This presentation reviews the current neurosurgical management of patients with medulloblastoma, including the data on molecular subtyping; uses “medulloblastoma” as a springboard to discuss other topics / tumor cell biology in general; and formulates research questions to further advance neurosurgical basic science.

1. Medulloblastoma – Taking A Closer Look
Herb Engelhard, M.D., Ph.D., F.A.C.S.
The University of Illinois at Chicago
“The more you know, the more you realize there is to know” – probably Einstein

2. Objectives for this talk
Review the current neurosurgical management of
patients with medulloblastoma, including the data on
molecular subtyping.
Use “medulloblastoma” as a springboard to discuss
other topics / tumor cell biology in general.
Practice formulating research questions to further
advance neurosurgical basic science.
Note: Some images for this talk were taken from open sites on the Web

3. Brain tumor treatment
Surgery / radiosurgery is usually the primary
treatment, to the extent that it is “safe”
Histologic diagnosis
“Molecular markers”
Alleviation of mass effect
“Cytoreduction” – delays progression
Nutrition, education, psychological support –
always important
The physician should
be the patient’s
expert / advocate.
Surgeons should
always appreciate
the trust their
patients put in them.

4. Medulloblastoma – illustrative case
8 year-old male comes into the ER, with headaches,
lethargy and nausea / vomiting
No significant past medical or family history.
Exam: Pulse 60, BP normal, easily aroused, difficulty
with balance while walking, else negative.
Head CT done; neurosurgery consulted.
Classic: vermian mass
= PNET of
posterior
fossa

5. Medulloblastoma
Most common malignant brain tumor of
childhood / second peak in younger adults
20% of all primary tumors of the central nervous
system among children less than 19 years of age
Peak incidence : 5 - 9 years of age
Occurs exclusively in the cerebellum (name)
Rare after the fourth decade of life
Belongs to the family of small round blue cell
tumors
Medulloblastoma
Overall survival in adult
medulloblastoma
Symptoms and signs:
1) From IICP,
2) Specific to location

6. MRI findings in medulloblastoma
T1: similar to hypointense to grey matter T1 C+ (Gd): 90%
enhance, often heterogeneously
T2: heterogeneous due to calcification, necrosis and cyst
formation; iso- to hyperintense to grey matter
FLAIR: hyperintense to surrounding brain
DWI: shows restricted diffusion
MR spectroscopy: elevated choline, NAA decreased, may
show a taurine peak
May involve cerebellar hemisphere
Differential diagnosis of posterior fossa
masses: Ependymoma, JPA, metastasis,
hemangioblastoma, CPP, glioma, other rare
MRI - Suggests tumor type
Guides surgical approach
Used to evaluate for metastatic
spread – craniospinal axis –
preoperatively if possible

7. Medulloblastoma: Clinical features
 Symptoms of increased ICP
Headache (a.m. classic), N/V, Δ MS, CN VI
 Midline cerebellar tumor
Gait ataxia, truncal instability
 Hemispheric tumor
Limb clumsiness, incoordination, RAM
 Other cranial nerves / dizziness
JPA with Gd
Ependymoma
Brainstem
glioma

8. Medulloblastomas are associated
with a number of syndromes:
 Coffin-Siris syndrome
 Cowden syndrome
 Gardner syndrome
 Gorlin syndrome
 Li-Fraumeni syndrome
 Rubinstein-Taybi syndrome
 Turcot syndrome

9.  Medulloblastoma: EVD may be required – issue
of decompression, upward herniation. Tumor
seeding associated with shunting.
 Usually prone, midline suboccipital,
transvermian approach.
 What is safe to remove? What about normal
brain cells mixed with tumor cells?
 Surgeon: “I got it all” Better: “I removed
everything that I safely could.”
 If postoperative imaging reveals residual tumor,
additional resection is considered – especially if
group 4 medullo (described below).
Surgical treatment of a brain tumor: Cut it out!
Stages of surgical competence

10. Brain tumors considered benign / low grade –
resection effective; sometimes not even needed
Meningioma
Schwannoma
Neurofibroma
Oligodendroglioma (?)
Pineocytoma
Hemangioblastoma
Epidermoid / dermoid
Astrocytoma
Grade I
Pituitary adenoma
Neurocytoma
Ependymoma
Subependymoma
Choroid plexus papilloma
Gangliocytoma / ganglioglioma
DNT (Dysembryoplastic neuroepithelial tumor),
teratoma
Cysts OTHERS
DNT

11. Patient care philosophy
Follow the Golden Rule i.e. “do unto others …”
Patients and their families need lots of information
Options and choices are important
Often, there is not just one right answer
Doctors should freely allow second opinions
No bullying / coercing … e.g. “if you don’t have this
surgery next week, you’ll be paralyzed.”
That being said, there may be risks to not doing surgery –
document these as well.

