medulloblastoma current treatment and future directions n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
MEDULLOBLASTOMA: Current Treatment and Future Directions PowerPoint Presentation
Download Presentation
MEDULLOBLASTOMA: Current Treatment and Future Directions

Loading in 2 Seconds...

play fullscreen
1 / 60

MEDULLOBLASTOMA: Current Treatment and Future Directions - PowerPoint PPT Presentation


  • 196 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'MEDULLOBLASTOMA: Current Treatment and Future Directions' - gil-gallegos


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
medulloblastoma current treatment and future directions
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
cushing and pediatric brain tumours
Cushing and Pediatric Brain Tumours

Acta Pathologica, Microbiologica et

Immunologica Scandinavica 7:1-86, 1930

Surgery, Gynecology and Obstetrics

52: 129-204, 1931

clinical presentation of the child with a medulloblastoma
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 medulloblastoma1
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
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

medulloblastoma1
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
Medulloblastoma - The Evolution of Pediatric Neuro-radiology
  • Skull Xrays
  • Angiography
  • Ventriculography
  • Pneumo-encephalography
  • Myelography
  • CT Scan
  • PET
  • MRI
  • MEG
  • DTI
medulloblastoma2
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%
medulloblastoma3
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
medulloblastoma4
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
medulloblastoma5
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.med.utoronto.ca/neuro/slides.html

Met along shunt tubing

Diffuse bone mets

CSF spread

medulloblastoma6
MEDULLOBLASTOMA

RISK SEGREGATION

Low RiskHigh Risk

> 3 yrs < 3 yrs

No residual tumor > 1.5 cm2 residual

No distant metastases Metastases

All patients with medulloblastoma are high risk

Kintomo Takakura

medulloblastoma7
MEDULLOBLASTOMA
  • IMAGING STUDIES
    • Hyperdense lesion on CT before contrast
    • Heterogeneous enhancement after contrast

Pre-contrast Post-contrast

medulloblastoma8
MEDULLOBLASTOMA

TUMOR LOCATION

Midline, vermian

Hemispheric

CP angle

Brainstem (rare)

Supratentorial (PNET)

Pre-operative MRI Spine!!

medulloblastoma spine mri
MEDULLOBLASTOMA: Spine MRI

Pre-operative spinal imaging is mandatory!

medulloblastoma imaging
MEDULLOBLASTOMA: Imaging

Diagnosis of leptomeningeal disease

medulloblastoma lessons learned
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
medulloblastoma9
MEDULLOBLASTOMA
  • OPERATIVE APPROACH
    • Midline, vermian split
    • Lateral hemispheric
    • Inferior medullary velum - telovelar
    • CP angle
medulloblastoma10
MEDULLOBLASTOMA

INTRA-OPERATIVE NUANCES

Removing tumor from

Floor of IVth

Inspecting anatomical

Structures with tumor

removed

medulloblastoma11
MEDULLOBLASTOMA

Surgery, XRT

And Chemo

5 years

Surgery, XRT And Chemo

4 years

medulloblastoma12
MEDULLOBLASTOMA
  • POST-OPERATIVE COMPLICATIONS
    • Cerebellar, cranial nerve deficits
    • Hydrocephalus requiring shunt or ETV
    • Meningitis
    • Pseudomeningocele
    • Cerebellar Mutism
medulloblastoma how to avoid cerebellar mutism
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!

LancetOncology June 2008

medulloblastoma effects of xrt on the cns
MEDULLOBLASTOMAEffects of XRT on the CNS
  • Neurocognitive
  • Moya moya
  • Endocrinopathy
  • Vasculopathy
  • Cavernous malformation
  • Secondary neoplasms
chemotherapy for medulloblastoma proven effective but
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

medulloblastoma13
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%

future treatment of medulloblastoma
Future Treatment of Medulloblastoma
  • Advanced Cytogenetics
  • Differential Gene Expression
  • SNP array platforms
  • Next generation sequencing
  • Epigenetics
  • Stem Cells
advanced cancer cytogenetics
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

slide40

Nature Genetics 31: 306-310, 2002

The Globe and Mail June 20, 2002

gene discovery cdna microarray analysis
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
slide42

Hybridization

Scanning

Analysis

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

slide43

Medulloblastoma tumor specimens

Cell lines

HMB1

HMB35

HMB24

HMB19

HMB8

DAOY

ONS76

UW426

TE671

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

GAGE7

GAGE7B

GAGE3

GAGE6

GAGE4

GAGE2

MAGEA9

GAGE1

MAGEE1

MAGEA10

MAGEC1

MAGEB3

BAGE

GAGEB1

MGEA12

MAGEA11

MAGE6

MAGEA3

MAGEA8

MAGEB4

MAGEB2

MAGEB1

MAGEA1

MAGE1

Hierarchical Clustering of MAGE and GAGE by microarray

advanced genetic platforms for medulloblastoma
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)
slide45

Previous studies:

~20-30 samples

1-10 Mb

“small” dataset

Current study:

5-10 Kb

212 samples

“large” dataset

Resources

Resolution

Results

=

slide46

212 MBs

(201 primaries, 11 cell lines)

100K & 500K GeneChip Mapping Arrays

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

animal models more reliably predicting clinical response
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
MURINE MRI

Medulloblastoma in PTCH+/- Mice

slide51

DNA methylation

Epigenetic Mechanisms

In Medulloblastoma

--Chromatin remodeler

Histones

--Transcription

--Histone tails

MicroRNAs

Chromosome

Nature, 2008

what is spint2 a novel target for hgf cmet inhibition
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)

cd15 lex ssea1 gal b 1 4 fuc a 1 3 glcnac b
CD15/ LeX /SSEA1Galb1-4(Fuca1-3)GlcNAcb-

Adult Brain

Embryonic Brain

GFAP

Sally Temple

Neuron 35: 865, 2002

Developmental Biology 291:300, 2006

A new stem cell marker!

targeting the brain tumor stem cell implications for treatment
Targeting the Brain Tumor Stem CellImplications for Treatment

Reya et al, Nature 414: 105-111, 2001

medulloblastoma prediction 2019
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