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MEDULLOBLASTOMA: Current Treatment and Future Directions

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Title: MEDULLOBLASTOMA: Current Treatment and Future Directions


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
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3
The Past
4
Cushing and Pediatric Neurosurgery
5
Cushing and Pediatric Brain Tumours
Acta Pathologica, Microbiologica et Immunologica
Scandinavica 71-86, 1930
Surgery, Gynecology and Obstetrics 52 129-204,
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 morningThe
    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 soonthe 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
    finallyextensor 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 Cushings 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 Canadas 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 ofPediatric Brain Tumors
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
  • PFS _at_ 5 yrs 85 for entire group
  • PFS _at_ 5 yrs 67 for children with metastases
  • PFS _at_ 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)

The Harold J Hoffman Slide Collection www.surg.me
d.utoronto.ca/neuro/slides.html
Met along shunt tubing
Diffuse bone mets
CSF spread
17
MEDULLOBLASTOMA
  • RISK SEGREGATION
  • Low Risk High Risk
  • gt 3 yrs lt 3 yrs
  • No residual tumor gt 1.5 cm2 residual
  • No distant metastases Metastases

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
MedulloblastomaLessons 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
INTRA-OPERATIVE NUANCES
Removing tumor from Floor of IVth
Inspecting anatomical Structures with
tumor removed
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
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30
MedulloblastomaHow 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
MEDULLOBLASTOMAEffects of XRT on the CNS
  • Neurocognitive
  • Moya moya
  • Endocrinopathy
  • Vasculopathy
  • Cavernous malformation
  • Secondary neoplasms

32
NEJM 2005352978-986
33
Chemotherapy for MedulloblastomaProven effective
but.
6 year old male Short history GTR Excellent
post-op course
Cycles of chemotherapy Stem cell
transplant Infectious complications Toxic
mortality
34
MEDULLOBLASTOMA
  • CURRENT BEST TREATMENT
  • Maximum safe neurosurgical resection
  • Radiation therapy (reduced craniospinal
    irradiation, avoid irradiating children lt 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 ANDGERMLINE SUFU MUTATION
40
Nature Genetics 31 306-310, 2002
The Globe and Mail June 20, 2002
41
Gene DiscoverycDNA 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
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
43
Hierarchical Clustering of MAGE and GAGE by
microarray
44
Advanced Genetic Platformsfor Medulloblastoma
  • Single nucleotide polymorphism (SNP) array
    platforms (CNAs)
  • PCR-directed exon resequencing
  • DNA methylation assays (epigenetics)
  • DNA histone alterations (epigenetics)
  • Next generation (deep) DNA sequencing (454
    Roche, Solexa Illumina, SOLiD Applied Bioscience)

45
Resources
Resolution
Results
?

46
Strategy for identification of novel genetic
events in medulloblastoma
Amplifications 191 Homozygous Deletions 159
  • Known genes/pathways
  • - Myc family
  • - PDGF signaling
  • OTX2

Novel genes/pathways - chromatin H3K9
47
Whole genome copy numberprofiling 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
DNA methylation
Epigenetic Mechanisms In Medulloblastoma
--Chromatin remodeler
Histones
--Transcription
--Histone tails
MicroRNAs
Chromosome
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 19q13
  • 28.2 kDa
  • Serine protease inhib
  • Dissection of downstream signaling pathways
  • HGF/cMET pathway inhibition (small molecule
    PHA-665752)

55
STEM CELLS AND MEDULLOBLASTOMA
56
Stem Cells andHuman Malignant Brain Tumors
57
CD15/ LeX /SSEA1Galb1-4(Fuca1-3)GlcNAcb-
Adult Brain
Embryonic Brain
GFAP
Sally Temple Neuron 35 865, 2002 Developmental
Biology 291300, 2006
A new stem cell marker!
58
Targeting the Brain Tumor Stem CellImplications
for Treatment
Reya et al, Nature 414 105-111, 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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