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9500 Euclid Avenue, Cleveland, OH 44195
The Cleveland Clinic Foundation is an independent, not-for-profit, multispecialty academic medical center. It is dedicated to providing quality specialized care and includes an outpatient clinic, a hospital with more than 1,000 available beds, an education division and a research institute.
How to Refer a Patient to the Cleveland Clinic Brain Tumor InstituteMembers of the Brain Tumor Institute are available for consultation 24 hours a day, seven days a week. Their goal is to see patients with diagnosed or suspected brain tumors within 24 to 48 hours.
216.445.8971 or 800.553.5056, ext. 58971 (weekdays 8 a.m. to 5 p.m.) for consultations and/or hospital admission.
216.444.2200 (nights and weekends). Ask for neuro-oncology staff or the chief neurosurgical or neurological resident on
call. For pediatric patients, ask for the chief pediatric neurological resident on call.
Patient appointment line:
216.445.8971 or 800.223.2273, ext. 58971
Clinical trials information:
Toll-free 866.223.8100 (Cancer Answer Line)
Cleveland Clinic Florida (Weston):
954.659.5000
For details about the Brain Tumor Institute, please visit clevelandclinic.org/braintumor
06-BTI-003
Brain Tumor Institute2005 Annual Report prepared by Gene H. Barnett, M.D., Chairman
A team approach to individualized care
III Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Table of Contents01 Letter from Chairman
02 Executive Summary
02 Invited Lectures
03 Educational Activity
04 Support and Grants
05 Membership
05 Recruitment
06 Research
07 Marketing, Advertising, Media Relations
07 Expanded Services
07 Patient Education
08 Clinical Programs
14 Clinical Research
17 Laboratory Research
26 Publications
33 Appendix A – Adult and Pediatric Clinical Trials
38 Appendix B – Charts and Statistics
39 Appendix C – Articles
44 Faculty
On the Cover: High power photomicrograph of macrophage (stained with green) showing red quantum dots phagocytized inside lysomes within the cells. These cells carry the QDots into the tumors, allowing them to be identified with optical imaging.
2005 Annual Report A team approach to individualized care �
Established in 2001, the Brain Tumor Institute (BTI) at Cleveland Clinic is among the
leading brain tumor centers in the nation. We are serving more patients than ever;
expanding our services and improving patient satisfaction; attracting world-class
physicians and scientists; making giant leaps in research and discovery; and acquiring
photobleaching. Their electron-dense metallic cores
suggest they may have utility in computed tomogra-
phy as well as optical imaging. Coreshell zinc sulfide-
cadmium selenide quantum dots were studied in
magnetic resonance and computed tomography
phantoms. In addition, the Qdots were injected
into rat brain using convection-enhanced delivery,
intravenously to co-localize with rat brain tumor
models, and studied with CT and MRI. Data suggests
that current formulations of Qdots are phagocytized
by macrophages and co-localize with brain tumors
in vivo after IV injection. Phantoms and CED imaging
of animals show that Qdots may be imaged with CT,
but not MRI, suggesting that quantum dots have the
potential to function as multimodal imaging platforms
in vivo.
Steven Toms, M.D., directs the Section of Metastatic
Disease for the BTI and devotes the majority of his
clinical operating time on intraoperative monitoring,
awake craniotomy techniques and intraoperative
ultrasound.
Current translational research involves identifying and developing
new compounds that are directed against targets relevant to
malignant gliomas.
Center for Translational Therapeutics“Translating Novel Therapies for Malignant Brain Tumors from the Bench to the Bedside”The cornerstone of the BTI is the Center for Translational
Therapeutics. Directed by Dr. Michael Vogelbaum, aggressive
preclinical testing of the most promising anticancer agents is
under way. One goal of the center is to accelerate the lengthy
and expensive process of testing new drugs targeted against
brain tumors and to safely move them into clinical trials as
quickly as possible, for the benefit of patients.
Physicians, researchers and scientists involved in this center
work with both pharmaceutical companies and other medical
institutions to identify, obtain and test new compounds. The
center’s multi-million dollar efforts, including an international
search for all potential brain tumor-relevant therapies, have
yielded several promising agents for testing.
Testing of new agents involves evaluating the toxicity and efficacy
of these compounds in the laboratory and in animals that have
brain tumors. In addition, we also are investigating the optimal
route of delivery of these drugs.
Because many new therapeutic agents cannot penetrate the
central nervous system, center researchers are exploring
alternative delivery methods. In addition to investigating the
efficacy of oral delivery, researchers evaluate the efficacy of the
agents when delivered intracerebrally – directly into the brain –
via a specialized neurosurgical technique called convection-
enhanced delivery (CED).
The staff of the center is focused on translating these preclinical
results into Phase I and II clinical trials – giving the brain tumor
patient more therapeutic treatment options by broadening the
horizon of potential tools we may use to manage this deadly disease.
The CTT has started research projects with a number of pharmaceu-
tical and biotechnology companies, ranging in size from small
startup firms to some of the largest publicly traded companies.
What these companies have in common are novel drugs that are
close to or are in clinical trial and which are rationally designed to
be effective against malignant gliomas given the molecular and
genetic makeup of these tumors. These drugs are targeted against
molecules such as EGFR, VEGFR, Fas/Apo2, mTOR/Akt, Jak/STAT3
and Raf-1 kinase. Our first translational clinical trial is with Tarceva/
OSI-774, a selective EGFR kinase inhibitor small molecule drug.
CTT Staff Include:Director: Michael A. Vogelbaum, M.D., Ph.D.
Project Scientist: Baisakhi Raychaudhuri, Ph.D.
Technical Assistant: Hamid Daneshvar
Section of Metastatic Disease“Optical Adjuncts to Brain Tumor Therapy” NAD(P)H Autofluorescence in Cell Death – NADH and
NAD(P)H are pyridine nucleotides that function as electron
donors in oxidative phosphorylation. The pyridine nucleotides
also function as antioxidants in mitochondria and serve as major
intracellular fluorophores in their reduced states. Our long-term
goal is to design optical sensors to gauge the effectiveness of
chemotherapeutic drugs by measuring changes in NAD(P)H
fluorescence. We hypothesize that NAD(P)H fluorescence
declines prior to apoptotic cell death. We have observed that
1) the NAD(P)H fluorescence emission peak from UV wavelength
excitation is lost during a variety of insults, including hyperther-
mia, sodium azide poisoning and chemotherapy; 2) mass
spectrometry of cell lysates treated with chemotherapy shows
NAD(P)H losses that parallel cellular fluorescence declines; and
3) the decline in cellular fluorescence precedes nuclear conden-
sation and cell viability loss during apoptosis. Based upon these
observations, we are submitting grants to examine the role of
NAD(P)H in apoptosis, focusing upon changes in fluorescence
signal that may be used to detect cell and tissue viability.
20 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Molecular Genetics and Molecular Neuro-OncologyDr. Olga Chernova leads or participates in projects one through
five, while Dr. Mladen Golubic does so for projects six and seven.
Project �. Genetic alterations and biological characterization of
primary cell cultures derived from malignant gliomas. The initial
objectives of this project were a) finding conditions for establish-
ing short-term primary cultures from glial tumors that would
serve as a model for studies of glial tumors; b) establish a
method for fast and reliable evaluation of homogeneity of tumor
culture that would allow monitoring of culture content in different
growth conditions since variable contamination with normal cells
represented a problem. In a course of the work, we found that
modified medium used for propagation of normal neural stem
cells allow selective isolation of tumor cells in primary culture.
A genotyping assay was established, which allows semi-quantita-
tive evaluation of the homogeneity of the cultures. The growing
interest to the role of the stem cells in tumorigenesis prompted
a characterization of the origin and differentiation status of the
cultured tumor cells in collaboration with Dr. Robert Miller. Using
a set of antibodies detecting several neural stem cells markers, at
least two types of glioma cultures, which may potentially originate
from different pools of the neural stem cells, have been identified.
Analysis of tumorigenic potential of these primary tumor cultures
in nude mice is in progress.
Growing interest in stem cells in brain tumors resulted in two
collaborative projects with Cleveland Clinic researchers: (1) a
collaboration with Dr. Gregory Plautz to develop a vaccine for
brain tumors resulted in submission of RO1 NIH proposal; (2)
a collaboration with Drs. Jaharul Haque and Michael Vogelbaum
to study signal transduction pathways and gene expression in
brain tumor stem cells.
Project 2. Genetic alterations in GBMs (loss or gain of ��q, �p
and other novel alterations) and their correlations with patient
survival. Several recently published initial observations indicate
that numerical alterations in chromosomes 1p and 19q may be
predictive of clinical response or survival of patients with GBM.
To confirm and expand these initial observations, well-controlled
groups of 34 patients with newly diagnosed GBMs treated at
Cleveland Clinic and demonstrated either long (>20 months) or
short (between three and nine months) survival were selected.
Ten LOH markers distributed along 1p arm and 4 markers along
19q arm were used. Preliminary data indicate that both types of
allelic imbalance, loss or gain, of 1p and/or 19q could be found
in GBM tumors and occur in both groups of patients. However,
to complete this study, the same tumors should be analyzed
using FISH or multiplex PCR techniques to discriminate true
losses of chromosomes from their gains. Forty percent of the
specimens were analyzed by FISH at the Molecular Pathology
lab. The rest of the specimens are currently studied using
multiplex PCR assays for 1p and 19q. A recently developed
MLPA technique for multiplex PCR analysis of 1p/19q is being
used. This part of the study is in progress.
As an extension of this project, Drs. Chernova, Weil (BTI) and
Wigler (Cold Spring Harbor Laboratory) collaborated. Dr. Wigler
developed a high-density microarray-based comparative genomic
hybridization assay for analysis of numerical alterations in
genomic DNA. Using a set of six DNAs from long-term and
short-term surviving patients with GBM, preliminary data
was obtained that indicates the assay is extremely sensitive
and was able to identify novel regions of alterations.
Project �. Development of a clinical assay for detection of
deletions in CDKN2A, ARF, PTEN and p5� genes in gliomas.
We have developed a semi-quantitative assay for detection of
gene deletions based on multiplex PCR. The goal of the project
is development, validation and introduction of this prognostic
assay to the clinical laboratory. This assay will also be impor-
tant for the “Genotyping Arrays” project as a part of validation
of the array data.
Project �. Genotyping arrays as a prognostic tool: glioma
model. This project is a collaboration with Cleveland BioLabs
and the microarray manufacturing company Nimblegen. The aim
of the project is to develop a genotyping microarray-based assay
that will identify alterations in chromosome copy number and
allelic imbalances in critical chromosomal regions, as well as
mutations in genes that have prognostic significance in glial
tumors and predict response to therapy. Amended STTR
proposal had been resubmitted to the NIH in October 2005.
Project 5. Distinct alteration of chromosome �p in astrocytic
and oligodendrocytic tumors. The extent of 1p deletion in low-
and high-grade gliomas using LOH analysis was characterized.
The results indicate that oligodendroglial tumors almost uniformly
demonstrate very large deletions of 1p arm. Conversely, GBMs
have only partial deletions affecting the terminal part of 1p. This
data indicate that (1) only large deletions on 1p are associated
with positive prognosis (need to perform more statistical
analysis), and (2) partial 1p deletions in GBM are not associated
with positive prognosis (see also GBM survival project).
Project �. Role of Eicosanoids in Glioblastoma Tumorigenesis.
Eicosanoids are special type of fats produced in the human
body from diet-derived fats by the action of enzymes called
cyclooxygenases (COX-1 and COX-2) and lipoxygenases.
We have determined that 5-lipoxygenase (5-LO), an enzyme
that stimulates inflammation, is aberrantly overexpressed in
malignant brain tumors, anaplastic astrocytoma and GBM.
The two main interconnected aspects of this project are (1)
to investigate the expression of other eicosanoid enzymes of
the 5-LO pathway in the GBM tumor tissue and measure
eicosanoids in the blood of patients with GBM; and (2) to
explore novel ways to inhibit 5-LO and COX-2, the two main pro-
inflammatory enzymes that are aberrantly overexpressed in GBM.
To inhibit 5-LO, we are examining the use of Boswellic acids.
2005 Annual Report A team approach to individualized care 2�
Boswellic acids are naturally found in the gum resin exudate from
the Boswellia serrata (frankincense) tree. The herbal preparation
from B. serrata will be used in combination with a low-fat diet as
an adjuvant therapy for patients with GBM in a clinical study (see
Project 6. Molecular characterization of genes that are modulated
by Boswellic acids in GBM cells currently is in progress. The
levels of eicosanoids are measured not only in blood of patients
with GBM, but also in tumor tissue specimens that were surgically
removed. The goal of this collaborative study with Dr. Robert
Newman from the MD Anderson Cancer Center is to correlate
levels of eicosanoids in tumor tissue and blood with clinical
outcomes of patients with GBM.
To suppress the aberrantly overactive COX and 5-LO enzymes in
GBM cells, we are investigating the potential anticancer effects of
an anti-inflammatory herbal preparation (Zyflamend, by New
Chapter, Inc.). It consists of standardized extracts from 10 different
spices (including turmeric, ginger, rosemary and oregano) and
medicinal herbs. We have shown that Zyflamend induces
programmed cell death of GBM cells in vitro and inhibits produc-
tion of eicosanoids in surgically removed GBM tissue specimens.
This work is done in collaboration with Dr. Newman’s laboratory
and is supported by the research grant from New Chapter, Inc.
Recently, we identified more than 150 genes that are either
induced or suppressed in expression when GBM cells are treated
with Zyflamend. Currently, the functional significance of two of
those genes is being investigated further. The obtained results
were presented at the Annual Research Conference of the
American Institute for Cancer Research in Washington, D.C., in
July 2005, and at the 2nd International Conference of the Society
for Integrative Oncology in San Diego, Calif., in November 2005.
Project �. 5-Lipoxygenase Inhibition as an Adjuvant Glioma
Therapy A two-year clinical study supported by a grant from
the National Institutes of Health is currently in progress.
This study builds on knowledge obtained in this laboratory and
from clinical experience by German investigators. The primary
objective is to determine whether a suppression of pro-inflamma-
tory enzymes, including 5-LO, by a combination of an herbal
formulation and a diet can reduce brain swelling caused by GBM.
As brain swelling often causes symptoms, possible effects on
quality of life and survival of patients with GBM will also be
examined. Patients with a newly diagnosed GBM after surgical
removal of the tumor and radiation therapy will be randomly
assigned to two groups. The patients in the intervention group
will use a B. serrata herbal preparation (containing naturally
occurring inhibitors of 5-LO enzyme) in combination with a low-fat
vegan diet as an adjuvant to their main treatment. The control
group will eat a diet according to the guidelines by the American
Cancer Society, also as an adjuvant to their main treatment.
Molecular Biology of Brain Tumors Dr. Andrei Gudkov has established a facility aimed at identifica-
tion of molecular targets and development of target-based
therapies for treatment of brain cancer, based on an integrated
technological platform that includes: 1) gene target identification
based on the combination of novel functional genomic approach-
es with global gene expression profiling and advanced bioinfor-
matics and 2) identification of bioactive compounds with the
desired properties, using small molecule screening facility,
followed by pharmacological optimization of primary hits.
Dr. Gudkov is applying the established technology pipeline to the
generation of a genetic database and identification of candidate
genes associated with brain tumor development and progression,
with specific focus on tumor suppressor genes, drug sensitivity/
resistance genes and diagnostic markers. The aims of this work
are to: 1) identify and test prospective therapeutics among secreted
or membranal protein products of identified disease-specific genes;
2) develop high throughput technology of isolation of new anticancer
therapeutics by screening chemical libraries for prospective gene-
or pathway-specific drugs based on the discovered genes; and 3)
develop diagnostic assays that will grade tumor type and stage
of progression, facilitate selection of optimal therapy, provide an
accurate and reliable prognosis, and initiate a broad program of
clinical validation based on the selected combinations of candidate
disease-specific genes. This effort has already resulted in identifica-
tion of two prospective anticancer treatment molecular targets
that are currently being used for small molecule screening. A small
molecule inhibitor of multidrug resistance with a new mechanism
of activity associated with MRP1 and other multidrug transporters,
4H10, capable of sensitizing glioma cells to a variety of anticancer
agents has been isolated.
