1. health and fitness
2. disease
3. cancer
4. brain tumor

How to Refer a Patient to the
Cleveland Clinic Brain Tumor Institute
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.
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
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.
© The Cleveland Clinic Foundation 2006
06-BTI-003
Brain Tumor Institute
2005 Annual Report prepared by Gene H. Barnett, M.D., Chairman
A team approach to individualized care
Table of Contents
01 Letter from Chairman
02
Executive Summary
02 Invited Lectures
03 Educational Activity
04 Support and Grants
05 Membership
05 Recruitment
06 Research
07Marketing, 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.
III
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Letter from Chairman
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
much-needed funding, particularly philanthropic support.
In 2005, among the hundreds of clinical studies already under way, the BTI led 26
clinical studies that were funded by corporate sponsors or Cleveland Clinic, or through
consortia. Two of our researchers received a U.S. patent for a blood-brain barrier
technology that may help detect new brain tumors using a simple blood test.
Collaborating with Taussig Cancer Center, the largest cancer program in Ohio, also
grants us access to its clinical and research resources as well as the opportunity to
interact with other health care professionals who deal with cancer patients daily. Using
innovative therapy and a multidisciplinary structure – a model of organization that has
attracted recent national and international interest – we provide a team approach to
individualized care. We look forward to improving care as we continue to measure
our performance.
Gene H. Barnett, M.D.
Chairman, Brain Tumor Institute
2005 Annual Report
A team approach to individualized care
A Team Approach
an increase in new patient
volume of 192 percent
Brain Tumor Institute
Executive Summary
The Cleveland Clinic BTI is a leader in the diagnosis,
The vision of the BTI is fourfold:
treatment and research of brain tumors. Chaired by
1) To provide diagnosis and comprehensive management of brain
neurosurgeon Gene Barnett, M.D., the BTI comprises a
dedicated team of specialists who share the common
and spinal tumors
2) To provide excellent, compassionate care to every patient
3) To advance knowledge of the causes of brain tumor develop-
goal of advancing the diagnosis, research and treatment
ment and growth, and develop new treatment options
4) To educate the public and professionals about brain tumors
of brain tumors in adults and children. This group of
neurosurgeons, neuro-oncologists, medical oncologists,
neuroradiologists, radiation oncologists, neuropathologists, advanced practice nurses and nurse practitioners
and their management
Central to the success of the BTI is advancing the care of brain
tumor patients through better understanding of the causes and
mechanisms of these disorders. Our physicians and scientists are
collaborates on clinical management and research of
conducting valuable research with the goal of bringing new safe
brain tumors.
and effective therapies to patients as quickly as possible. It is this
This multidisciplinary approach is used to diagnose and treat
brain tumors that is the cornerstone of our work.
dedication to improving the lives of our patients and others with
adult and pediatric brain tumor patients, using state-of-the-art
diagnostic and therapeutic methods that can substantially
improve chances for survival and extend hope for a better quality
of life to those with previously untreatable tumors.
Invited Lectures
In March 2005, the BTI hosted Morris Groves, M.D., Director of
Inpatient Services, Department of Neuro-Oncology, University of
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Texas MD Anderson Cancer Center. Dr. Groves spoke on “AntiInvasion Strategies for the Treatment of High-Grade Glioma.”
In September, the BTI hosted Hienrich Elinzano, M.D., from the
Neuro-Oncology Branch of the National Institutes of Health. Dr.
radiotherapy, chemotherapy and alternative therapies to improve
the care of patients with central nervous system tumors. The BTI
also hosted a neuro-oncology mini-symposium in August.
The BTI hosted a regional physician dinner talk at the Glenmoor
Elinzano spoke on “Imaging Angiogenesis in Gliomas.” The BTI
Country Club in Canton, Ohio, in August 2005. Michael
also hosted Maciej Mrugala, M.D., from Massachusetts General
Vogelbaum, M.D., Ph.D., presented on Intracerebral Delivery
Hospital, who spoke on “Primary Central Nervous System
of Chemotherapy for Brain Tumors. Recent advances in neuro-
Lymphomas - Can we predict response to chemotherapy?”
oncology and the possible patient benefit of Convection
In October, the BTI hosted Simon Lo, M.D., Assistant Professor
of Clinical Radiation Oncology from the Indiana University
Enhanced Delivery were discussed.
The BTI’s Gamma Knife Center, under the direction of John
Medical Center. Dr. Lo discussed “The Role of Gamma Knife
Suh, M.D., continues to be a major thrust for the BTI. In 2005,
Radiosurgery in the Management of Unresectable Gross Disease
radiosurgeons treated the 1,500th patient since the center
or Gross Residual Disease After Surgery in Ependymoma.”
opened in 1997. The BTI is one of only three centers in the world
In November, the BTI hosted Jann Sarkaria, M.D., Assistant
Professor of Oncology from Mayo Clinic College of Medicine, who
spoke on “Investigating Mechanisms of Temozolomide Sensitivity
in a GBM Xenograft Model.”
certified by the manufacturer to train physicians new to Gamma
Knife radiosurgery. In 2005, the Gamma Knife Center upgraded
its system to the most technologically advanced model, the
Model 4C. Cleveland Clinic is one of only eight centers in the
U.S. to have this model. To support education, Cleveland Clinic
held four week-long Gamma Knife radiosurgery training courses
Educational Activities
in 2005, in addition to a two-day internal training course for
Continuing Medical Education
residents, fellows and Cleveland Clinic staff in January.