12. Classic
staging – but
molecular
subtype is
more
important!

13. Symptoms after posterior fossa surgery,
including cerebellar mutism (8-31%)
Cerebellar danger zones
Stay away from cerebellar nuclei,
and floor of fourth ventricle
Stay within tumor
Source: Posterior Fossa Society

14. Medulloblastoma
Invasiveness of primary brain cancer
Glioblastoma
Aggressive resection?

15. Key concepts in (malignant ) brain tumor cell biology
1. “Multifocal” malignant brain tumor = multiple tips to an iceberg
2. Cancer starts with a single cell 3. Tumor cell heterogeneity
Oh my gosh – a second tumor! (MRI does not see everything – cells
are on the order of 105 smaller)
Medulloblastoma
Clones

16. Tumor cell biology / molecular
biology for neurosurgeons – what is
relevant?
Focus on: 1) patient management
and their questions
2) Advances / research / cure
Many interesting topics: proliferation / cell cycle, invasiveness, BBB, drug delivery,
oncogenes / tumor suppressor genes, molecular markers, telomeres, epigenetics …
Bx vs. resect; tissue for what tests
and why?

17. Histopathology of medulloblastoma
Boards: Homer-Wright rosettes
Intraoperative diagnosis – differential for PF mass
Classic Desmoplastic

18. Postoperative radiation and chemotherapy
LP done 10 – 14 days postop for cytology
Initiated within 6 weeks postoperatively
Radiation of surgical bed: 50 – 55.8 Gy
Standard risk = no metastases, CSF negative, postop residual
< 1.5 cm  23.4 Gy spinal radiation
High risk = any metastases / CSF positive / more residual  high dose
spinal radiation = 36 Gy
Less than 3 years: chemotherapy only; radiation if recurrent

19. Chemotherapy for medulloblastoma
Groups: Standard risk (less benefit) vs. high risk
CCNU and vincristine during RT
Others: Cisplatin, cyclophosphamide, carboplatin, etoposide,
temozolomide, etc.
Stem cell rescue
Intrathecal methotrexate, cytarabine, etoposide
Recurrence  death (resistant clones; CSF dissemination)
Targeted therapies being tested – e.g. vismotegib for SHH pathway

20. Outcome for medulloblastoma
 Overall survival at 5 years is approximately 70%
 Diploid vs. aneuploid DNA pattern
 Survival greatly influenced by presence of
metastases / molecular subtype
 WNT subtype: > 90% five year survival

21. Medulloblastoma history: Late 1980s – Cellular DNA content by flow cytometry
Nuclei from formalin–fixed paraffin-embedded (FFPE)
tumor specimens analyzed
C-myc protein, cytoskeleton, DNA
Response to radiation?

22. Figure 8
Cancer Cell 2017 31, 737-754.e6DOI: (10.1016/j.ccell.2017.05.005)
Molecular subtyping of medulloblastoma – current scheme
4 groups; 12 subtypes – prognosis varies – especially WNT (= good)
All are
grade IV

23. Medulloblastomas, but not high-grade
gliomas, demonstrate spatially
homogeneous transcriptomes, which
allow for accurate subgrouping of
tumors from a single biopsy.
- Morrissey et al. Nat Genet. 2017;49(5):780-788.
What is WNT? What is SHH?
Medulloblastomas: less intratumoral heterogeneity

24. The Wnt signaling pathways are signal transduction
pathways initiated through cell surface receptors.
Wnt stands for 'Wingless/Integrated'.
Three Wnt signaling pathways have been characterized:
the canonical Wnt pathway, the noncanonical
planar cell polarity pathway, and the noncanonical
Wnt/calcium pathway.
All three pathways are activated by the binding of a
Wnt protein to a Frizzled family receptor, which passes
the biological signal to the Dishevelled protein inside
the cell.
Canonical Wnt pathway - regulation of gene transcription
Noncanonical planar cell polarity pathway - cytoskeleton
Noncanonical Wnt/calcium pathway - cellular calcium

25. Characteristics of the 3 molecular
subtypes of adult medulloblastoma
What is SHH?
The sonic hedgehog signaling molecule assumes various roles in patterning the CNS
during development.
The patched gene encodes for the ligand binding domain of the SHH receptor.

26. KEY ARTICLE With recurrence, the biology changes
Morrissy A … Taylor M et al. Divergent clonal selection
dominates medulloblastoma at recurrence.
Nature 2016; 529(7586):351-7.
Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy
medulloblastomas demonstrated substantial genetic divergence of the dominant clone
after therapy (<12% diagnostic events were retained at recurrence).
In both mice and humans, the dominant clone at recurrence arose through clonal
selection of a pre-existing minor clone present at diagnosis.
Targeted therapy is unlikely to be effective in the absence of the target, therefore our
results offer a simple explanation for the failure of prior clinical trials of targeted therapy.