The initial stages of this project were funded by a Finding the
Cures for Glioblastoma Award and by the Technology Action
Fund of Ohio Award.
Blood-Brain Barrier, Tumor Markers and Human Gliomas Project Previous attempts in this and other laboratories have failed to
achieve growth of a variety of malignant brain tumors consis-
tently in vitro, perhaps due to the non-physiological conditions
that traditional tissue culture provides. We are attempting to
grow malignant brain tumors (oligodendroglioma and glioblas-
toma) under so-called “dynamic conditions” in a 3-D tissue
culture apparatus where glia-endothelial co-culturing promotes
the establishment of a physiologic blood-brain barrier. When
a blood-brain barrier is formed, we position either solid or
disassociated tumors in the abluminal chamber in direct
proximity to normal glia (astrocytes). We will initially study the
ability of these human tumors to grow under dynamic conditions.
Genotyping and tumor mass determinations will be used to evalu-
ate similarity of growth patterns in vitro vs. in vivo. We also
propose to examine direct vs. indirect drug resistance of the
tumor by injecting chemotherapeutic agents either directly into
the abluminal site or intraluminally, where a blood-brain barrier
separates the “blood compartment” from the brain tumor itself.
22 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Another focus of this laboratory is to determine the role of S100
as a potential tumor marker. We are examining changes in S100
level with blood-brain barrier disruption and its correlation with
metastatic and glioma tumor burden. Related projects by Dr. Yan
Xu are examining phospholipid antibodies as a potential tumor
marker. Other markers of deranged p53 mechanisms and small
molecule modulators of blood-brain barrier function are evaluated
by Dr. Andrei Gudkov.
Immunology and Immunotherapy
New approaches are requisite if malignant gliomas are to be
treated successfully. Immunotherapy is an attractive approach in
this disease; however, this form of treatment has not been very
successful clinically. Growing evidence suggests that the poor
response to immunotherapy is likely due to the inability of current
therapeutic approaches to adequately reverse immune suppres-
sion. It is been well-documented that patients with gliomas are
characterized by systemic immune dysfunction, as demonstrated
by impaired cell-mediated immunity, lymphopenia and inability
Table �. Members of the Division of Pathology and Laboratory Medicine Actively Participating in Molecular Neuropathology
Project as of 9/30/05.
NeuropathologistsRichard Prayson, M.D. Specimen diagnosis. Validation of immunohistochemistry reagents Susan Staugaitis, M.D., Ph.D. Specimen diagnosis. Liaison among Pathology Laboratories and Clinicians for Molecular
Neuropathology test development and interpretation. Maintenance of Pathology Glioma Database. Consultant for BTI database.
MolecularGenetic PathologistsRaymond Tubbs, D.O. Director of Molecular Genetic Pathology Laboratory. Supervision of FISH. Review
of FISH results with technologists.Supervision research and development of array- based hybridization assays.
Ilka Warshawsky, M.D., Ph.D. Supervision DNA extraction, PCR based assay development, review of validated PCR based assays.
Gary W. Procop, M.D., Review of FISH results with technologists. James R. Cook, M.D., Marek Skacel, M.D.
Marybeth Hartke, B.S., M.T.(ASCP) Development and validation of FISH Assays. Performance of FISH analyses
Kelly Simmerman, M.T. (ASCP), Performance of FISH analyses Karen Keslar, M.S., Rosemary Neelon, B.S.
Tissue Procurement TechnologistsJessica Krimmel, B.S., Transport and processing of blood and tissues from OR. Communications Barbara Bekebrede, B.S., with BTI Specimen Bank Technologists. Jessica Roman, B.S., Carrie Nedbalski
Renata Klinkosz, B.S., M.T., Sectioning blocks for immunohistochemistry and genotyping, development and performance of Kathy Maresco, B.S., M.T.(ASCP), immunohistochemistry assays Michelle Wayman, B.S., H.T.(ASCP), Derek Mangalindan, B.S., M.T.
Reference LaboratoryMary Ann Kannenberg, B.S., M.T.(ASCP) Manager, Laboratory Services
(Reference Laboratory).
Kathy Leonhart, Client Services (Marketing)
Laboratory Information SystemsDale Duca Lead Systems Analyst. Contact for development of mechanisms for ordering and reporting test
results in CoPath, transfer to hospital information systems (LastWord, Epic, searches of CoPath for transfer of info to BTI database.
2005 Annual Report A team approach to individualized care 2�
Table 2: Summary of Molecular Genotyping Tests available during Reposting
Period 10/1/04 – 9/30/05.
Test Target specimens Status of test
FISH for 1p/19q All gliomas “FISH for 1p/19q” ordered as a single procedure within CCF and through CCF Reference Laboratory. 1p and 19q may also be ordered individually.
EGFR FISH High grade gliomas Orderable clinical test within CCF and through CCF Reference Laboratory. Tests are also performed on low grade gliomas of CCF patients and billed to research accounts.
1p LOH by PCR Performed upon request to characterize, Orderable clinical test within CCF and through CCF in greater detail, genetic alterations on Reference Laboratory. Chromosome 1p
19q LOH by PCR Performed upon request to characterize, CCF Technical Validation nearly completed. in greater detail, genetic alterations Two tests performed. on Chromosome 19q
TP53 sequencing Upon request on selected anaplastic Orderable clinical test within CCF and through CCF (exons 5-8) oligodendrogliomas. Immunohistochemistry Reference Laboratory. for p53 (>50% of cells positive) is predictive of mutation in most cases.
Table �. Numbers of Molecular Genotyping tests performed by Specimen Class*.
Specimen Class FISH FISH FISH �p LOH ��q LOH TP5� SEQ Totals for �p for ��q for EGFR** by PCR by PCR
* Specimen Classes SX and SO are patients treated by BTI Physicians.** Numbers to not include approximately 13 tests performed on low grade gliomas of CCF patients and billed to research accounts.
680 surgical procedures were performed in 2005
2� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
to mount delayed-type hypersensitivity reaction. Indeed some
of the immune suppression is likely related to the fact that a
higher percentage of T cells from glioma patients are undergoing
apoptosis as compared to T cells from healthy individuals. It is
important at this time to not only focus on boosting the immune
response to GBM but also to include a second arm in the
therapeutic strategy that will prevent the immune cells from
undergoing tumor-induced immune suppression. Previously we
showed that GBMs mediate immune suppression via promoting
T-cell death through receptor-dependent and receptor-indepen-
dent apoptotic pathways.
Recently we reported that gangliosides produced by GBM
lines contribute to the induction of T-cell apoptosis, since the
the abilities of all four GBM apoptogenic lines to kill lymphocytes
(Chahalvi A, et al. Cancer Research 2005). HPLC and mass-
spectroscopy demonstrated that GM2, GD3 and GD1a were
expressed by all four apoptogenic GBM-lines, but not by the two
GBMs lacking activity. The expression of GM2, GD3, GD2 and
GM1 has been recently demonstrated by immunostaining of
GBM lines with antibodies specific for each of these gangliosides.
To define the relative contribution that each of these gangliosides
makes to the tumor-induced killing of T cells, antibodies specific to
each of the gangliosides were added to co-culture of T cells and
CCF-52 cells. The antibodies or isotype control Ig was added at
the beginning of the cultures. These studies revealed that anti-
GM2 antibody was most effective at blocking T cell apoptosis,
while anti-GM1 displayed modest activity, and antibodies to GD2
and GD3 were ineffective. Thus, GM2 expressed by CCF-52 plays
an important role in promoting T-cell apoptosis. These studies are
being repeated using the other GBM lines, CCF4 and U87.
Additional supporting data demonstrating that GM2 is apopto-
genic for T cells was provided by transfecting CCF-52 tumor
cells with siRNA for GM2 synthase. Such treatment causes a
significant reduction in the expression of GM2 that is observed
within 24 hours and lasts for over 72 hours. RT-PCR analysis of
mRNA from these transfected cells revealed that messenger RNA
for GM2 synthase was reduced within 12 hours, with optimal
suppression occurring at 48 hours. The reduction in GM2 expres-
sion following transfection with siRNA for GM2 synthase was
selective since there was no decrease in the expression levels
of GM1 and GD3. Most important, the loss of GM2 expression
coincided with a reduction (50 percent) in the ability of CCF-52
to induce apoptosis in normal T lymphocytes. Similar studies are
planned for the other GBM lines.
Recent findings suggest GM2, which is produced by the CCF-52
cell line, is shed into the supernatant, where it can then bind T
cells. Immunofluorescence staining with anti-GM2 antibodies
demonstrated that T cells from normal individuals do not express
detectable GM2. However, after a one- to two-day incubation of
these T cells with conditioned medium from cultured CCF-52
cells, GM2 was detected by anti-GM2 antibody staining. The
expression of GM2 coincided with the appearance of apoptosis in
the T cells exposed to CCF-52 supernatant but not T cells cultured
in media alone. Similar findings were observed when T cells from
normal donors were co-cultured with a monolayer of CCF-52 cells.
We are now interested in analyzing T cells from GBM patients to
determine whether a portion of these cells are GM2 positive and
whether the presence of GM2+ T cell correlates with increased
levels of GM2 in patient plasma and with T-cell apoptosis.
We are currently testing whether the iron chelator/antioxidant
desferoxamine (DFO) is able to protect T cells in rats that bear the
syngenic transplantable tumor, S635. Previously, we showed that
in vitro DFO can protect T-cells from apoptosis induced by isolated
GBM gangliosides and GBM cell lines by 45 to 85 percent. New
studies show that administration of DFO via an implantable pump
can significantly reduce the percentage of apoptotic T cells that are
present in the peripheral blood and tumor. We are in the process
of testing whether DFO administration will enhance the antitumor
activity of adoptively transferred T cells derived from the draining
lymph nodes of S636-bearing mice.
Cerebrovascular Research Center Dr. Damir Janigro leads the Cerebrovascular Research Center
in cooperation with Dr. Luca Cucullo.
Alternating current electrical stimulation enhanced chemotherapy:
a novel strategy to bypass multidrug resistance in tumor cells.
BMC Cancer. 2006 Mar 17;6(1):72 PMID: 16545134
Tumor burden can be pharmacologically controlled by inhibiting
cell division and by direct, specific toxicity to the cancerous tissue.
Unfortunately, tumors often develop intrinsic pharmacoresistance
mediated by specialized drug extrusion mechanisms such as P-
glycoprotein. As a consequence, malignant cells may become
insensitive to various anticancer drugs. Recent studies have shown
that low intensity, very low frequency electrical stimulation by
alternating current (AC) reduces the proliferation of different tumor
cell lines by a mechanism affecting potassium channels while
intermediate frequencies interfere with cytoskeletal mechanisms of
cell division. The aim of the present study is to test the hypothesis
that permeability of several MDR1 over-expressing tumor cell lines
to the chemotherapeutic agent doxorubicin is enhanced by low
frequency, low intensity AC stimulation.
We grew human and rodent cells (C6, HT-1080, H-1299, SKOV-
3 and PC-3), which over-expressed MDR1 in 24-well Petri
dishes equipped with an array of stainless steel electrodes
connected to a computer via a programmable I/O board.
We used a dedicated program to generate and monitor the
electrical stimulation protocol. Parallel cultures were exposed
for three hours to increasing concentrations (1, 2, 4, and 8 m)
of) M doxorubicin following stimulation to 50 Hz AC (7.5 mA)
or MDR1, inhibitor XR9576. Cell viability was assessed by
determination of adenylate kinase (AK) release. The relationship
between MDR1 expression and the intracellular accumulation
2005 Annual Report A team approach to individualized care 25
of doxorubicin as well as the cellular distribution of MDR1
was investigated by computerized image analysis immunohisto-
chemistry and Western blot techniques.
By using a variety of tumor cell lines, we show that low frequen-
cy, low intensity AC stimulation enhances chemotherapeutic
efficacy. This effect was due to an altered expression of intrinsic
cellular drug resistance mechanisms. Immunohistochemical,
Western blot and fluorescence analysis revealed that AC not only
decreases MDR1 expression but also changes its cellular distribu-
tion from the plasma membrane to the cytosol. These effects
synergistically contributed to the loss of drug extrusion ability
and increased chemosensitivity.
In the present study, we demonstrate that low frequency, low
intensity alternating current electrical stimulation drastically
enhances chemotherapeutic efficacy in MDR1 drug-resistant
malignant tumors. This effect is due to an altered expression
of intrinsic cellular drug resistance mechanisms. Our data
strongly support a potential clinical application of electrical
stimulation to enhance the efficacy of currently available
chemotherapeutic protocols.
Surgical EngineeringWork in this area was led by Dr. Barnett and Eric LaPresto
and focused on two areas: (1) Development of a brain image
processing program capable of fusing up to 64 sets of images
(CT, MRI, PET, DTI, etc) and correlating location and intensity of
any given point (voxel) over time. This program has moved into
frequent clinical use to fuse low-resolution imaging (such as PET)
with MRI, as well as new modalities such as MR and CT blood
volume imaging. It also has proved useful showing trends in
tumor size over time. (2) Ongoing development of the BTI
research/clinical database – a secure repository of clinical
information, imaging, pathology and results of molecular
investigations in a Web-accessible, IRB-approved format.
IL-�� Induction of Glioma ApoptosisDr. Martha Cathcart directs work in this laboratory that has been
defining the relevant IL-13 receptors in several cell types and
identifying the downstream signal transduction cascades. Her lab
is interested in understanding the IL-13-mediated induction of
apoptosis, the regulation of IL-13 signal transduction pathways
and the regulation by receptor composition. To date Dr. Cath-
cart’s laboratory has identified the heterodimeric receptor
molecules, IL-13Ra1 and IL-4 receptor. They associate with
activated Jak family members, Jak2 and Tyk2. These tyrosine
kinases then phosphorylate Stats 1, 3, 5 and 6. Stats 1 and 3
are also phosphorylated on serine 727 in an IL-13-dependent
manner. Recent studies indicate the Stat serine phosphorylation
is regulated by both p38 MAP kinase as well as PKCd. Her
laboratory is interested in understanding the alternative signal
transduction pathways utilized in normal cells versus glioblas-
toma cells to further understand IL-13 induction of apoptosis.
Recent data indicate the existence of a novel signalosome
complex that is induced by IL-13 and contains Src kinase, p38
MAP kinase, PKCd and Stat3. Each of these molecules has been
shown to be required for 15-lipoxygenase expression, which
appears to regulate apoptosis.
Molecular Pathology of Gliomas: “Glioma Genotyping”Reporting period: 10/1/04 through 9/30/05
During the past reporting period, it was decided that the initiative
for development of tests for possible translation into the clinical
laboratory would begin in the research labs of the BTI. Once the
research laboratories concluded that a specific test was feasible
on biopsy and surgical specimens, and the clinicians indicated
that the results of such tests would be used in treatment
planning, Dr. Susan Staugaitis would bring the test proposal to
the clinical laboratory for prioritization in their test implementa-
tion schedule and assist in coordinating efforts for technical
validation, ordering and reporting.
Several improvements for glioma genotyping ordering and execution
have occurred in the past reporting period. All glioma genotyping
tests are now ordered directly within the Pathology Information
System, CoPATH. This streamlines the process and permits
retrieval of test information for annual reports and other operational
purposes. Microdissection of samples for DNA extraction and LOH
was transferred to the technologists in the Immunohistochemistry
Laboratory. This laboratory performs the microdissection for colon
cancer microsatellite analysis by the same techniques as the glioma
specimens and permits adequate volume to maintain expertise in
the technique by several technologists.
Transcription Factors and Brain Tumors Dr. Michael Vogelbaum directs work in this laboratory. Patients
with malignant gliomas continue to have a very poor prognosis
despite multiple new approaches to their treatment. In particular,
most of these tumors are resistant to DNA-damaging treatments,
including radiation therapy and most standard forms of chemo-
therapy. A growing body of evidence supports the hypothesis that
aberrant activation of key transcription factors is critical for the
development and progression of these tumors. A greater under-
standing of the biology of these transcription factors should help
us develop new, more effective therapeutic modalities.
In collaboration with Dr. Jaharul Haque, Institute’s Department
of Cancer Biology, we have found two transcription factors,
STAT3 and NF-kB, which are aberrantly constitutively activated
in malignant gliomas. Activation of these transcription factors
results in resistance to chemotherapy and/or radiation therapy,
and stimulates tumor cell invasion. The mechanisms underlying
constitutive activation of these transcription factors are being
actively investigated, and we are investigating methods to
reverse the biological effects mediated by these factors.
