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MEDULLOBLASTOMA: Current Treatment and Future Directions James T Rutka, MD, PhD, FRCSC, FACS Division of Neurosurgery The Hospital for Sick Children The.

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Presentation on theme: "MEDULLOBLASTOMA: Current Treatment and Future Directions James T Rutka, MD, PhD, FRCSC, FACS Division of Neurosurgery The Hospital for Sick Children The."— Presentation transcript:

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

2

3 The Past

4 Cushing and Pediatric Neurosurgery

5 Cushing and Pediatric Brain Tumours Acta Pathologica, Microbiologica et Immunologica Scandinavica 7:1-86, 1930 Surgery, Gynecology and Obstetrics 52: , 1931

6 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…”

7 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

8 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

9 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

10 Medulloblastoma - The Evolution of Pediatric Neuro-radiology Skull Xrays Angiography Ventriculography Pneumo- encephalography Myelography CT Scan PET MRI MEG DTI

11 Early CT Imaging of Pediatric Brain Tumors Air encephalography Early CT scans Circa 1976

12 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%

13 MEDULLOBLASTOMA IMPROVING PATIENT SURVIVAL – 63 high risk children; cis-plat, VCR, CCNU – 5 yrs = 85% for entire group – 5 yrs = 67% for children with metastases – 5 yrs = 90% for children with local disease – Packer et al, J Neurosurg 81: 690, 1994

14 The Present

15 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

16 MEDULLOBLASTOMA BIOLOGICAL BEHAVIOUR – 40% infiltrate the brainstem – 20-50% CSF dissemination along the neuraxis – 10% systemic metastases (lung, lymph node, bone) Diffuse bone metsCSF spread Met along shunt tubing The Harold J Hoffman Slide Collection

17 MEDULLOBLASTOMA RISK SEGREGATION Low Risk High Risk > 3 yrs< 3 yrs No residual tumor> 1.5 cm 2 residual No distant metastasesMetastases All patients with medulloblastoma are high risk Kintomo Takakura

18 MEDULLOBLASTOMA IMAGING STUDIES – Hyperdense lesion on CT before contrast – Heterogeneous enhancement after contrast Pre-contrast Post-contrast

19 MEDULLOBLASTOMA TUMOR LOCATION Midline, vermian Hemispheric CP angle Brainstem (rare) Supratentorial (PNET) Pre-operative MRI Spine!!

20 MEDULLOBLASTOMA: Spine MRI Pre-operative spinal imaging is mandatory!

21 MEDULLOBLASTOMA: Imaging Diagnosis of leptomeningeal disease

22 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

23 MEDULLOBLASTOMA OPERATIVE APPROACH – Midline, vermian split – Lateral hemispheric – Inferior medullary velum - telovelar – CP angle

24 MEDULLOBLASTOMA Removing tumor from Floor of IVth Inspecting anatomical Structures with tumor removed INTRA-OPERATIVE NUANCES

25 Intra-operative video

26 MEDULLOBLASTOMA Surgery, XRT And Chemo 5 years Surgery, XRT And Chemo 4 years

27 With Medulloblastoma, the More Tumor You Remove, the Better!

28 MEDULLOBLASTOMA POST-OPERATIVE COMPLICATIONS – Cerebellar, cranial nerve deficits – Hydrocephalus requiring shunt or ETV – Meningitis – Pseudomeningocele – Cerebellar Mutism

29

30 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

31 MEDULLOBLASTOMA Effects of XRT on the CNS Neurocognitive Moya moya Endocrinopathy Vasculopathy Cavernous malformation Secondary neoplasms

32 NEJM 2005:352:

33 Chemotherapy for Medulloblastoma Proven effective but…. Cycles of chemotherapy Stem cell transplant Infectious complications Toxic mortality 6 year old male Short history GTR Excellent post-op course

34 MEDULLOBLASTOMA CURRENT BEST TREATMENT Maximum safe neurosurgical resection Radiation therapy (reduced craniospinal irradiation, avoid irradiating children < 3 yrs) Chemotherapy (active agents, autologous stem cell transplant, new agents) 5 year survival standard risk – 70% 5 year survival high risk – 50%

35 Future Treatment of Medulloblastoma Advanced Cytogenetics Differential Gene Expression SNP array platforms Next generation sequencing Epigenetics Stem Cells

36 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

37 Examine a panel of differentially expressed genes in patient samples linked to clinical outcome and survival data. Tissue Microarray Technology

38 Tissue Array Prediction of Patient Outcome

39 MEDULLOBLASTOMA AND GERMLINE SUFU MUTATION

40 The Globe and Mail June 20, 2002 Nature Genetics 31: , 2002

41 Gene Discovery cDNA microarray analysis Atlas 1200 gene cancer array Ability to find genes that are both up- and down- regulated compared to normal cerebellum Gene discovery strategy

42 Samples Medulloblastoma cell lines (DAOY, TE671, UW426, ONS76 ) and Human adult cerebellum 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 Hybridization ScanningAnalysis Flowchart of the procedure The Future of Medulloblastoma

43 Hierarchical Clustering of MAGE and GAGE by microarray UW426 DAOY ONS76 TE671 GAGE7 GAGE7B GAGE3 GAGE6 GAGE4 GAGE2 MAGEA9 GAGE1 MAGEE1 MAGEA10 MAGEC1 MAGEB3 BAGE GAGEB1 MGEA12 MAGEA11 MAGE6 MAGEA3 MAGEA8 MAGEB4 MAGEB2 MAGEB1 MAGEA1 MAGE1 Cell lines 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 Medulloblastoma tumor specimens HMB1 HMB19HMB24HMB35 HMB8

44 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)

45 ResourcesResolutionResults 1-10 Mb 5-10 Kb “small” dataset“large” dataset ~20-30 samples 212 samples Previous studies: Current study:  =

46 100K & 500K GeneChip Mapping Arrays Amplifications: 191 Homozygous Deletions: MBs (201 primaries, 11 cell lines) Known genes/pathways - Myc family - PDGF signaling - OTX2 Novel genes/pathways - chromatin: H3K9 Strategy for identification of novel genetic events in medulloblastoma…

47 Whole genome copy number profiling of MB

48 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

49 MURINE MRI Medulloblastoma in PTCH +/- Mice

50 Gene Silencing in Medulloblastoma

51 --Chromatin remodeler Histones --Transcription --Histone tails MicroRNAs Chromosome DNA methylation Epigenetic Mechanisms In Medulloblastoma Nature, 2008

52 Role of epigenetic silencing in medulloblastoma Cancer Res Dec 2008

53 Mice Implanted with SPINT2 Expressing MB Cells Have Prolonged Survival

54 What is SPINT2? A Novel Target for HGF/cMET inhibition Chr 19q kDa Serine protease inhib Dissection of downstream signaling pathways HGF/cMET pathway inhibition (small molecule PHA )

55 STEM CELLS AND MEDULLOBLASTOMA

56 Stem Cells and Human Malignant Brain Tumors

57 CD15/ LeX /SSEA1 Gal  1-4(Fuc  1-3)GlcNAc  - Sally Temple Neuron 35: 865, 2002 Developmental Biology 291:300, 2006 Adult BrainEmbryonic Brain GFAP A new stem cell marker!

58 Targeting the Brain Tumor Stem Cell Implications for Treatment Reya et al, Nature 414: , 2001

59 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

60 Thank you!


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