27. Patient question: Can’t you boost my
immune system, in order to kill this tumor?
Short answer: This is still being tried, but the tumor
cells are your cells, not foreign cells.
In April, 2010, Sipuleucel-T became the first FDA-
approved tumor vaccine (prostate cancer). 2011:
Ipilimumab for melanoma.
UIC participated in the DC-Vax study.
CAR T therapy is currently being tried for GBM.

28. Classic topic: Mechanisms of tumor escape from attack by the immune system
Successful tumors have evaded attack by the immune system
Tumor – specific antigens (also tumor-associated antigens), while
present in animal models, may not be present in real life
Effector mechanisms (whether cell mediated: T lymphocytes,
macrophages, NK cells; or humoral: antibody – dependent) depend
on antigen recognition.
Tumor cells are deranged internally, not externally!

29. The role of the immune system in
glioblastoma has been studied at
least dating back to 1972!
1909 – Ehrlich suggested the
immune system may be responsible
for elimination of altered host
constituents.
1912 – Report that coated tumor
cells may resist host attack.
1957 – Immune surveillance theory

30. Medulloblastoma: rationale for research
 Medulloblastoma is the most common malignant brain
tumor in the pediatric age group.
 Surgery, postoperative radiation, and chemotherapy, are
standard treatment for patients with medulloblastoma.
 Despite advances regarding molecular subtyping,
prognosis continues to be poor.
 Medulloblastoma cells are notorious for disseminating
within cerebrospinal fluid (CSF) pathways.
 CSF dissemination is found in 30-40% at initial diagnosis
and the majority at recurrence.
 Leptomeningeal seeding is a major cause of death for
these patients.
 Intrathecal chemotherapy, such as with etoposide or
methotrexate, has been used for patients with CSF
dissemination.
Taken from Low S et al. (2018)
PLoS ONE 13(5): e0196696. https://doi.org/
10.1371/journal.pone.0196696

31. How can we improve
drug delivery, and kill
more cancer cells
within CSF pathways?

32. How can we improve
drug delivery, and kill
more cancer cells
within CSF pathways?
 Magnetic nanoparticles (MNPs) have
potential for improving drug targeting
for cancer therapy.
 IMRA America, Inc. has developed Au-
FE alloy particles, conjugated to
streptavidin (SA).
 This allows drugs to be bound to the
particle through SA-biotin bonding.

33. Intrathecal injection of iron-oxide (magnetic) antibodies for
the treatment of cancer cells in the CSF
Problem: does not
work at human
distances!
New
system

34. A Novel Etoposide-Bound Magnetic
Nanoparticle Designed for Remote
Targeting of Medulloblastoma Cells
Departments of Neurosurgery, Bioengineering, and Chemical Engineering; and
The Cancer Center, The University of Illinois at Chicago, Chicago, IL;
and IMRA America, Inc., Ann Arbor, MI

35. Particles are
coated with
streptavidin

36. Background – Etoposide
 Etoposide is a plant alkaloid (epipodophyllotoxin)
which acts as an inhibitor of topoisomerase II .
 Etoposide inhibits DNA synthesis by forming a ternary
complex with DNA and topoisomerase II, inducing
breaks in double stranded DNA.
 Accumulated breaks in DNA prevent entry into mitosis
and lead to cell death.
 Drugs targeting DNA topoisomerase II are important,
effective, and widely-used cancer agents.
 Etoposide is often used as one of the components in
multidrug regimens for medulloblastoma.
 Magnetic nanoparticle -enhanced local delivery of
etoposide for use against leptomeningeal seeding in
cancer patients has not yet been attempted .

37. Methods: 1) Characterization of Etoposide-MNPs
2) Effects on medulloblastoma cells
Dynamic Light Scattering
UV-Visible Spectroscopy
Electron Microscopy – Scanning and Transmission
Velocity of MNPs in Response to a Rotating Magnet
Culture and Treatment of Human Medulloblastoma Cells
Viability Testing by MTT Assay
Flow Cytometry – DNA and Light Scatter
Data Display and Tests of Statistical Significance

38. Results
Biotinylated etoposide
still has its
chemotherapeutic effect
This can be bound to the
base nanoparticles –
released at the cell
surface
Effect on D283 (human medulloblastoma) cells

39. Dynamic light
scattering:
Biotinylated
etoposide does
successfully bind
to base particles in
order to form
Etop-MNPs -
particles are larger.

40. Velocity of Etop-MNPs in response to the rotating magnet

41. Results: Imaging by light microscopy and SEM
D283 medulloblastoma cells

42. Decrease in cell
viability
according to
amount of
chemotherapy
loaded to
particles – MTT
assay
Conclusion: etoposide magnetic nanoparticles may
be useful for treating leptomeningeal seeding

43. Conclusions
Reviewed the current neurosurgical management of
patients with medulloblastoma, including the data on
molecular subtyping.
Used “medulloblastoma” as a springboard to discuss
other topics / introduced some research questions.
Thank you!