Together we have received a research grant from the National
Cancer Institute and additional submissions are planned.
2� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Paper Published or In PressBatra PS, Citardi MJ, Lee JH, Bolger W, Roh HJ, Lanza DC. Endoscopic resection of sinonasal malignancies: A preliminary Report. Am J of Rhinology. 2005. In press.
Batra PS, Citardi MJ, Worley S, Lee JH, Lanza DC. Resection of anterior skull base tumors: Comparison of combined traditional and endoscopic techniques. Am J of Rhinology 2005; 19:521-528.
Chahlavi A, Rayman P, Richmond AL, et al. Glioblastomas Induce Apoptosis of T Lymphocytes By Two Distinct Pathways Involving Gangliosides and CD70. Cancer Research 2005; 65(12):5428-38.
Chahlavi A, Staugaitis SM, Yahya R, Vogelbaum MA. Intracranial collision tumor mimicking an octreotide-SPECT positive and FDG-PET negative meningioma. J Clin Neurosci 2005; 12(6):720-3.
Chao ST, Lee SY, Borden LS, Joyce MJ, Krebs VE, Suh JH. External beam radiation helps prevent heterotopic bone formation in patients with history of heterotopic ossification. J Arthroplasty 2005. In press.
Chao ST, Joyce MJ, Suh JH. Treatment of heterotopic ossification. Orthoped 2005. In press.
Chen PG, Lee SY, Barnett GH, Vogelbaum MA, Saxton JP, Fleming PA, Suh JH. Use of the RTOG RPA classification system and predictors for survival in 19 women with brain metastases from ovarian cancer. Cancer 2005. In press.
Chen PG, Lee SY, Barnett GH, Vogelbaum MA, Saxton JP, Fleming PA, Suh JH. Use of the Radiation Therapy Oncology Group recursive partitioning analysis classification system and predictors of survival in 19 women with brain metastases from ovarian carcinoma. Cancer 2005; 104(10):2174-80.
Cohen BH. Altered States of Conscious-ness. In: Maria BL. Current Management in Child Neurology, 3rd Edition. BE Decker, Hamilton, Ontario, Canada. 2005; 551-562.
Cohen BH. Mitochondrial Cytopathies. In: Maria BL. Current Management in Child
Neurology, 3rd Edition. BE Decker, Hamilton 2005; 551-562.
Doolittle ND, Abrey LE, Blyer WA, et al. New frontiers in translational research in neuro-oncology and the blood-brain-barrier: report of the tenth annual blood-brain barrier consortium meeting. Clinical Cancer Research 2005; 11:421-8.
Dreicer R, Byzova T, Plow E, Klein E, Peereboom D, Elson P. Phase II trial of GM-CSF + thalidomide in patients with androgen-independent metastatic prostate cancer. Urol Oncol 2005; 23:82-6.
Farag E, Deboer G, Cohen BH, Niezgoda J. Metabolic acidosis due to propofol infusion. [comment]. Anesthesiology. 2005; 102(3):697-8.
Farray D, Ahluwalia M, Cohen B, et al. Pre-irradiation 9-Amino [20s] camptoth-ecin (9-AC) in patients with newly diagnosed glioblastoma multiforme. Invest New Drugs. 2005 Aug 2.
Fritz M, Sade B, Wood B, Lee JH. Benign fibrous histiocytoma of the pterigopala-tine fossa with intracranial extension. Acta Neurochirurgica date. 2005 Feb 25. In press.
Hartsell WF, Scott CB, Watkins Bruner D, et al. Phase III randomized trial of 8 Gy in 1 fraction vs. 30 Gy in 10 fractions for palliation of painful bone metastases: Analysis of RTOG 97-14. J Natl Ca Inst 2005. In press.
Hughes G, Lee JH, Ruggieri P. Cystic lesions of the petrous apex. In: Clinical Otology, 3rd Edition (Hughes & Pensak, editors). Thieme, NY, 2005. In press.
Kanner AA, Staugaitis SM, Castilla EA, et al. The Impact of Genotype on the Outcome in Oligodendroglioma: Validation of the loss of chromosome arm 1p as a factor of importance in clinical decision making. J Neurosurgery. March 2006. In press.
Kanner A, Vogelbaum M. Intraoperative MRI. In Computer Assisted Neurosurgery. Barnett GH, Robert D, Maciunas R, eds. 2005. In press.
Kelly TW, Prayson RA, Barnett GH, Stevens GHJ, Cook JR, Hsi ED. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue arising
in the lateral ventricle: case report and literature review. American J of Surg Path. 2005. In press.
Komaki R, Swan R, Ettinger DS, et al. Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) Protocol 97-12. Int J Radiol Oncol Biol Phys 2005; 62:342-350.
Latif T, Wood L, Connell C, et al. Phase II Study of Oral Bis (aceto) Ammine Dichloro (cyclohexamin) Platium (IV) (JM-216, BMS-182751) given Daily x 5 in Hormone Refractory Prostate Cancer. Invest New Drugs 2005; 23:79-84.
Lee JH, Evans JJ, Steinmetz MP, Krishnaney AA. Surgical Technique for Removal of Clinoidal Meningiomas. In: Badie B, ed. Neurosurgical Operative Atlas, 2nd ed. Neuro-Oncology. Thieme, NY: 2005. In press.
Lee JH, Krishnaney AA, Steinmetz MP, Lee DK. Intracranial Meningiomas. In: Barnett GH, ed. Computer-Assisted Neuro-surgery. 2005. In press.
Lee JH, Steinmetz M, Krishaney A, Lee DK. Intracranial Meningiomas. In: Barnett G, Roberts D, Maciunas R, eds. Computer-Assisted Surgical Navigation in Neurosur-gery. 2005. In press.
Lee JH, Sade B, Choi E, Prayson R, Golubic M. Midline skull base and spinal meningiomas are predominantly of the meningothelial histologic subtype. J Neurosurgery. In press.
Lee JH, Tobias S, Kwon, JT, Sade B, Kosmorsky G. Wilbrand’s knee: Does it exist? Surgical Neurology. In press.
Lin WC, Mahadevan-Jansen A, Weil RJ, Johnson M, Toms SA. Intraoperative optical spectroscopy accurately distin-guishes radiation necrosis versus recurrent tumor in vivo. Neurosurgery. In press.
Lin WC, Mahadevan-Jansen A, Johnson MD, Weil RJ, Toms SA. In vivo optical spectroscopy detects radiation damage in brain tissue. Neurosurgery, 57:518-525, 2005.
Lo SS, Chang EL, Suh JH. Stereotactic radiosurgery with and without whole-brain
Brain Tumor Institute
Publications
2005 Annual Report A team approach to individualized care 2�
Lonser RR, Buggage R, Weil, RJ. Malignant cerebellar swelling in a patient with neuro-Behçet’s disease. J Neurosur-gery: Pediatrics. 2005;103: 292.
Mahelas TJ, Lee JH. Neurosarcoidosis: A cause of compressive, infiltrative optic neuropathy. Ocular Surgery News. 2005; 23 (18):64-66.
Mangels KJ, Johnson MD, Weil RJ. Thoracic intermediate-grade melanocy-toma mimicking meningioma. Brain Pathology. 2005. In press.
Mason A, Toms SA, Hercbergs A. Biological Response Modifiers. In: Barnett GH, ed. Malignant Gliomas. 2005. In press.
Moulder S, Johnson D, Toms SA. Metastatic breast cancer. In: Sawaya R ed. Intracranial Metastases: Current Manage-ment Strategies. Armonk; NY: Futura Publishing Co. In press.
Nathoo N, Cavusoglu M, Vogelbaum M, Barnett G. In Touch with Robotics: Neurosurgery for the future. Neurosurgery. March 2005; 56(3):237-242.
Nathoo N, Chalavi A, Barnett GH, Toms SA. Pathobiology of Brain Metastasis. Journal of Clinical Pathology. 2005; 58:237-42.
Nathoo, N, Lautzenheiser F, Barnett GH. George W. Crile, Ohio’s First Neurosur-geon, and his relationship with Harvey Cushing. Journal Neurosurgery. 2005; 103: 378-386.
Nathoo N, Prayson R, Bodnar J, Vargo L, et al. 5-Lipoxygenase is Overexpressed in High-Grade Astrocytomas. Neurosurgery. May 2005. In press.
Nathoo N, Steiner C, Barnett G, Roberts D. Surgical Navigation System Technolo-gies. In: Barnett G, Roberts D, Maciunas R, Peereboom DM, eds. Computer-Assisted Neurosurgery. Chemotherapy in Brain Metastases. Neurosurg Suppl. Nov 2005.
Nathoo N, Nair D, Phillips M, Vogelbaum MA. Mapping prosody: correlation of functional magnetic resonance imaging with intraoperative electrocorticography recordings in a patient with a right-sided temporooccipital glioma. Case illustration. J Neurosurg. 2005; 103(5):930.
Pack SD, Qin LX, Pak E, Wang Y, Ault DO, Mannan P, Jaikumar J, et al. Common
genetic changes in hereditary and sporadic pituitary adenomas detected by compara-tive genomic hybridization (CGH). Genes, Chromosomes, and Cancer. 2005; 43(1):72-82.
Quan AL, Barnett GH, Lee SH, Vogelbaum MA, Toms SA, Staugaitis SM, Prayson RA, et al. Epidermal Growth Factor Receptor Amplification Does Not Have Prognostic Significance In Patients With Glioblastoma Multiforme. International Journal of Radiation Oncology. June 1, 2005.
Rahaman SO, Vogelbaum MA, Haque SJ. Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13R{alpha}2. Cancer Research. 2005; 65(7):2956-63.
Rahaman SO, Vogelbaum MA, Haque SJ. Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13R (alpha)2. Cancer Research. 2005; 65(7):2956-63.
Robinson CG, Prayson RA, Hahn JF, Kalfas IH, Whitfield MD, Lee SY, Suh JH. Long-term survival and functional status of patients with low-grade astrocytomas of the spinal cord. Int J Radiat Oncol Biol Phys. 2005; 63:91-100.
Sade B, Evans JJ, CY Kweon, Lee JH: Enhanced carotico-oculomotor triangle following anterior clinoidectomy: an anatomic morphometric study. Skull Base Surgery. 2005; 15: 157-162.
Sade B, Lee JH: Outcome following meningioma surgery: A personal series of 600 cases. Meningiomas. Springer-Verlag, London. In review.
Sade B, Lee JH, Lee DK. Postoperative psychosis and depression following removal of a giant skull base hemangio-pericytoma. Surgical Neurology. In press.
Sajja R, Barnett GH, Lee SY, Stevens GHJ, Lee J, Suh JH. Intensity-modulated radiation therapy (IMRT) for newly diagnosed and recurrent intracranial meningiomas: the Cleveland Clinic Foundation experience. Technol Cancer Res Treat. December 2005; 4(6): 675-682.
Schwartz SA, Weil RJ, Thompson RC, et al. Proteomic-based prognosis of brain tumor patients using direct-tissue MALDI mass spectrometry. Cancer Research. 2005; 65:7674-7681. (co-senior author).
Sinha TK, Dawant BM, Duay V, et al. A method to track cortical surface deforma-tions using a laser range scanner. IEEE
Transactions on Medical Imaging. 2005; 24:767-81.
Siomin V, Barnett G. Brain Biopsy and Related Procedures. In: Barnett G, Roberts D, Maciunas R., eds. Computer Assisted Neurosurgery. 2005. In press.
Siomin, V., Angelov, L., Liang, L.,Vogelbaum, M.A. Results of a Survey of Neurosurgical Practice Patterns Regarding the Prophylactic Use of anti-EpilepsDrugs in Patients with Brain Tumors. J. Neurooncol. 2005 Sep; 74(2):211-5.
Solares CA, Fakhri S, Batra PS, Lee JH, Lanza DC. Trans-nasal endoscopic resection of lesions of the clivus: a preliminary report. Laryngoscope. 2005; 115:1917-1922.
Song JK, Weil RJ. An unusual cause of acromegaly. Archives of Pathology & Laboratory Medicine. 2005; 129:415-416.
Spencer A, Lee JH, Prayson RA. Optic nerve choristoma: A case report and review of the literature. Ann. of Diagnostic Path. 2005; 9:348-354, 2005.
Steinmetz MP, Krishnaney AA, Lee DK, Lee JH. Convexity Meningiomas. In: Badie b, ed. Neurosurgerical Operative Atlas 2nd Edition. Neuro-Oncology. New York; NY: Thieme 2005. In press.
Stevens G. General Consideration. In: Barnett GH. High-grade Gliomas. Totowa; NJ: Humana Press. 2005. In press.
Stevens GHJ. Antiepileptic Drug Use in Patients with Brain Tumors. Profiles in Seizure Management. 2005; 4:4-9.
Stevens GHJ. Antiepileptic therapy in patients with central nervous system malignancies. In: Lesser G, ed. Current Treatment Options in Oncology. 2005. In press.
Suh JH, Stea B, Nabid N, et al. Results from a phase 3 study evaluating efaproxi-ral as an adjunct to whole brain radiation therapy for the treatment of patients with brain metastases. J Clin Oncol. 2005. In press.
Tobias S, Kim CH, Kosmorsky G, Lee JH. Clinoidal Meningiomas. Surgical Manage-ment. 2005. In press.
Tobias S, Kim CH, Sade B, Lee JH. Benign neuromuscular choristoma of the trigeminal nerve in an adult. Acta Neurochir. 2005. In press.
Toms SA, Lin WC, Weil RJ, Johnson MD, Jansen ED, Mahadevan-Jansen A.
2� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Intraoperative optical spectroscopy identifies infiltrating gliomas margins with high sensitivity. Neurosurgery. 2005; 57 [ONS Suppl 3]: 382-291.
Ugokwe K, Nathoo N, Prayson R, Barnett GH. Trigeminal nerve schwannoma with ancient change. Journal Neurosurgery. 2005; 102;1163-1165.
Vogel TW, Brouwers FM, Lubensky IA, et al. Differential expression of erythropoietin and its receptor in von Hippel-Lindau-associated and MEN type 2-associated pheochromocytomas. Journal of Clinical Endocrinology and Metabolism. 2005; 90:3747-3751.
Vogel TW, Zhuang Z, Vortmeyer AO, et al. Protein and protein pattern differences between glioma cell lines and glioblastoma multiforme. Clinical Cancer Research. 2005; 11:3624-3632.
Vogelbaum MA. Convection-enhanced Delivery for the Treatment of Malignant Gliomas: Symposium Review. Journal of Neuro-oncology. 2005; 73(1):57-69.
Vogelbaum MA, Masaryk T, Mazzone P, et al. S100beta as a predictor of brain metastases. Cancer. 2005; 104(4):817-24.
Weil RJ, Lonser RR, Quezado MM. Skull and brain metastasis from tibial osteosar-coma. J Clinical Oncology. 2005; 23:4226-4229.
Weil RJ, Lonser RR. Selective Excision of Metastatic Brain Tumors Originating in the Motor Cortex with Preservation of Function. Journal of Clinical Oncology. 2005; 23:1209-17.
Weil RJ, Palmieri D, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. American Journal of Pathology. 2005; 167:913-920.
Books Barnett, GH, Maciunas R, Roberts D, eds. Computer-Assisted Neurosurgery. Ontario, Canada; BC Decker Publishing Co; 2005. In preparation.
Barnett GH, ed. High Grade Gliomas: Diagnosis and Treatment. Totawa, NY; Humana Press. 2005, In preparation.
Book Chapters Barnett GH. Image-Guided Needle Biopsy. In: Advanced Techniques in Image-Guided Brain and Spine Surgery. Thieme Publisher. 2005. In press.
Barnett GH. Intraoperative MRI. Contem-porary Neurosurgery. Baltimore, MD: Williams & Wilkins. 2005. In press.
Barnett GH. Barnett GH, ed. Surgical Techniques. In: High Grade Gliomas: Diagnosis and Treatment. Totawa, NJ: Humana Press. 2005. In preparation.
Barnett GH. Molecular Classifications. In: High Grade Gliomas: Diagnosis and Treatment. Barnett GH, ed. Totawa, NJ: Humana Press. 2005. In preparation.
