Cerebellar Mutism Medulloblastoma How to avoid cerebellar mutism? • Nobody knows! • Work quickly and efficiently with the cavitron • Avoid self retaining retractor systems. • Be careful with traction on or dissection into the cerebellar peduncles • Assess tractography post-op! Lancet Oncology June 2008 MEDULLOBLASTOMA Effects of XRT on the CNS Neurocognitive Moya moya Endocrinopathy Vasculopathy Cavernous malformation • Secondary neoplasms • • • • • NEJM 2005:352:978-986 Chemotherapy for Medulloblastoma Proven effective but…. 6 year old male Short history GTR Excellent post-op course Cycles of chemotherapy Stem cell transplant Infectious complications Toxic mortality MEDULLOBLASTOMA • CURRENT BEST TREATMENT • Maximum safe neurosurgical resection • Radiation therapy (reduced craniospinal year survival standard risk – 70% children < 3 irradiation,5 avoid irradiating 5 year survival high risk – 50% yrs) • Chemotherapy (active agents, autologous stem cell transplant, new agents) Future Treatment of Medulloblastoma • Advanced Cytogenetics • Differential Gene Expression • SNP array platforms • Next generation sequencing • Epigenetics • Stem Cells Advanced Cancer Cytogenetics Chromosomes 7 & 17 rearrangements Gene amplification in 30% (2q) Loss of chromosome 10 Three techniques led to identification Of greatest number genetic alterations Tissue Microarray Technology Examine a panel of differentially expressed genes in patient samples linked to clinical outcome and survival data. Tissue Array Prediction of Patient Outcome MEDULLOBLASTOMA AND GERMLINE SUFU MUTATION Nature Genetics 31: 306-310, 2002 The Globe and Mail June 20, 2002 Gene Discovery cDNA microarray analysis • Atlas 1200 gene cancer array • Ability to find genes that are both up- and downregulated compared to normal cerebellum • Gene discovery strategy The Future of Medulloblastoma Gene Discovery Experiment Using: GeneChip Affymetrix Human Genome U133 Plus 2.0 Array Comprehensive coverage of the human genome More than 47,000 transcripts studied Samples Medulloblastoma cell lines (DAOY, TE671, UW426, ONS76 ) and Human adult cerebellum Flowchart of the procedure Hybridization Scanning Analysis GAGE7 GAGE7B GAGE3 GAGE6 GAGE4 GAGE2 MAGEA9 GAGE1 MAGEE1 MAGEA10 MAGEC1 MAGEB3 BAGE GAGEB1 MGEA12 MAGEA11 MAGE6 MAGEA3 MAGEA8 MAGEB4 MAGEB2 MAGEB1 MAGEA1 MAGE1 Medulloblastoma tumor specimens BAGE GAGE4 GAGE1 GAGE2 MAGEB4 MAGEB3 GAGE7B GAGE6 MAGEB2 GAGE2 MAGEA8 MAGEA9 GAGE1 MAGEC1 MAGEB1 GAGE3 MAGE1 GAGE7 MAGEA1 MAGEA11 GAGEB1 MAGE10 MGEA12 MAGEE1 MAGEA3 MAGE6 HMB8 HMB35 HMB24 HMB19 HMB1 Cell lines UW426 DAOY ONS76 TE671 Hierarchical Clustering of MAGE and GAGE by microarray Advanced Genetic Platforms for Medulloblastoma 1. Single nucleotide polymorphism (SNP) array platforms (CNAs) 2. PCR-directed exon resequencing 3. DNA methylation assays (epigenetics) 4. DNA histone alterations (epigenetics) 5. Next generation (“deep”) DNA sequencing (454 Roche, Solexa Illumina, SOLiD Applied Bioscience) Resources Resolution = Results Previous studies: ~20-30 samples 1-10 Mb “small” dataset Current study: 212 samples 5-10 Kb “large” dataset 212 MBs Strategy for identification of191novel Amplifications: (201 primaries, 11 cell lines) Homozygous Deletions: 159 genetic events in medulloblastoma… 100K & 500K GeneChip Mapping Arrays Known genes/pathways Novel genes/pathways - Myc family - chromatin: H3K9 - PDGF signaling - OTX2 Whole genome copy number profiling of MB Animal Models More Reliably Predicting Clinical Response • • • • • • • • Ptch Ptch + p53 XRCC4 knockout Smo activation Shh injection Lig4 + p53 Parp + p53 Shh + Akt or IGF2 Sufu Sufu + Costal2 Gli2 MURINE MRI Medulloblastoma in PTCH+/- Mice Gene Silencing in Medulloblastoma DNA methylation Epigenetic Mechanisms In Medulloblastoma --Chromatin remodeler Histones --Transcription --Histone tails MicroRNAs Chromosome Nature, 2008 Role of epigenetic silencing in medulloblastoma Cancer Res Dec 2008 Mice Implanted with SPINT2 Expressing MB Cells Have Prolonged Survival What is SPINT2? A Novel Target for HGF/cMET inhibition Chr 19q13 28.2 kDa Serine protease inhib Dissection of downstream signaling pathways • HGF/cMET pathway inhibition (small molecule PHA665752) • • • • STEM CELLS AND MEDULLOBLASTOMA Stem Cells and Human Malignant Brain Tumors CD15/ LeX /SSEA1 Galb1-4(Fuca1-3)GlcNAcb- Adult Brain Embryonic Brain GFAP Temple A newSally stem cell marker! Neuron 35: 865, 2002 Developmental Biology 291:300, 2006 Targeting the Brain Tumor Stem Cell Implications for Treatment Reya et al, Nature 414: 105-111, 2001 Medulloblastoma: Prediction 2019 • Imaging diagnosis of tumor • Stereotactic biopsy for molecular profiling and subclassification • Chemotherapy alone (conventional and novel pharmacotherapeutics) • Aggressive surgical therapy and radiation therapy will be relegated to the past Thank you!