Barnett GH. Image-Guided Surgery. In: Neurosurgical Oncology. Black P, ed. Totawa, NJ: Humana Press. 2005. In preparation.
Cohen B. Altered States of Consciousness In: Maria BL, ed. Current Management in Child Neurology. 3rd Ed. Ontario, Canada: BE Decker, Hamilton; 2005: 551-562.
Cohen B, Nicholson C. Brainstem Gliomas. In: Schiff D, O’Neill BP, eds. Principles of Neuro-Oncology. New York, NY: McGraw-Hill; 2005: 333-342.
Cohen B. Mitochondrial Cytopathies. In: Maria BL, ed. Current Management in Child Neurology. 3rd Ed. BE Decker, Hamilton; 2005: 277-284.
Prayson R, Angelov L, Barnett GH. Mixed Neuronal-Glial Tumors. In: Berger M, Prados M, eds. Textbook of Neuro-Oncology. Philadelphia, PA: Elsevier Saunders; 2005: 30: 222-226.
Siomin V, Barnett GH. Brain Biopsy and Related Procedures. In: Barnett GH, Maciunas R, Roberts D, eds. Computer-Assisted Neurosurgery. Ontario, Canada: BC Decker, Hamilton; 2005. In preparation.
Suh JH, Barnett GH. Radiosurgery. In: Barnett GH, ed. High Grade Gliomas: Diagnosis and Treatment. Totawa, NJ: Humana Press; 2005. In preparation.
Vogelbaum M and Kanner A. Intraopera-tive MRI. In: Barnett G, Maciunas R, Roberts D, Marcel Dekker, eds. Computer-Assisted Neurosurgery. New York, NY: Inc. Publishers; 2005. In press.
Vogelbaum M and Siomin V. Image-guided Treatment of Metastatic Brain Tumors. In: Barnett G, Maciunas R, Roberts D, eds. Computer-Assisted Neurosurgery. New York, NY: Marcel Dekker Inc. Publishers; 2005. In press.
Abstracts Angelov L. The use if tissue equivalent Super Stuff Bolus ™
material to treat skull metastases with Gamma Knife Radiosurgery. 7th Interna-tional Stereotactic Radiosurgery Society Congress: Poster Presentation. Brussels, Belgium; September 2005.
Angelov L. Blood Brain Barrier Disruption and Intra-Arterial Methotrexate theray for Primary CNS Lymphoma: The Cleveland Clinic Experience. 2005 Congress of Neurological Surgeons Annual Meeting: Talk & Poster Presentation. Boston, MA; Oct 2005.
Brewer CJ, Suh JH, Stevens GHJ, et al. Phase II trial of erlotinib with temozolo-mide and concurrent radiation therapy in patients with newly-diagnosed glioblastoma multiforme. J Clin Oncol. June 1, 2005; 23(16):130S-130S Part 1 Suppl. S.
Chao ST, Barnett GH, Toms SA, et al. Salvage Stereotactic Radiosurgery Effectively Treats Recurrences from Whole Brain Radiation Therapy. ASTRO, 2005.
Fleseriuu M, Weil RJ, Prayson, Hamrahian AH. Lack of significant immunostaining for growth hormone in patients with acro-megaly. Poster presented at: 7th International Pituitary Conference, June 2005, San Diego, CA. Selected for endocrinology fellow’s research award.
Haut JS, Klaas PA, Cohen BH. Cognitive Decline in a 10-Year-Old with MELAS: Regression or Developmental Plateau? The Clinical Neuropsychologist. 2005.
Peereboom DM, Brewer C, Schiff D, et al. Phase II multicenter study of dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma. Neuro-Oncol. 2005; 7:401. (Abstract 470)
Peereboom D, Carson K, Lawson D, Lesser G, Supko J, Grossman S for The New Approaches to Brain Tumor Therapy Consortium. A phaseI/II trial of BMS-247550 for patients with recurrent high-grade gliomas. Proc Am Soc Clin Oncol. 2005; 23:129s. (Abstract 1563)
Pineyro M, Makdissi A, Hamrahian AH, et al. Poor correlation of serum alpha subunit with postsurgical pituitary MRI in patients with nonfunctional pituitary adenomas: The Cleveland Clinic Experience. Poster presented at: Endocrine Society, 87th Annual Meeting; June 2005; San Diego, CA.
2005 Annual Report A team approach to individualized care 2�
Usmani A, Makdissi A, Hamrahian A, Reddy S, Weil R, et al. Hypothalamic-pituitary-adrenal axis testing using a twenty-five microgram Cotrosyn stimula-tion test. American Academy of Clinical Endocrinologists 2005 Annual Meeting.
Weil R, DeVroom, Vortmeyer A, et al. Adeomas confined to the neurohypophysis in Cushing’s Disease. Endocrine Society 87th Annual Meeting; June 2005; San Diego, CA.
Barnett GH. Surgery for Gliomas. Cleveland Clinic Neuro-oncology Sympo-sium, Lake Buena Vista, FL; Jan 2005.
Barnett GH. Moderator: Gliomas II. Cleveland Clinic Neuro-oncology Sympo-sium, Lake Buena Vista, FL; Jan 2005.
Barnett GH. Stereotactic Frame Applica-tion, Introduction to Planning System, Gamma Knife Shot Strategy, Functional Planning and Procedures, AVM Planning. Cleveland Clinic Gamma Knife Course, Cleveland, OH; April 2005.
Barnett GH. Practical Course 386/387: Non-Invasive Preoperative and Intraopera-tive Brain Mapping. American Association of Neurological Surgeons Annual Meeting, New Orleans, LA; April 2005.
Barnett GH. Moderator: Scientific Session I: Tumors, American Association of Neurological Surgeons Annual Meeting, New Orleans, LA; April 2005.
Barnett GH, Nathoo N, Lautzenheiser F. Crile: Ohio’s First Neurosurgeon and his relationship to Harvey Cushing. American Association of Neurological Surgeons Annual Meeting, New Orleans, LA; April 2005.
Lee DK, Lee JH. Surgical management of tentorial meningiomas. Oral presentation: Korean Skull Base Society Annual Meeting, Seoul, Korea; December 2005.
Lee, JH. Grand Skull base surgery: basic principles: Invited Lecture: Grand Rounds, Interdisciplinary Skull Base Surgery Conference, Cleveland Clinic, Cleveland, OH; January 2005.
Lee, JH. Unique features of meningothelial meningiomas. Invited Lecture: Cleveland Clinic Neuro-Oncology Symposium, Orlando, Florida; January 2005.
Lee, JH. Meningiomas: When and when not to operate?: Invited Lecture: Mayfield Clinic/Cleveland Clinic Neuroscience Symposium, Snowmass, CO; February 2005.
Lee, JH. Twelve years of skull base surgery: the lessons learned. Invited Lecture: Mayfield Clinic/Cleveland Clinic Neuroscience Symposium, Snowmass, CO; February 2005.
Lee, JH. When and when not to operate?: Invited Lecture: Grand Rounds, Interdisci-plinary SBS Conference, Cleveland Clinic, Cleveland, OH; March 2005.
Lee JH, Sade B, Park BJ. A novel ‘CLASS’ algorithm for patient selection in menin-gioma surgery. Oral presentation: The 7th Congress of the European Skull Base Society. Fulda, Germany; May 2005.
Peereboom DM. Hematology Oncology Associates Grand Rounds State of the Art Treatment Approaches for Brain Metasta-ses. Syracuse, NY; January 2005.
Peereboom DM. Palliative Medicine Grand Rounds Multidisciplinary Management of Brain Metastases: State of the Art 2005. Cleveland, OH; January 2005.
Peereboom DM. University of Utah Neurosciences Grand Rounds New Strategies in Primary Brain Tumors. Salt Lake City, UT; April 2005.
Peereboom DM. Failure of Chemotherapy for Brain Tumors: Focus on Drug Delivery and Drug Resistance Chemotherapy for High-Grade Gliomas: Pitfalls and Possibilities. Cleveland, OH; March, 2005.
Peereboom DM. Cleveland Clinic International Neuro-oncology Symposium. Role of Chemotherapy in High-grade Gliomas. Cleveland, OH; August, 2005.
Peereboom DM. Cleveland Clinic Neuro-oncology Symposium: Current Concepts Emerging Medical Therapies for High-grade Gliomas: Where do we stand and where are we going?. Orlando, FL; January 2005.
Peereboom DM. Cleveland Clinic NeuroOncology 2005: Current Concepts.
Clinical Trials of NABTT (New Approaches to Brain Tumor Therapy) Consortium. Orlando, FL; January 2005.
Peereboom DM. World Federation of Neuro-Oncology. Phase II multicenter study of dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma. Edinburgh, UK; May 2005.
Peereboom DM. Cleveland Clinic Taussig Cancer Center ASCO Review. CNS Malignancies. Cleveland, OH; June 2005.
Peereboom DM. The Human Epidermal Growth Factor Receptor as a Target for Therapy of Solid Tumors. Akron, OH; January 2005.
Peereboom DM. Schering-Plough Oncology North America Temodar Investigator Advisory Board Meeting .Alternative Dosing Regimens for Temo-zolomide: Do they work? Atlanta, GA; February 2005.
Peereboom DM. Schering-Plough Oncology North America Temodar Investigator Advisory Board Meeting. Temozolomide for Newly Diagnosed Pure and Mixed Anaplastic Oligodendroglioma.Atlanta, GA; February 2005.
Peereboom DM. St. Luke’s Medical Center Cancer Conference
“The Human Epidermal Growth Factor Receptor as a Target for Therapy of Solid Tumors” Madison, WI; February 2005.
Peereboom DM. Blood-Brain Barrier Consortium Meeting. State of the Art Treatment Approaches for Brain Metasta-ses. Portland, OR; March 2005.
Peereboom DM. Cleveland Metro General Hospital Oncology Speaker Series. Management of Primary Brain Tumors: 2005. Cleveland, OH; April 2005.
Peereboom DM. Gliadel Wafer Investigator Meeting. Chemotherapy for Brain Metastases: State of the Art 2005. Miami, FL; June 2005.
Peereboom DM. Glioblastoma Multiforme: The Multidisciplinary Approach to Treatment. Cleveland, OH; September 2005.
Peereboom DM. Glioblastoma Multiforme: The Multidisciplinary Approach to Treatment. Peioria, IL; November 2005.
Peereboom DM. Blood-Brain Barrier Consortium Meeting. Treatment of CNS Metastases – Summary Discussion. Portland, OR; March 2005.
�0 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Peereboom DM. Blood-Brain Barrier Consortium Meeting. Conflict of Interest Management and Policy Development for the Blood-Brain Barrier Consortium. Minneapolis, MN; September 2005.
Prayson R, Barnett GH. Current Concepts in the Diagnosis of Gliomas. United States & Canadian Academy of Pathology Annual Meeting. San Antonio, TX; March 2005.
Sade B, Lee JH. Clinoidal meningiomas: Surgical outcome in 41 patients. Oral presentation, Annual Meeting, NASBS, Toronto, ON Canada; April 2005.
Suh JH. Advances in Pituitary Radiothera-py. Pituitary update conference. Lake Buena Vista, FL; Jan 2005.
Suh JH. Moderator for new therapeutic approaches for brain tumors. Cleveland Clinic Neuro-oncology Symposium. Lake Buena Vista, FL; Jan 2005.
Suh JH. Moderator for complementary medicine for brain tumors. Cleveland Clinic Neuro-oncology Symposium. Lake Buena Vista, FL; Jan 2005.
Suh JH. Overview of Brain Metastases. European Investigator’s meeting for ENRICH study. Paris, France; Feb 2005.
Suh JH. Review of RT-009 study. European Investigator’s meeting for the ENRICH study. Paris, France; Feb 2005.
Suh JH. Management of Efaproxiral toxicity. European Investigator’s meeting for the ENRICH study. Paris, France; Feb 2005.
Suh JH. Radiation Oncology. Cleveland Clinic Taussig Cancer Center National Leadership Board meeting. Cleveland, OH; June 2005.
Suh JH. Overview of Gamma Knife Radiosurgery. Cleveland Clinic Interna-tional Neuro-oncology Symposium. Cleveland, OH; Aug 2005.
Toms SA. Optical Imaging in Neuro-Oncology: New Techniques and Their Applications. 7th Neuro-oncology Update 2005; January 2005.
Toms SA. Quantum dots detect malignant glioma. Cambridge Healthtech Institute›s 6th Annual Targeted Nanodelivery for Therapeutics and Molecular Imaging; August 2005.
Toms SA. Video presentation: «Surgical resection of brain metastasis», Congress of Neurological Surgeons; October 2005.
Toms SA. Surgical Resection of Brain
Metastasis: Basic and Special Techniques. Congress of Neurological Surgeons; October 2005.
Toms SA. Quantum dots detect malignant glioma. OpticsEast; October 2005.
Toms, SA. Quantum Dots are phagocy-tized by macrophages and detect experimental malignant glioma. Interna-tional Association for Nanotechnology; November 2005.
Usmani A, Makdissi A, Hamrahian A, Reddy S, Weil RJ, Faiman C. Hypotha-lamic-pituitary-adrenal (HPA) axis testing using a twenty-five (25) microgram Cotrosyn stimulation test. Poster presented at: American Academy of Clinical Endocrinologists, Annual meeting; 2005.
Vatolin S, Navaratne K, Weil RJ. Method for detection of microRNA targets. Plat-form presentation: RNAi course; Cold Spring Harbor Laboratory; September 28-October 2, 2005.
Videtic GM, Reddy CA, Chao ST, et al. Women with Brain Metastases from Non-Small Cell Lung Cancer Live Longer than Men: An outcomes study utilizing the RTOG RPA class stratification. ESTRO, 2005.
Vogelbaum MA. Mayfield Clinic-Cleveland Clinic-Mayo Clinic Winter Neuroscience Symposium. Overview of Convection-enhanced Delivery. Snowmass, CO; February 2005.
Vogelbaum MA. Tumor Margin Dose Affects Local Control Following Stereotac-tic Radiosurgery of Brain Metastases; February 2005.
Vogelbaum MA. Radiation Therapy Oncology Group Brain Tumor Symposium. Convection-enhanced Drug Delivery; June 2005.
Vogelbaum MA, Berkey B, Peereboom D, et al. RTOG 0131: Phase II Trial of Pre-Irra-diation and Concurrent Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendrogliomas and Mixed Anaplastic Oligodendrogliomas. ASCO, 2005.
Vogelbaum MA, Sampson JH, Kunwar S, et al. Convection-enhanced delivery of cintredekin besudotox (IL13-PE38QQR) followed by radiation therapy without and with temozolomide. A phase I study in newly diagnosed malignant glioma patients. CNS, 2005.
Vogelbaum MA, Mazzone P, Masaryk T, et al. Low serum S100 levels in patients with
newly diagnosed lung cancer correlate with an absence of brain metastases on MRI. World Federation of Neuro-Oncology, 2005.
Weil RJ, DeVroom, Vortmeyer AO, Nieman L, Oldfield EH. Adenomas confined to the neuro-hypophysis in Cushing’s Disease. Poster presented at: Endocrine Society, 87th Annual Meeting; June 2005; San Diego, CA.
Weil RJ. Advances in Tumor Diagnostics: Genomics, Epigenomics, and Proteomics. Cleveland Clinic Neuro-oncology Sympo-sium. Orlando, FL; January 2005.
Weil RJ. Potential Proteomic Approaches to Analysis of Drug Resistance Proteins in Gliomas. Invited Speaker, Cleveland Clinic Foundation Cancer Center Symposium, Failure of Chemotherapy in Malignant Brain Tumors: The Roles of the Blood-Brain-Barrier and Drug Resistance Genes. Cleveland, OH; March 2005.
Weil, RJ. CNS Metastases in Women with Breast Cancer: Challenges and Opportuni-ties. Invited speaker, Molecular and Genetic Markers in Breast Cancer Working Group and the Cleveland Clinic Women’s Center. Cleveland, OH; May 2005.
Weil RJ. Pituitary Surgery and Endoscopic Approaches: Overview, Problems, and Expectations. Invited faculty member and speaker, Cleveland Clinic Foundation Neuro-Endoscopy Surgical Techniques Course. May 2005.
Weil RJ. Pituitary Surgery: Conventional and Endoscopic Approaches. Invited speaker and faculty member, Cleveland Clinic Foundation International Neuro-oncology Symposium, Cleveland Clinic Foundation. August 2005.
Weil RJ. Invited lecturer and panelist, Congress of Neurological Surgeons. Medical and Surgical Management of Seizures in patients with low-grade gliomas. Luncheon Seminar T-24, Manage-ment of low-grade gliomas: current strategies and dilemmas. CNS Annual Meeting. Boston, MA; October 2005.
Manuscripts Submitted Angelov L, Barnett GH. Awake Craniotomy and Intra-op Imaging. In Image guided Surgery (Barnett, Maciunas,Roberts eds). Marcel Dekker, Inc. New York 2005. Submitted.
Barnett G and Thomas T. Imaged-Guided Surgery. In: Black P, ed. Neurosurgical
2005 Annual Report A team approach to individualized care ��
Oncology.
Barnett GH, Park J. Craniopharyngioma. In: Ragahaven, ed. Textbook of Uncom-mon Cancer, 3rd ed. Sent to publisher August 2005.
Chahlavi A, Borsellino S, Barnett GH, Vogelbaum MA. The use of skull-implanted fiducials for computer-assisted sterotactic brain stem and posterior fossa brain biopsies. Submitted.
Chen PG, Lee SY, Barnett GH, Vogelbaum MA, Saxton JP, Fleming PA, Suh JH. Use of the RTOG RPA classification system and preditors of survival in 19 women with brain metastases from ovarian cancer. Cancer. March 16, 2005. Submitted.
Hercbergs AA, Suh JH, Toms SA, et al. Propylthiouracil-induced thyroid hormone depletion improves survival and response rates in recurrent high-grade glioma patients treated with tamoxifen. Cancer, August 2005. Submitted.
Kanner A, Marton LJ, Barnett GH, Vogelbaum MA. Targeting Polyamines. A strategy to treat brain neoplasms. 2005. In review.
Kanner A, Vogelbaum MA, Staugaitus S, Chernova O, Prayson RA, Suh JH, Lee SY, Barnett GB. Effect of allelic loss of chromosome 1p on survival in oligoden-drogliomas independent of therapy. 2005 J Neurosurg. Submitted.
Lee JH, Sade B, Choi E, Golubic M, Prayson R. Midline Skull Base and Spinal Meningiomas are Predominantly of the Meningothelial Histological Subtype. Journal of Neurosurgery. June 8, 2005. Submitted.
Lee JH, Sade B, Park BJ. Surgical Technique for Removal of Clinoidal Meningiomas. Neurosurgery for their Operative Nuances issue. June 29, 2005. Submitted.
Lee JH. Management options and basic surgical principles. Meningiomas. Springer-Verlag, London. In review.
Lee JH. Meningioma surgery: Personal philosophy. Meningiomas. Springer-Verlag, London. In review.
Lupica K, Ditz G. Nursing Considerations. In High-Grade Gliomas: Diagnosis and Treatment.
Mahmoud-Ahmed A, Suh J, Lee SY, Hamrahian A, Barnett GH, Mayberg MR. Gamma Knife Radiosurgery Induces Biochemical Cure in Patients with
Acromegaly Faster than External Beam Radiation. 2005. Submitted.
Mason A, Toms SA, Hercbergs A. Biological Modifiers. In High-grade Gliomas. Submitted.
Taban M, Cohen B, Rothner D, Traboulsi E. Association of Optic Nerve hypoplasia with Mitochondrial Cytopathies. Submit-ted.
Nathoo N, Chahlavi, A, Barnett GH, Toms, SA. Pathobiology of Brain Metastasis. 2005. Submitted.
Nathoo N, Ugokwe K, Chang A, et al. The Role of 111 indium-octreotide brain scintigraphy in the diagnosis of cranial, dural-based meningiomas. Neurosurgery. March 2005. Submitted.
Rogers LR, Rock JP, Sills AK, et al. Brain Metastasis Study Group, Shaw EG. Results of a phase II trial of GliaSite Radiation Therapy System for the treatment of newly diagnosed resected single brain metasta-ses. J Neurosurg. July 2005. Submitted.
Sajja R, Barnett GH, Lee SY, Stevens GH, Lee J, Suh JH. Intensity-Modulated Radiation Therapy (IMRT) for Newly Diagnosed and Recurrent Intracranial Meningiomas: The Cleveland Clinic Foundation Experience. International Journal Radiology Oncology, Biology, Physiology. 2005. Submitted.
Sajja R, Barnett GH, Lee SY, Vogelbaum M, Stevens G, Lee JH, Suh J. Local control of intracranial meningiomas with Gamma Knife radiosurgery: The Cleveland Clinic Foundation Experience. International Journal Radiology Oncology, Biology, Physiology. 2005. In review.
Sajja R, Barnett GH, Lee SY, Vogelbaum MA, Stevens GHJ, Lee J, Suh JH. Local control on intracranial meningiomas with gamma knife radiosurgery (GKRS): The Cleveland Clinic Foundation Experience. 2005. Submitted.
Sajja R, Barnett GH, Lee SY, Stevens GHJS, Lee JH, Suh J: Intensity-modulated radiation therapy (IMRT) for newly diagnosed and recurrent intracranial meningiomas: The Cleveland Clinic Foundation Experience. Journal Radiology Oncology, Biology, Physiology. 2005. In review.
Suh JH, Curran W, Mehta MP, et al. Predictors for survival for patients with brain metastases: results of a randomized phase III trial. Int J Radiat Oncol Biol Phys. August 2005. Submitted.
Taban M, Cohen B, Rother D, et al. Association of Optic Nerve hypoplasia with Mitochondrial Cytopathies. 2005. Submitted.
Tobias S, Kim C-H, Burak S, Staugaitis SM, Lee JH. Benign neuromuscular choristoma of the trigeminal nerve in an adult: Case report and literature review. Acta Neurochirurgica February 2005. Submitted.
Ugokwe K, Nathoo N, Prayson R, Barnett GH. Trigeminal Nerve Schwannoma with Ancient Change: Case Report and Review of the Literature. 2005. Submitted.
Vogelbaum M, Thomas T. Contemporary Investigational Treatments for Malignant Brain Tumors: Small Molecule Agents. In: Barnett GH. High-grade Gliomas: Diagnosis and Treatment. Totawa, NJ: Humana Press. 2005. Submitted.
Vogelbaum MA, Angelov L, Lee SY, Li L, Barnett GH, Suh JH. Local control of Brain Metastases by Stereotactic Radiosurgery Depends Upon the Dose to the Tumor Margin. Journal of Neurosurgery. February 2005. Submitted. (Accepted with revisions.)
Vogelbaum MA, Barnett, GH. Response of Recurrent Glioblastoma Multiforme to Tarceva (OSI774) with Subsequent Leptomeningeal Failure. 2005. Submitted.
Vogelbaum, M. A., Angelov, L., Lee, S-Y., Barnett, G.H., Suh, J.H., Factors affecting local control in patients with metastatic brain tumors treated with Gamma Knife stereotactic radiosurgery. Journal of Neurosurgery. 2005. Submitted.
WIP Angelov L, Lee SY, Barnett GH, Suh JH, Vogelbaum MA. The response to treatment of melanoma brain metastasis with stereotactic radiosurgery alone or in combination with whole brain radiation therapy. In progress.
Angelov L, Vogelbaum MA, Barnett GH, Stevens GHJ, Suh JH, Miller M, Peere-boom DM. Temozolomide therapy in the management of primary central nervous system lymphomas. In progress.
Barnett GH. High-Grade Gliomas. Diagnosis and Treatment. In progress.
Chahlavi A, Krishnany A, Nagel S, Lee JH. Aggressive and Malignant Meningiomas are Rare in the Skull Base Locations. In progress.
�2 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Chahlavi A, LaPresto E, Vogelbaum MA. Analysis of Patients with Glioblastoma Multiforme and amplified EGFR. In progress.
Chahlavi A, Park J, Staugatis S, Lee JH. Incidental Intraoperative Finding of Vestibular Nerve Heterotopia: case report. In preparation.
Golubic M, Lee JH. Emerging treatment modalities for meningiomas: Targeting the NF-2 and Ras pathways. Meningiomas. Springer-Verlag, London. In review.
Golubic M, Angelov L, Sade B, Lee JH. Molecular basis of meningioma tumorigen-esis and progress. Meningiomas. Springer-Verlag, London. In review.
Krishnaney A, Steinmetz MP, Golubic M, Lee JH. Meningioma location is associ-ated with histologic subtype and risk of aggressive behavior. Manuscript. In progress.
Krishnany A, Chahlavi A, Nagel S, Lee J. Meningiomas of the midline / paramedian skull base are predominantly meningothe-lial. In preparation.
Lee JH, Sade B, Park BJ. The «CLASS» algorithmic scale for patient selection in meningioma surgery: rationale and validity – a retrospective study. In progress.
Lee JH, Sade B. Dural reconstruction following meningioma resection: Non-watertight closure. Meningiomas. Springer-Verlag, London. In progress.
Lee JH, Sade B. Meningiomas of the central neuraxis. Unique tumors. Meningiomas. Springer-Verlag, London. In review.
Lee JH, Sade B. Surgical management of clinoidal meningiomas. Meningiomas. Springer-Verlag, London. In review.
Lee JH, Sade B. The factors influencing outcome in meningioma surgery. Meningiomas. Springer-Verlag, London. In review.
Lin WC, Mahadevan J, Chari R, Toms SA. Optics of cell and tissue viability. In preparation.
Mahelas TJ, Lee JH. Sequential visual loss from skull base neurosarcoidosis. In review.
Mason A, Barnett G. Retrospective review and case report of peritumoral malignant edema from perisagital meningiomas after gamma knife. In review.
Park BJ, Kim HK, Lee JH. Epidemiology of meningiomas. Meningiomas. Springer-Verlag, London. In review.
Quan AL, Ross JS, Lee SY, et al. Prognos-tic implication of multicentric and multifocal disease in patients with glioblas-toma multiforme. In preparation.
Sade B, Lee JH. Tuberculum sellae meningiomas: surgical management and outcome. In progress.
Sade B, Chahlavi A, Krishnaney A, Nagle S, Choi E, Lee JH. The WHO Grade II and III meningiomas are rare in the skull base and spinal locations. Neurosurgery. In review.
Sade B, Lee JH, Lee DK, Hughes GB, Prayson R. Cavernous angioma of the petrous bone. Laryngoscope. In review.
Sade B, Lee JH. Recovery of low frequency sensori-neuronal hearing loss following resection of a greater superficial petrous and nerve schwannoma. Journal of Neurosurgery. In review.
Sade B, Lee JH. Validity and utility of the ‘CLASS’ algorithmic scale. Meningiomas. Springer-Verlag, London. In review.
Sade B, Park BJ, Lee JH. The factors influ-encing early outcome in meningioma surgery. In progress.
Sade B, Prayson R, Lee JH. Giosarcoma with infratemporal fossa extension. Journal of Neurosurgery. In review.
Sajja R, Barnett GH, Lee SY, et al. Gamma Knife radiosurgery for newly diagnosed and recurrent intracranial meningiomas. In progress.
Siomin V, Toms SA. En bloc resection of skull base metastasis is achievable with good clinical outcomes. In preparation.
Spotta A, Nathoo N, Stevens GHJ, Barnett GH. Primary cranial vault lymphoma with complete occlusion of the superior saggital sinus and subgaleal extension without bone erosion: A case report and review of the literature. In preparation.
Stevens GHJ, Vogelbaum MA, Peereboom DA, Suh J, Barnett GH. Brain tumor patients and driving: special considerations regarding seizures. In preparation.
Stevens GHJ, Vogelbaum MA, Peereboom DA, Suh J, Barnett GH. Brain tumor patients and treatment of epilepsy: Is it time for a paradigm shift? The Cleveland Clinic experience for conversion of phenytoin to levatriracitam. In preparation.
Suh JH, Barnett GH, Regine WF. Role of radiosurgery for brain metastases. Principles and Practice of Stereotactic Radiosurgery.
Toms SA, Muhammed O, Damishear H, Vogelbaum MA. Computed tomography detects quantum dots in vivo. In prepara-tion.
Toms SA, Daneshvar H, Nelms J, Muhammed O, Jackson H, Vogelbaum MA, Bruchez M. Optical Detection of Brain Tumors Using Quantum Dots. In prepara-tion.
Toms SA, Konrad P, Weil RJ, Lin WC. Neurological applications of optical spectroscopy. In preparation.
Toms SA, Muhammed O, Damishear H, Vogelbaum MA. Gradient echo MRI detects quantum dots in vivo. In prepara-tion.
Toms SA, Tasch J, Muhammed O, Jackson H, Lin W-C. Decline in NAD(P)H Autofluorescence Precedes Apoptotic Cell Death from Chemotherapy. In preparation.
Toms SA, Yuan S, Miller DW, Muhammed O, Tasch J, Williams BRG. Identification of an alternate splice of hSLK, hSLKS. In preparation.
Ugokwe K, Toms SA. Renal Cell Carci-noma Brain Metastases. Renal Cell Carcinoma. In preparation.
Vogelbuam M. Small Molecule Agents. High-Grade Gliomas. Diagnosis and Treatment.
2005 Annual Report A team approach to individualized care ��
Consortia: NABTT: New Approaches Brain Tumor Therapy ACOSOG: American College of Surgeons Oncology Group BBBD: Blood-Brain Barrier Disruption RTOG: Radiation Therapy Oncology Group SWOG: South West Oncology Group COG: Children’s Oncology Group
Adult ProtocolsIV Chemotherapy for High-Grade Gliomas Description: Phase II Clinical Trial of Patients with High-Grade Glioma Treated with Intra-arterial Carboplatin-based Chemotherapy, Randomized to Treatment with or without Delayed Intravenous Sodium Thiosulfate as a Potential Chemoprotectant against Severe ThrombocytopeniaEligibility: Histologically confirmed high-grade glioma, age 18-75.Study Design: Phase II, multi-institutional trialContact: Glen Stevens, D.O., Ph.D., 216.445.1787
AP2�5�� in Progressive or Recurrent Malignant GliomaDescription: A Phase I Sequential Ascending Dose Trial of AP23573 in Patients with Progressive or Recurrent Malignant GliomaEligibility: Radiographically suspected progressive or recurrent primary malignant glioma (glioblastoma multiforme, gliosarcoma or WHO Grade 4) and must have failed standard therapy. Patients may not have received any systemic therapy for the treatment of this recur-rence or relapse. Age >= 18.Study Design: Phase I, multi-institutionalContact: TEMPORARILY NOT ACCEPT-ING PATIENTS
Erlotinib with Temozolomide & Radiation for Newly Diagnosed GBMDescription: A Phase II Trial of Erlotinib with Temozolomide & Concurrent Radiation Therapy Post-operatively in Patients with Newly Diagnosed Glioblastoma Multiforme Eligibility: Newly diagnosed glioblastoma multiforme, ≥18 years old. Study Design: Phase II internal study
Contact: David Peereboom, M.D., 216.445.6068
Celecoxib & Anticonvulsants for Newly Diagnosed GBM’s undergo-ing Radiation TherapyDescription: A Pharmacokinetic Study of the Interaction between Celecoxib & Anticonvulsant Drugs in Patients with Newly Diagnosed Glioblastoma Multiforme Undergoing Radiation Therapy (NABTT 2100) Eligibility: Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme). Age ≥18. Study Design: Pharmacokinetic cooperative group study Contact: CURRENTLY NOT ACCEPTING PATIENTS
Tarceva (Recurrent/Progressive Glioblastoma Multiforme)Description: A Phase II study of OSI-744 used alone in patients with recurrent malignant gliomas. Eligibility: Patients must be at least 18 years of age and have Histologically confirmed WHO grade IV astrocytoma (glioblastoma multiforme), with radio-graphic evidence of recurrence. Study Design: Internal, Phase II Contact: Michael Vogelbaum, M.D., Ph.D., 216.444.856
ACOSOG Z0�00 (One to Three Cerebral Metastases)Description: A Phase III Randomized Trial of the Role of Whole Brain Radiation Therapy in Addition to Radiosurgery in the Management of Patients with One to Three Cerebral Metastases Eligibility: Patient must be at least 18 years of age Study Design: ACOSOG Consortium, Phase III Contact: CURRENTLY NOT ACCEPTING PATIENTS
BMS (Recurrent Malignant Glioma)Description: A Phase I/II Study of BMS-24755A Phase I/II Study of BMS-247550 for Treatment of Patients with Recurrent Malignant Gliomas (NABTT 2111) Eligibility: Patients must be 18 years of age or older and have histologically proven malignant glioma (anaplastic astrocytoma or glioblastoma multiforme), which is
progressive or recurrent following radiation therapy ± chemotherapy. Patients with previous low-grade glioma who pro-gressed after radiotherapy +/- chemo-therapy and are biopsied and found to have a high-grade glioma are eligible. Study Design: NABTT consortium, Phase I/II Contact: David Peereboom, M.D., 216.445.6068
OXALIPATIN (Newly Diagnosed Glioblastoma Multiforme) Description: Phase I/II Trial of Oxaliplatin as Neoadjuvant Treatment in Adults with Newly Diagnosed Glioblastoma Multi-forme NABTT 9902 Eligibility: Patients must be at least 18 years of age and have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme). Study Design: NABTT consortium, Phase I/II Contact: CURRENTLY NOT ACCEPTING PATIENTS
Karenitecin (Recurrent Malignant Gliomas)Description: Phase I Evaluation of the Safety of Karenitecin in the Treatment of Recurrent Malignant Gliomas NABTT 2006 Eligibility: Patients must be 18 years of age or older and have histologically proven malignant glioma (anaplastic astrocytoma, anaplastic oliogodendroglioma or glioblastoma multiforme) which is progressive or recurrent following radiation therapy +/- chemotherapy. Patients with previous low-grade glioma who pro-gressed after radiotherapy +/- chemo-therapy and are biopsied and found to have a high-grade glioma are eligible. Study Design: NABTT consortium, Phase I Contact: CURRENTLY NOT ACCEPTING PATIENTS
Tamoxifen-Hypothyroid GBM Description: High-dose Tamoxifen in combination with reduction of thyroid hormone during and post external beam radiotherapy. Study Design: Internal study: Phase II Eligibility: Newly diagnosed GBM, Age >18yrs Contact: CURRENTLY NOT ACCEPTING PATIENTS
Brain Tumor Institute
Appendix A – Clinical Trials
�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
RTOG-���� (Anaplastic Astrocytoma) Description: Radiation with randomization to one of three chemotherapy options Study Design: RTOG-98-13, Phase I/III trial Eligibility: Anaplastic astocytoma, Age 18 yrs Contact: John Suh, M.D., 216.444.5574
NABTT ��0� (Gliadel and O�-BG for Malignant gliomas) Description: Surgical resection and placement of gliadel wafer with systemic O6BG Study Design: Phase I study Eligibility: Supratentorial malignant glioma, Age >18yrs Contact: CURRENTLY NOT ACCEPTING PATIENTS
NABTT ��0� (procarbazine for malignant gliomas)Description: oral procarbazine, 2 arm: P450 vs. non P450 inducing medications Study Design: NABTT 9901, Phase I/II study Eligibility: recurrent high-grade glioma, 3 months post XRT, only one prior chemo Contact: CURRENTLY NOT ACCEPTING PATIENTS
NABTT ��0� (Col-� for recurrent malignant gliomas) Description: Col-3 (anti-angiogenesis) for high-grade gliomas Study Design: NABTT 9809, Phase I/II trial, P450 and non P 450 arms Eligibility: recurrent high-grade glioma, 2 or less prior chemos and 3 months post XRT Contact: CURRENTLY NOT ACCEPTING PATIENTS
SWOG S000�: Upfront Treatment for Newly Diagnosed GBMsDescription: Randomization to Radiation therapy + O6-BG + BCNU vs. Radiation + BCNU Alone Study Design: Phase III SWOG study Eligibility: Newly diagnosed GBM, KPS >60Contact: CURRENTLY NOT ACCEPTING PATIENTS
IL-��Description: Pre-Operative IL13-PE38QQR Infusion in Patients with Recurrent or Progressive Supratentorial Malignant Glioma Study Design: A Phase I/II Study Eligibility: Patients must have prior histologic diagnosis of supratentorial malignant gliomas. Eligible histologies: glioblastoma multiforme, anaplastic astrocytoma, or malignant mixed oligoas-trocytoma (excludes glioma of know grade or “pure” oligodendroglioma). Patients with
clinical /radiographic diagnosis of malignant glioma may be registered pending histologic confirmation. Patients must have recurrent or progressive supratentorial tumor compared with a previous study. Patients must be > 18 years old.Contact: CURRENTLY NOT ACCEPTING PATIENTS
IL-��Description: Phase I study of convection-enhanced delivery (CED) of IL13-PE38QQR cytotoxin after resection and prior to radiation therapy with or without temozolomide in patients with newly diagnosed supratentorial malignant glioma Study Design: Phase I Eligibility: Age > 18 years old., must have undergone a gross total resection of the solid contrast-enhancing lesions(s) > 1.0 cm in diameter, must be able to have catheters placed within 14 days of tumor resection (including a planned Gross Total Resection following an initial biopsy or subtotal resection) and must have histopathologic documentation of malignant glioma from resection speci-men. Diagnosis must be consistent with either GBM, AA or mixed OA. Contact: Mike Vogelbaum, M.D., 216.444.5381
IL-��Description: Phase III Randomized Evaluation of Convection-enhanced Delivery of IL13-PE38QQR Compared to Gliadel Wafer with Survival Endpoint in Glioblastoma Multiforme Patients at First Recurrence Study Design: Phase III Eligibility: Patients with glioblastoma multiforme (GBM) at first recurrence who are considered candidates for resection and meet the specified eligibility criteria may be enrolled in the study. Contact: CURRENTLY NOT ACCEPTING PATIENTS
WBRT +/- RSR�� in Women with Brain Metastases from Breast CancerDescription: A Phase III Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy with Supplemental Oxygen, with or without Concurrent RSR13 (efaproxiral), in Women with Brain Metastases from Breast Cancer Study Design: Phase III Eligibility: Age >= 18 years old, histologically or cytologically confirmed breast cancer in women with radiographi-cally confirmed metastases to the brain.
Contact: John Suh, M.D., 216.444.5574
Melatonin for Brain MetastasesDescription: A Randomized Phase II Study of A.M. and P.M. Melatonin for Brain Metastases in RPA Class II Patients Study Design: Phase II Eligibility: Brain metastasis from histologically documented solid tumors (except germ cell tumors). Biopsy proof from the brain metastasis is preferred when clinical history and radiologic findings are equivocal. Contact: CURRENTLY NOT ACCEPTING PATIENTS
Focal Radiation for �-� Brain MetastasesDescription: A Phase II Study Utilizing Focal Radiation in Patients with 1-3 Brain Metastases Study Design: Phase II Eligibility: Have 1 to 3 newly diagnosed supratentorial metastatic brain lesions with at least one being dominant and eligible for surgical resection as visualized on enhanced MRI scan. Have histological evidence of metastatic carcinoma on intraoperative pathology (frozen section) or final pathology report. Contact: Mike Vogelbaum, M.D., Ph.D., 216.444.5381
Temozolomide for Anaplastic Oligodendrogliomas & Mixed OligoastrocytomaDescription: Phase II Trial of Continuous Dose Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendro-gliomas and Mixed Oligoastrocytoma Study Desgin: Phase II trial Eligibility: Newly Diagnosed Anaplastic Oligodendroglioma, Newly Diagnosed Mixed Anaplastic Oligodendroglioma Contact: David Peereboom, M.D., 216.445.6068
Intraoperative Optical Spectroscopy for Glial TumorsDescription: Detection of glial tumor margins with intraoperative optical spectroscopy Study Design: Internal study Eligibility: Unifocal or multifocal supratentorial glial neoplasm suspected on MRI & patient is a surgical candidate for craniotomy Contact: Steven Toms, M.D., 216.445.7303
Gliasite BrachytherapyDescription: Phase I Brachytherapy Dose Escalation Using the Gliasite RTS in Newly Diagnosed Glioblastoma Multi-
2005 Annual Report A team approach to individualized care �5
forme in Conjunction with External Beam Radiation Therapy Study Design: Phase I trial Eligibility: Newly Diagnosed GBM Contact: Michael Vogelbaum, M.D., Ph.D., 216.444.8564
Dietary & Herbal Complementary Alternative Medicine ApproachDescription: Phase II Randomized Evaluation of 5-Lipoxgenase Inhibition by Dietary and Herbal Complementary and Alternative Medicine Approach Compared to Standard Dietary Control as an Adjuvant Therapy in Newly Diagnosed Glioblastoma Multiforme Study Design: Phase II Randomized Eligibility: Newly Diagnosed GBM Contact: Mladen Golubic, M.D., Ph.D., 216.445.7641
Bay ��-�00� for Recurrent/Progres-sive Malignant GliomasDescription: A Phase I Trial of Bay 43-9006 for Patients with Recurrent or Progressive Malignant Glioma Study Design: Phase I trial Eligibility: Recurrent Anaplastic Astrocy-toma, Recurrent Anaplastic Oligodendro-glioma, Recurrent GBM, Recurrent Gliosarcoma Contact: David Peereboom, M.D., 216.445.6068
EMD & RT for Newly Diagnosed GBM’sDescription: A Safety Run-In/Randomized Phase II Trial of EMD 121974 in Conjunc-tion with Radiation Therapy in Patients with Newly Diagnosed Glioblastoma Multiforme NCI #: NABTT 0306Study Design: NABTT Cooperative Phase II TrialEligibility: Newly Diagnosed GBM, Newly Diagnosed GliosarcomaContact: David Peereboom, M.D., 216.445.6068
Temozolomide for Low-grade GliomasDescription: A Phase II Study of Temozolo-mide-Based Chemotherapy Regimen for High Risk Low-Grade GliomasStudy Design: Phase II trialEligibility: Low-Grade GliomasContact: John Suh, M.D., 216.444.5574
Talampanel w/RT & Temozolomide for Newly Diagnosed GBM’sDescription: A Phase II Trial of Talam-panel in Conjunction with Radiation Therapy with Concurrent and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma Multiforme
Study Design: Phase II TrialEligibility: Newly Diagnosed GBM, Newly Diagnosed GliosarcomaContact: David Peereboom, M.D., 216.445.6068
Lymphoma Blood-Brain Barrier Disruption (Primary Central Nervous System Lymphoma) Description: A Phase II Trial involving Patients with Recurrent PCNSL Treated with Carboplatin/BBBD, by Adding Rituxan (Rituximab), an anti-CD-20 Antibody, to the Treatment RegimenEligibility: Patients must be 18-75 yrs of age histologically confirmed Primary CNS Lymphoma as documented by brain biopsy, or cytology (analysis from CSF or vitrectomy), & CD20 positive. Study Design: Internal, Phase II, multi-institutionalContact: CURRENTLY NOT ACCEPTING PATIENTS
Blood-Brain Barrier Disruption (Primary Central Nervous System Lymphoma)Description: Combination Chemotherapy (Methotrexate, Cyclophosphamide and Etoposide Phosphate) Delivered in Conjunction with Osmotic Blood-Brain Barrier Disruption (BBBD), with Intraventricular Cytarabine +/- Intra-Ocular Chemotherapy, in Patients with Primary CNSEligibility: 16-75 years old; histologically confirmed intermediate/high-grade primary CNS lymphoma Study Design: Internal, multi-institutional Contact: Glen Stevens, D.O., Ph.D., 216.445.1787
Meningioma SWOG-���� (Benign Meningioma)Description: Chemotherapy with hydroxyurea Study Design: Phase II, cooperative group Eligibility: Primary, recurrent or residual benign meningioma which is unresect-able, Age >18yrs, XRT > 1 yr Contact: CURRENTLY NOT ACCEPTING PATIENTS
MetastasisZeiss INTRABEAM System for Solitary Brain MetastasisDescription: A Phase I/II Study Utilizing the Zeiss INTRABEAM System for the Treatment of a Resected Solitary Brain
MetastasisEligibility: Newly diagnosed supratentorial single metastatic brain tumor as visualized on enhanced MRI scan that is surgically resectable. CT scans may be substituted for MRI only for those patients in whom MRI scans cannot be safely performed. Age >= 18.Study Design: Phase I/II, internal study.Contact: Steven Toms, M.D., 216.445.7303
WBRT with Temozolomide or Placebo for Non-Small Cell Lung Cancer Brain MetastasesDescription: A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Temozolomide or Placebo added to Whole Brain Radiation Therapy for the Treatment of Brain Metastases from Non-Small Cell Lung CancerEligibility: Histologically or cytologically confirmed non-small cell lung cancer. Eligible histologies include squamous cell and adenocarcinoma (including large cell carcinoma) and non-small cell cancer not otherwise specified. A biopsy of meta-static disease in the brain is not required for study enrollment. Age >= 18.Study Design: Phase III, randomized, double-blind, placebo controlled.Contact: John Suh, M.D., 216.444.5574
Radiation therapy plus Thalidomide for Multiple Brain MetastasesDescription: A Phase III Study of Conventional Radiation Therapy Plus Thalidomide vs. Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118) Eligibility: Histopathologically confirmed extracranial primary malignancy. Age ≥18. Study Design: Phase III cooperative group study Contact: CURRENTLY NOT ACCEPTING PATIENTS
WBRT +/- RSR�� in Women with Brain Metastases from Breast CancerDescription: A Phase III Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy with Supplemental Oxygen, with or without Concurrent RSR13 (efaproxiral), in Women with Brain Metastases from Breast CancerStudy Design: Phase IIIEligibility: Age >= 18 years old, histologically or cytologically confirmed breast cancer in women with radiographi-cally confirmed metastases to the brain.Contact: John Suh, M.D., 216.444.5574
�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Xcytrin for Non-Small Cell Lung Cancer Brain MetastasesDescription: Randomized Phase III Trial of Xcytrin® (Motexafin Gadolinium) Injections for the Treatment of Brain Metastases in Patients with Non-Small Cell Lung Cancer Undergoing Whole Brain Radiation Therapy. Study Design: Phase III Randomized trial Eligibility: Non-small cell lung cancer with brain metastases Contact: CURRENTLY NOT ACCEPTING PATIENTS
WBRT & SRS +/- Temozolomide/Gefitinib for Non-Small Cell Lung Cancer & Brain MetastasesDescription: RTOG 0320: A Phase III Trial Comparing Whole Brain Radiation and Stereotactic Radiosurgery Alone Versus with Temozolomide or Gefitinib in Patients with Non-Small Cell Lung Cancer and 1-3 Brain MetastasesStudy Design: RTOG Cooperative Phase III TrialEligibility: Non-Small Cell Lung Cancer with Brain MetastasesContact: John Suh, M.D., 216.444.5574
Motexafin Gadolinium with WBRT & SRS Boost for Brain MetastasesDescription: Phase II Trial of Motexafin Gadolinium with Whole Brain Radiation Therapy Followed by Stereotactic Radiosurgery Boost in the Treatment of Patients with Brain MetastasesStudy Design: Phase II trialEligibility: Brain MetastasesContact: John Suh, M.D., 216.444.5574
Child and Adolescent Protocols
Newly Diagnosed MalignanciesHead Start III: Dose-Intensive Chemotherapy for Children Less Than �0 Years of Age Newly Diagnosed with Malignant Brain TumorsDescription: The study uses an intensified chemotherapeutic regimen for five months followed by a highly intensive single-drug treatment course and stem cell rescue with lower-dose radiation to try to increase the chance of cure for children with certain malignant brain tumors.Eligibility: Children less than 10 years (120 months) of age at time of histologic or cytologic diagnosis of malignant brain tumor who have not previously received
irradiation or chemotherapy (except corticosteroids). Patients with the following tumor types ma y be eligible: medulloblastoma, primitive neuroecto-dermal tumor, ependymoma, choroid plexus carcinoma, atypical teratoid/rhabdoid tumor, or malignant glioma. Specific criteria apply depending on brain tumor type.Study Design: Nonrandomized Phase II study with 2-stage design.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
Chemo-Radiation Therapy for CNS AT/RT (IRB #���0)Description: The study represents a multi-institutional effort to estimate activity of an aggressive multimodality (systemic and intrathecal) chemotherapeutic regimen for highly malignant atypical teratoid-rhabdoid tumors of the CNS. Treatment showed promising results in a very limited number of these extremely rare cases. Favorable study results may occasion a full-scale national trial proposal.StudyDesign: Phase II.Eligibility: Patients must be < 18 years of age. Target tumors: histologically confirmed primary intracranial CNS AT/RT or tumor that possesses the INI1 gene mutation.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182
C.O.G.-ACNS0�2�: A Phase II Trial of Conformal Radiation Therapy for Pediatric Patients with Localized Ependymoma, Chemotherapy Prior to Second Surgery for Incompletely Resected Ependymoma, and Observa-tion for Completely Resected Differ-entiated, Supratentorial EpendymomaDescription: The study attempts to define a standard for treatment of intracranial ependymoma based on tumor location, degree of resection, and histological characteristics. Treatment will fall into one of four groups. The study will include children under 3 years of age for treatment with conformal radiation.Eligibility: Patients must be > 12 months and < 21 years of age at time of enrollment. Patients must have had no prior treatment except previous surgery or corticosteroid therapy. Target tumors: histologically confirmed intracranial ependymoma. Patients with differentiated or anaplastic ependymoma are eligible. (Patients with primary spinal cord ependy-moma, myxopapillary ependymoma,
subependymoma, ependymoblastoma, or mixed gliomas are not eligible.)Study Design: Phase II clinical trial with four treatment arms, based on tumor loca-tion, degree of resection, and histology.Contact: Joanne M. Hilden, M.D., 216.444.8407 or Bruce H. Cohen, M.D., 216.444.9182.
C.O.G.-ACNS0�22: A Phase II Study to Assess the Ability of Neoadjuvant Chemotherapy +/– Second-Look Surgery to Eliminate All Measurable Disease Prior to Radiotherapy for NGGCTDescription: The protocol aims to improve progression-free survival and overall survival of children with nongerminomatous germ cell tumor through a new therapy regimen combining anticancer drugs, radiation therapy, and, based on response, “second-look” surgery and potentially stem cell transplant.Eligibility: Patients must be at least 3 years old and less than 25 years of age at diagnosis of one of the following: endoder-mal sinus tumor (yolk sac tumor), embryonal carcinoma, choriocarcinoma, immature teratoma and teratoma with malignant transformation, or mixed germ cell tumor.Study Design: Phase II. During the first 18 weeks, patients receive three-drug chemotherapy regimen for induction with subsequent status assessment. Status will direct further treatment options—conformal radiation versus second-look surgery followed by radiation or further chemotherapy.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
C.O.G.-ACNS0�2�: A Phase II Study of Temozolomide in the Treatment of Children with High-Grade GliomasDescription: The protocol tests the effectiveness of FDA-approved temozolomide combined with radiation therapy against hard-to-treat high-grade gliomal or diffuse intrinsic pontine gliomal brain tumors.Eligibility: Patients must be > 3 years of age and < 22 years of age at time of enrollment. Target tumors: anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, and diffuse intrinsic pontine gliomas. Patients with primary spinal cord malignant gliomas are also eligible. Patients with high-grade gliomas must have histologic verification of diagnosis. Metastatic disease-ineligible.Study Design: Phase II. Initially patients receive temozolomide concurrently with
2005 Annual Report A team approach to individualized care ��
radiation therapy on 42-day schedule. Four weeks after radiation therapy, patients receive temozolomide daily for 5 days, beginning a new cycle every 28 days; 10 cycles total.Contact: CLOSED TO PATIENT ACCRUAL.
C.O.G.-ACNS0���: A Study Evaluat-ing Limited-Target Volume Boost Irradiation and Reduced-Dose Craniospinal Radiotherapy (��.00 Gy) and Chemotherapy in Children with Newly Diagnosed Standard-Risk Medulloblastoma: A Phase III Double-Randomized TrialDescription: The trial seeks to reduce nervous system damage caused by radiation therapy in children diagnosed with medulloblastoma. Children at least 3 years of age to less than 8 years of age will receive craniospinal radiation dosing at a rate reduced by 25%, supplemented by moderate intensification of adjuvant chemotherapy. The study will also explore the safety of reducing boost-volume irradiation dosing from the whole posterior fossa to the tumor bed area plus a circumscribed margin by using conformal radiation.Eligibility: Patients must be at least 3 years old and less than 22 years of age when diagnosed with posterior fossa medulloblastoma.Study Design: Phase III, randomized trial.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
C.O.G.-P����: Systemic Chemothera-py, Second-Look Surgery, and Conformal Radiation Therapy Limited to the Posterior Fossa and Primary Site for Children > � Months and < � Years with Nonmetastatic MedulloblastomaDescription: The study serves as a historical control to see if the proposed chemotherapy and conformal radiation treatment plan will be more effective (in terms of one-year event-free survival rates) than the combined treatments given to children of the same age and extent of disease on the POG-9233 trial.Eligibility: Patients greater than 8 months of age and less than three years of age with primary histology diagnosis of medulloblastoma or posterior fossa primitive neuroectodermal tumor (PNET) and no evidence of metastases.Study Design: Phase III trial; no randomization.Contact: Joanne M. Hilden, M.D.,
216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
Refractory / Progressive / Relapsed MalignanciesCCG-A��52: Chemotherapy for Progressive Low-Grade Astrocytoma in Children Less Than Ten Years OldDescription: The study compares event-free survival rates of two chemotherapeu-tic regimens in children less than ten years old who have progressive or incompletely resected astrocytoma or other glioma.Eligibility: Children less than 10 years old (120 months) with low-grade astrocyto-mas (grade 1 and 2) or other low-grade gliomas and who have progressive disease following surgical excision or an incom-plete excision (< 95% or > 1.5 cm2 residual tumor) with necessity to begin treatment because of risk of neurologic impairment with progression.Study Design: Phase III trial, two randomized regimens. NF1 patients, however, will be nonrandomly assigned.Contact: CLOSED TO PATIENT ACCRUAL.
C.O.G.-ACNS022�: A Phase II Study of R��5��� (Zarnestra) (NSC# �02���, IND# 5��5�) in Children with Recurrent or Progressive High-Grade Glioma, Medulloblastoma/PNET or Brainstem GliomaDescription: The protocol tests effective-ness of investigational drug R115777 (Zarnestra) in treating recurrent malignant childhood brain tumors.Eligibility: Patients must be < 21 years of age at enrollment. Target tumors: recurrent or progressive anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglio-ma, recurrent or refractory medulloblas-toma/PNET, or diffuse intrinsic brainstem glioma. Patients must have histopatho-logic verification of diagnosis from either initial presentation or at time of recurrence except for brainstem glioma patients. Patients must have radiographically documented measurable disease and have relapsed or become refractory to conventional therapy. Patients must have life expectancy of at least 8 weeks. Patients are excluded for uncontrolled infection, allergy to azoles, or for taking enzyme-inducing anticonvulsants.Study Design: Phase II. Patients receive study drug for 21 days followed by 7-day rest period. The 28-day cycles may be
repeated for up to two years in the absence of disease progression or unacceptable toxicity.Contact: CLOSED TO PATIENT ACCRUAL.
ADVL0�2�: A Phase II Study of Oxaliplatin in Children with Recurrent Solid TumorsDescription: The study seeks to determine the response rate of various disease strata of recurrent or refractory malignant tumors of childhood to the investigational drug oxaliplatin.Eligibility: Patients must be no more than 21 years of age inclusive when originally diagnosed. The trial includes the following malignancies for the brain tumor stratum: recurrent or refractory high-grade astrocytoma, multiforme glioblastoma, low-grade astrocytoma, brain stem glioma and ependymoma.Study Design: Phase II trial.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
C.O.G.-P���2: A Phase II Trial of Intrathecal Topotecan in Patients with Refractory Meningeal MalignanciesDescription: The study seeks to determine the therapeutic activity (response rate and time to CNS progression) of intrathecal topotecan in patients with recurrent or refractory neoplastic meningitis.Eligibility: Patients must be at least 1 year of age but less than 22 years of age at study entry. Patients must have neoplastic meningitis. Patients with meningeal lymphoma or leukemia must be refractory to conventional therapy including radiation therapy (meaning 2nd or greater relapse).Study Design: Phase II trial.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
C.O.G.-P����: A Phase II Trial of Irinotecan in Children with Refractory Solid TumorsDescription: The study seeks to determine efficacy of irinotecan in treatment of refractory pediatric brain tumors.Eligibility: Children must be at least one year and no more than 21.99 years of age at original diagnosis. Patients with histologi-cally documented brain tumors who exhibit recurrent or refractory tumor growth will be eligible. Patients will be stratified based on histology into the following groups: medulloblastoma/PNET, ependymoma, brain stem glioma, other CNS tumors.Study Design: In this Phase II trial,
�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
500
1000
0
Surgical Procedures | Annualized
‘01 ‘02 ‘03 ‘04 ‘05
Gamma Knife Cases
Surgical Cases
The Brain Tumor Institute (BTI) continues to grow in
volume of procedures. More than 240 stereotactic
radiosurgery (Gamma Knife) and 680 surgical procedures
were performed in 2005, which is a 57 percent increase
compared with 2001.
Brain Tumor Institute
Appendix B – Charts & Statistics
3250
6500
0
Total Outpatient Visits
‘01 ‘02 ‘03 ‘04 ‘05
Total outpatient visits increased by
250 percent over the past five years,
reaching a high point of more than
5,900 visits in 2005.
patients receive irinotecan 5 of every 21 days; patients demonstrating continued response or stable disease without significant toxicity may continue treat-ment. Subsequent radiographic evalua-tions would be performed every 3 months as indicated.Contact: CLOSED TO PATIENT ACCRUAL.
RegistryATT/RT Registry (IRB #5���): Central Nervous System Atypical Teratoid/Rhabdoid Tumor RegistryDescription: The registry collects information (with patient consent) about the clinical course, treatment, and outcomes of patients with atypical teratoid/rhabdoid tumor of the CNS.Eligibility: Patients with atypical teratoid/rhabdoid tumor of the central nervous system.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.
Biology StudiesCCG-B���: Protocol for Collection of Biology Specimens for Research StudiesDescription: The study provides a specimen accrual mechanism within C.O.G.-participating institutions for human pediatric cancer tissues.Eligibility: All patients up to and including 21 years of age who have had biology specimen(s) suspected of malignancy obtained and/or enrolled in a C.O.G. thera-peutic trial.Contact: CLOSED TO PATIENT ACCRUAL.
CCG-B���: Prognostic Significance of Ki-�� Proliferative Index Utilizing the MIB-� Antibody in Low-Grade Gliomas in Young ChildrenDescription: This biology study attempts to determine the value of the Ki-67 proliferative index utilizing the MIB-1 antibody in predicting time to progression in low-grade gliomas in young children a) following initial diagnosis and b) at time of tumor progression if surgery is performed.Eligibility: Patients entered on CCG-A9952.
Study Design: Unstained slides are sent to C.O.G. at time of study entry.Contact: Joanne M. Hilden, M.D., 216.444.8407 or Bruce H. Cohen, M.D., 216.444.9182.
CCG-B���: Molecular Biology of Pediatric Brain TumorsDescription: This biology study will correlate molecular and cytogenetic findings with outcomes on C.O.G. clinical trials.Eligibility: All patients less than 21 years of age with a primary CNS malignancy consistent with PNET/MB or ATT/RT who are entered on CCG front-line studies. Patients cannot have received any prior radiation treatment before the tissue was obtained. Study credit will be given for specimens obtained retrospectively on closed CCG studies, providing samples are adequate for analysis.Study Design: Tissue is accessed at time of study entry.Contact: CLOSED TO PATIENT ACCRUAL.
2005 Annual Report A team approach to individualized care ��
250
500
0
New Outpatient Visits
‘01 ‘02 ‘03 ‘04 ‘05
New patient visits have increased by 192 percent since
2001, setting a new mark
of 529 visits in 2005.
250
500
0
Patient Enrollment
‘01 ‘02 ‘03 ‘04 ‘05
Therapeutic Trials
Genetic Trials
Over the past five years, the number of patients on
research trials has increased from 94 to 431, or 358
percent.
Brain Tumor Institute
Appendix C – ArticlesClinic Researchers Earn Patent for Blood-Brain Barrier TechnologyCleveland Clinic researchers have received a U.S. patent for technology they developed to measure damage to a person’s blood-brain barrier. The patent covers the researchers’ work to develop a blood test capable of indicating when a person’s blood-brain barrier has been compromised, if neuronal damage exists, and when the person might be more responsive to therapies that need to reach the brain to treat tumors or other neurological disorders.
The patent was issued to Cleveland Clinic researchers Damir Janigro, Ph.D., and Gene Barnett, M.D. Dr. Janigro is a professor of molecular medicine and director of cerebrovascular research for Cleveland Clinic Lerner College of Medicine. Dr. Barnett is chairman of the Cleveland Clinic Brain Tumor Institute and professor of surgery and oncology.
“Determining the integrity of the blood-brain barrier is crucial in understanding disease states,” Dr. Janigro says. “This blood test is a quick and easy way to determine the most appropriate treatment for many different patients.”
The blood test would provide a minimally invasive alternative to painful spinal taps currently used to assess the condition of a patient’s blood-brain barrier. In addition, Dr. Janigro says, this blood test has the potential to save millions of dollars in MRI and CT scan costs.
MRI FLAIR Axial View with Enhancement
Axial View with Enhancement
Coronal View with Enhancement
Axial View MRI FLAIR
S-100 beta levels in patient with small (top) vs. larger brain metastases (bottom). Higher numbers indicate greater breakdown of the blood-brain barrier.
Small Metastases 0.��
Large Metastases 0.��
�0 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
CCF Innovations, the Cleveland Clinic’s technology transfer arm, is actively working to commercialize the technology through a license or a new company.
The work of Drs. Janigro and Barnett has shown that when a high level of S100b, a protein normally found in brain cells, is detected in the blood stream, it can signal a disruption of the blood-brain barrier. This disruption, in turn, can indicate the
Proteomic Profiling Holds Promise for Identifying Markers of InterestRobert J. Weil, M.D., Associate Director of Basic Research, Brain Tumor Institute
Early detection of cancer is crucial for its treatment, control and prevention. Identifica-tion of diagnostic and prognostic markers, as well as therapeutic targets, is a major goal in cancer research. Correlation of morphologic phenotypes of cancer with their expres-sion profile is a promising approach to detecting unique markers that can assist in the diagnosis and management of disease or serve as targets for therapy. A variety of new and powerful methods have been developed in recent years to foster these goals, including microarrays (DNA or “gene” chips).
Among recent technologic advances, proteomics (modeling of many proteins, the products of the genes, which are the source of all the action inside normal, as well as cancerous, cells) may have great potential as a facile tool to identify a number of
presence of a brain tumor or brain injury. In contrast, when an individual’s blood-brain barrier is intact or working properly, the level of S100b in the bloodstream is low or even undetectable.
“This test could prove useful in the early detection of brain tumors, particularly in patients with lung, breast or other systemic cancers where the risk of their cancer spreading to the brain is one in four,” Dr. Barnett says.
Robert J. Weil, M.D.
2005 Annual Report A team approach to individualized care ��
Figure LegendsFigure �. A schematic representation of the method of analyzing tissues with two-dimensional gel electrophoresis and identifying the unique proteins with mass spectrometry (LC/MS/MS).
Figure 2. Representative picture of the two types of GBMs with proteins common to the two types and unique to one or the other type. The boxes below show a small segment of a 2-D gel to illustrate the individual proteins.
Figure �. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) methodology. A nitrogen laser is shot at cells, and the absorption of energy leads to scattering of individual proteins, which are picked up in the mass
spectrometer and characterized. Sophisticated computer programs are used to smooth out the data, which are first studied to get information about tumor type and then compared to different tumors to detect subtle differences between tumors of the same type.
Figure �. An example of how comparing the spectra from tumors of the same type can reveal subtle differences in otherwise similar-appearing tumors of the same type, for example, gliomas. Here we see that it is possible to divide a group of patients, followed over many years, into those who are likely to do well (blue line, top) from those who are less responsive to treatment (red line, bottom).
markers of interest. Proteomic profiling to characterize the expression patterns of benign cells and to compare them with cancer cells appears to be a promising approach to identifying markers of interest.
A variety of methods, including two-dimensional gel electrophore-sis (2DGE), matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), surface-enhanced laser desorption-ionization (SELDI), and protein microarrays, have been utilized to study normal and cancer cells, as well as a selection of body fluids, such as blood, saliva and urine, to look for changes that predict the presence of cancer. In the study of gliomas, we have focused recently on two methods, 2DGE and MALDI-MS.
Gliomas are the most common primary brain tumors of adults, with a yearly incidence of approximately 25,000 cases in the United States. The most common form of glioma is the glioblas-toma multiforme (GBM), an aggressive and malignant tumor. Despite decades of research on tumor biology and treatment, patients with GBMs continue to have a poor prognosis, with a median survival of one year following aggressive surgical and adjuvant therapy. GBMs account for an estimated 2.5 percent of all cancer deaths in the United States, and treating these tumors remains a high priority for researchers and clinicians.
2DGE protein identification and proteomic profiling methods have seen considerable technological improvements since 2DGE was first used to analyze gliomas in the 1980s. 2DGE analysis is an effective method to identify proteins involved in human disease. Despite its potential, however, many proteomic methodologies are limited by the complexity of cancer tissues, where a mixture of neoplastic and non-neoplastic cells can hamper the effort to acquire a pure tumor cell signature. In addition, heterogeneity among tumor types at a single site can increase the complexity of proteomics and other gene expression approaches.
Further refinements in gene expression and protein profiling were realized with the more recent development of selective tissue microdissection, which enables the procurement of pure populations of cells of interest. In concert with colleagues at the National Institutes of Health, we used selective tissue microdis-section of primary tumor samples to study a group of GBMs.
Two types of GBMs have previously been described: de novo or primary GBMs, which typically arise in older individuals, and secondary or progressive GBMs, which arise several years after the first manifestation of a lower grade glioma, typically found in younger patients.
We used selective tissue microdissection to procure pure populations of glioblastoma cells and analyzed them by 2DGE. In each case, the protein expression patterns could be classified into one of two groups, which coincided with the clinical distinction of primary or secondary. Unique expression of a number of proteins was identified on a large scale between members of the primary or secondary tumors. We isolated and sequenced some of these proteins and identified several proteins known or suspected in gliomas and/or other cancers. In addition, we identified several proteins not previously known to be expressed in normal brain and glial tissue or to be a part of gliomagenesis.
In a second study, in collaboration with colleagues at the National Institutes of Health and Vanderbilt University, we used a direct-tissue protein profiling approach to tumor analysis using mass spectrometry (MALDI-MS) to correlate protein patterns obtained directly from tumor biopsies with patient survival trends. MALDI is not only a powerful method to confirm the diagnosis of a brain tumor, but it also can be used to “crunch” a tremendous amount of information to distinguish between people with the same type of tumor—for example, a GBM—and to identify protein patterns that predict different survival trends.
Both of these types of protein studies, along with others, can be used to improve diagnosis; identify prognostic markers in tumors and other tissues and fluids, like the blood; and, in the future, serve as useful adjuncts for predicting response to treatment and overall outcome.
These studies are still in their infancy; not just technologically, but also as predictive tools. These and other methods will be developed and studied in the Brain Tumor Institute in a larger group of patients, where their uses and limitations will become better understood.
�2 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor
Surgical Management of Spinal Tumors Revolutionizes TreatmentThe days of a single therapeutic approach to all metastatic spine tumors are coming to a close.
For more than 20 years, external beam radiation has been the standard of care for patients with these tumors. Now the paradigm is shifting to surgical treatment prior to radiation as a better option for many patients, a strategy that Cleveland Clinic physicians Steven Toms, M.D., M.P.H., and Edward Benzel, M.D., believe offers significant advantages.
“There is compelling evidence that aggressive management of these tumors, including radiosurgery or surgical resection and decompression, followed by radiotherapy to sterilize the tumor bed, improves pain control and ambulation, preserves or restores bowel and bladder function and may confer a survival benefit,” Dr. Toms says.
Based on their personal experience as well as data from several small retrospective studies, Dr. Benzel, Chairman of the Cleveland Clinic Spine Institute, and Dr. Toms, a neurosurgeon in the Cleveland Clinic Brain Tumor Institute, have been promot-ing this broader treatment approach for patients with meta-static spine tumors for several years. A recent study in Lancet (2005;366(9486):643-648), in which surgery plus radiothera-py resulted in significantly better outcomes in quality of life measures and pain control compared with radiosurgery alone, has sparked wide-spread interest in surgical treatment as an adjunct to radiotherapy for these patients.
At Cleveland Clinic, surgical resection and spinal reconstruction, kyphoplasty to stabilize the spine, radiosurgery with the Novalis system, external beam radiation and chemotherapy all are potential elements of the treatment plan for spinal tumor patients.
“The key is to create an individualized plan for each patient based on tumor stage, the levels of the spine involved, the patient’s age and life expectancy, and quality of life considerations,” Dr. Benzel notes. Because of the often complex nature of these cases, the treatment decision is best made by a multidisciplinary team that includes spine surgeons, oncologists and radiation oncologists, he adds.
To implement this strategy at Cleveland Clinic, Drs. Toms and Benzel have established a Spine Tumor Board, an interdisciplin-ary committee that meets regularly to discuss these cases and plan appropriate treatment. The main candidates for consider-ation are patients with primary renal cell carcinoma, melanoma, or lung or breast cancer that has metastasized to the spine.
This multidisciplinary approach also offers advantages in the management of multiple myeloma. Cleveland Clinic orthopaedic surgeon Isador Lieberman, M.D., pioneered the use
of kyphoplasty in multiple myeloma patients to stabilize the spine prior to chemotherapy and/or tumor resection and spinal decompression. He has demonstrated that kyphoplasty can be performed at multiple levels in the spine and relieves pain, improves the ability to walk and significantly improves quality of life for these patients.
“Patients with pancoast tumors that have penetrated to the vertebral bodies are another population that may benefit from more aggressive surgical management,” Dr. Toms adds. At least one study has demonstrated that resection with negative margins and spinal reconstruction followed by radiotherapy confers a significant survival benefit in these patients.
To refer patients with spinal tumors to the Spine Tumor Board, call the Cleveland Clinic Spine Institute at 216.444.2225 or 800.223.2273, ext. 42225.
Figure 1 [L5 spine met files]: Patient presented with low back pain and leg pain with a history of renal cell carcinoma. Preoperative saggital MRI shows a collapsed vertebral body at the fifth lumbar level (L5) with tumor extending into the pedicle and causing compression of an exiting nerve root. The tumor was removed using a posterior approach and reconstructed with methylmeth-acrylate (bone cement), Steinmann pins and pedicle screws fixation. The patient’s pain resolved, and he remained ambulatory after surgery.
Figure 2: Patient presented with a persistent cough and new hand pain and numbness. Pre-operative axial MRI shows a lesion of the apex of the lung (superior sulcus) representing a primary lung cancer. The tumor, which had invaded the brachial plexus and vertebral body of the spine, was removed via thoracotomy. The brachial plexus was identified, and arm and hand motor function preserved. A partial vertebrectomy was performed to remove the tumor from the vertebral body while avoiding the need for anterior spinal column reconstruction. The extensive bony and soft tissue resection did require spine stabalization using lateral mass and pedicle screws from a posterior approach in a staged second surgery.
2005 Annual Report A team approach to individualized care ��
Mladen Golubic, M.D., Ph.D.
A Dietary and Herbal Approach to Reducing Peritumoral Brain EdemaCleveland Clinic cancer researchers have initiated a clinical study of the effect of a vegan diet combined with herbal therapy on edema caused by glioblastoma multiforme (GBM). The two-pronged approach will be used as an adjuvant to standard therapy.
Because 5-LO-derived eicosanoids stimulate tumorigenesis and inflammation that lead to development of peritumoral brain edema, inhibition of 5-LO is an attractive therapeutic target.
“Cancer results from complex interactions between a genetically susceptible host and a variety of environmental factors. Diet is an important, modifiable environmental factor. Foods contain a spectrum of compounds that may modulate carcinogenesis by several mechanisms, including pro- and antioxidant effects, regulation of enzymes that detoxify carcinogens and alterations of hormone metabolism. Modulation of inflammation by compounds found in foods and herbs has recently attracted a lot of attention because of identification of critical molecular links between the processes of inflammation and carcinogenesis,” says Principal Investigator Mladen Golubic, M.D., Ph.D., of the Cleveland Clinic’s Brain Tumor Institute and Center for Integrative Medicine.
Dr. Golubic’s team recently demonstrated that a pro-inflamma-tory 5-lipoxygenase (5-LO) enzyme is aberrantly upregulated in GBM. 5-LO oxidizes nutritionally relevant fatty acids present in abnormally high concentrations in GBM, turning them into biologically active eicosanoids. Because 5-LO-derived eico-sanoids stimulate tumorigenesis and inflammation that lead to development of peritumoral brain edema, inhibition of 5-LO is an attractive therapeutic target. The research team is hoping their twopronged approach will inhibit 5-LO eicosanoid production and decrease peritumoral brain edema with fewer side effects than glucocorticoids.
In this study, funded by the national cancer institute, patients are randomized to a low-fat vegan diet plus boswellia serrata (frankincense) or to a diet recommended for cancer survivors by the american cancer society. B. serrata resin contains boswellic acids that inhibit 5-LO in a direct, non-redox, and non-competi-tive way distinct from that of other inhibitors. In two small german studies, crude herbal preparation of B. serrata was found to be beneficial in reducing brain edema in some patients with GBM. However, patients were not asked to reduce intake of dietary fats, which 5-LO uses to produce pro-inflammatory and pro-tumorigenic eicosanoids.
In the Cleveland Clinic study, B. serrata is combined with a low-fat vegan diet. Arachidonic acid, the key fatty acid from which eicosanoids are produced, is derived almost exclusively from animal sources. Thus, the intervention diet will consist exclusively of plant foods such as vegetables, legumes, unrefined whole grains, spices and fruits. A novel standardized preparation of B. serrata is used in place of crude extract. Because the preparation is solubilized in lipids, boswellic acids are expected to be more bioavailable.
GBM tumor growth, peritumoral brain edema and use of glucocorticoids are monitored every two months. Plasma measurements of 5-LO eicosanoids and boswellic acids are taken to evaluate adherence to therapy. “Incorporation of a combina-tion of dietary and herbal approaches as an adjuvant to standard
care allows patients to take charge of their lives, which is a major reason why patients with GBM are attracted to nutritional and herbal therapies,” says Dr. Golubic. To reach Dr. Mladen Golubic, call 216.445.7641 or e-mail [email protected].
Frankincense, Key Medicinal Herb of the Ancient WorldTWO THOUSAND YEARS AGO, the “bestselling drug” was frankincense. The herb, with medicinal properties, is the product of a medium-to-large tree, Boswellia serrata, found in the dry hills of North Africa, the Middle East and India. The resin, exuded by the tree during winter months and deposited on the bark, contains oils, terpenoids and gum.
Historically, crude preparations of oleoresin exudate from the frankincense tree were widely used to treat wounds and various types of skin lesions. Hippocrates used frankincense to treat persistent ulcers. Avicenna, the foremost Arab physician of the 11th century, recommended it for inflammation, infections of the urinary tract, tumors, fevers, vomiting and dysentery. In Indian Ayurvedic medicine, frankincense is used as a remedy for rheumatism as well as inflammatory conditions of the eye and respiratory system. Modern clinical studies concur with ancient medical wisdom regarding its effectiveness in patients with bronchial asthma, ulcerative colitis, Crohn’s disease and osteoarthritis.
NeurosurgeryGene H. Barnett, M.D., F.A.C.S. Chairman, Brain Tumor Institute
Lilyana Angelov, M.D.
William Bingaman, M.D.*
Nicholas Boulis, M.D. *
Joseph F. Hahn, M.D.*
Damir Janigro, M.D.*
Joung Lee, M.D. Director, Section of Neurofibromatosis and Benign Tumors Head, Section of Skull Base Surgery
Mark Luciano, M.D., Ph.D.*
Peter Rasmussen, M.D.*
Samuel Tobias, M.D.*
Steven Toms, M.D., M.P.H. Head, Section of Metastatic Disease
Michael A. Vogelbaum, M.D., Ph.D. Director, Center for Translational Therapeutics
Robert Weil, M.D. Section Head, Pituitary and Neuroendocrine Surgery and Associate Director of Basic Laboratory Research
Henry Woo, M.D.*
NeurologyBruce H. Cohen, M.D.* Co-Director, Pediatric & Adolescent Brain Tumor Program
Glen H. Stevens, D.O., Ph.D. Head, Section of Adult Neuro-Oncology
Radiation OncologyAleck Hercbergs, M.D.*
Roger M. Macklis, M.D.*
John H. Suh, M.D. Director, Gamma Knife Center
Radiation Physics Christopher Deibel, Ph.D.
Gennady Neyman, Ph.D.
Martin S. Weinhous, Ph.D.
NeuropathologyRichard Prayson, M.D.*
Susan Staugaitis, M.D., Ph.D.*
Hematology & Medical OncologyBrian Bolwell, M.D.*
Medical OncologyDavid Peereboom, M.D. Head, Section of Medical Oncology
ResearchGene H. Barnett, M.D. Chairman, Brain Tumor Institute
Nabila Bennani-Baiti, Ph.D.
Olga Chernova, Ph.D.
Peter Cohen, M.D.*
Mladen Golubic, M.D., Ph.D.
Andrei Gudkov, Ph.D.*
Jaharul Haque, M.D.*
Damir Janigro, Ph.D.*
Robert Miller, Ph.D. Senior Consultant
Gregory Plautz, M.D., Ph.D.*
Suyu Shu, Ph.D.*
Susan Staugaitis, M.D., Ph.D.*
Steven Toms, M.D., M.P.H. Head, Section of Metastatic Disease
Bruce Trapp, Ph.D.*
Raymond Tubbs, D.O.*
Michael A. Vogelbaum, M.D., Ph.D. Director, Center for Translational Therapeutics
Ilka Warshawsky, M.D.*
Robert Weil, M.D. Associate Director, Basic Laboratory Research Section Head, Pituitary and Neuro-Endocrine Surgery
Bryan Williams, Ph.D.*
Nursing/Physician AssistantsCathy Brewer, R.N.
Gail Ditz, R.N., B.S.N.
Sandra Ference, M.S.N., C.N.P.
Michele Gavin, M.P.A.S., P.A.-C.
Betty Jamison, R.N., B.S.N.
Debra Kangisser, P.A.-C.
Kathy Lupica, M.S.N., C.N.P.
Mary Miller, R.N., B.S.N.
Carol Patton, R.N.
Rachel Perez, R.N., B.S.N.
Sherry Soeder, M.S.N., C.N.P.
Lisa Sorenson, M.S.N., A.C.N.P.
Laural Turo, R.N., B.S.N.
Carla Yoder, M.S.N., C.N.P.
AdministrationKim Blevins Medical Secretary Work Leader
Michael Lawson, MBA Taussig Cancer Center Division Administrator
George Lawrence IV, MBA BTI Administrator
Henrietta-English West Patient Access Coordinator
Wendi Evanoff, B.A.
Noreen Flowers*
Charlotte Horner Patient Access Coordinator
Eric LaPresto
Systems Engineer
Sally McCartney
James Saporito Executive Director of Development
Kristin Swenson, MBA* Marketing Associate
Martha Tobin* Continuing Medical Education
Sherri Wilson
Tanya Wray, MBA* Marketing Manager
Cancer Center Research SupportJoanne Civic
Robert Gerlach
John Pellecchia
Kathy Robinson
Patricia Weiss, R.N.
Brain Tumor Institute Faculty*Denotes joint appointment
2005 Annual Report A team approach to individualized care �5
Members of the Brain Tumor Institute are available for consultation 24 hours a day, seven days a week. Their goal is to see patients with diagnosed or suspected brain tumors within 24 to 48 hours.
216.445.8971 or 800.553.5056, ext. 58971 (weekdays 8 a.m. to 5 p.m.) for consultations and/or hospital admission.
216.444.2200 (nights and weekends). Ask for neuro-oncology staff or the chief neurosurgical or neurological resident on call. For pediatric patients, ask for the chief pediatric neurological resident on call.
How to Refer a Patient to the Cleveland Clinic Brain Tumor Institute
Patient appointment line: 216.445.8971 or 800.223.2273, ext. 58971