Supporting Professional Education. As part of the BTI’s mission
to advance brain tumor treatment and research through
collaboration and education, the BTI and the Department of
Neurosurgery coordinated and hosted a major symposium in
January 2005, called “Neuro-Oncology 2005: Current Concepts.”
The symposium, which was held in Orlando, Fla., attracted
national and international leaders in the clinical care and
laboratory investigation of brain tumors. This successful event
brought together faculty and participants who spent three days
discussing advances in imaging, molecular biology, surgery,
Professional Education
Sponsoring symposia and publishing papers help to enhance the
reputation of the BTI among peers and patients, as well as to
encourage collaboration with colleagues locally, nationally and
internationally. Papers and abstracts generally are based on the
results of basic, translational and clinical research. Involvement
in these activities demonstrates our commitment to pursuing
a higher standard of research, professional education and,
ultimately, patient care.
Gamma Knife Radiosurgery Course
to Individualized Care
2005 Annual Report
A team approach to individualized care
In 2005, the staff of the BTI continued to increase editorial
activity with more than 100 journal articles, four book chapters
and two books published or in press. Currently, 59 journal
articles, 11 book chapters and two books are works in progress.
Support and Grants
Philanthropy. Never before now has a group of donors been
so involved with and dedicated to the long-term success and support of the Brain Tumor Institute. Because of the generosity and
In 2005, the BTI published its first edition of outcomes. The
involvement of our donors, the BTI is better equipped to pioneer
report is a brief summary of the department and a synopsis of its
advanced surgical procedures, develop more accurate imaging
surgical statistics and outcomes, with a comparison to published
techniques, investigate more effective treatments and, ultimately,
standards and benchmarks. The outcomes booklet was mailed
save more lives than we could alone. In January 2005, James
Saporito joined our team as the Director of Development for the
to appropriate physician specialties across the country.
Taussig Cancer Center. Also in 2005, the Brain Tumor Institute
The BTI continues to place a high priority on hosting and
Leadership Board expanded membership and Norma Lerner
participating in physician education. In 2006, the BTI will
became our Honorary Co-Chair of the Board. The Leadership
host two major symposia: “Contemporary Issues in Pituitary
Board is instrumental in spreading the word about the important
Disease: Case-Based Management Update”, and “Cleveland
work being conducted by BTI physicians.
Clinic Symposium on Convection-Enhanced Drug (CED)
Delivery to the Brain,” led by an international faculty of top
Since the BTI was formed, we have secured $13.1 million in
CED investigators. In May 2006, the BTI will co-sponsor the
major pledges and contributions, including three endowed chairs.
international symposium “Neuro-Oncology 2006: Current
In addition, this year the BTI obtained a challenge grant for
Concepts” in Hamburg, Germany, with University Hospital
$750,000 for Gamma Knife Research. Our donors know that
Hamburg-Eppendorf. Also in May, the BTI will host the “3rd
philanthropic support is crucial if we are to continue to advance
Brain Tumor Summit,” focusing on glioblastoma. The BTI also
the frontier of brain tumor treatment and research. Our needs are
will hold five Gamma Knife radiosurgery training courses for
great. Additional philanthropic support will help sustain our
physicians and physicists new to Gamma Knife radiosurgery.
research and educational activities for years to come.
At the end of 2005, the BTI and Case Western Reserve University
Current Funding. Ongoing funding is crucial for BTI physicians,
(known jointly as the Cleveland Brain Tumor Initiative) held a Brain
researchers and scientists to continue to investigate potential
Tumor Biology Retreat in Cleveland to highlight emerging areas of
brain tumor therapies that may be used for treatment in the
investigation in the area. Scientific investigators from around the
future. In 2005, the BTI had 15 clinical studies funded by
region working in such fields as cancer, neurosciences, cell growth
corporate sponsors, seven clinical studies supported by Cleveland
and migration attended the daylong conference, with the goals of
Clinic, and four clinical studies funded through consortia. For
fostering interaction and encouraging collaboration.
example, the BTI’s award of a UO1 grant from the NCI to Dr.
Gene Barnett to support full membership in the NABTT consor-
The program consisted of a series of short talks and an interac-
tium means that some of these research activities receive direct
tive poster session. Some of the topics included molecular
federal support and that our patients will have access to more
control of tumor cell migration, suppression of brain tumor
clinical trials, including some that are conducted at just a few
growth by agonists of the nuclear receptor PPAR gamma,
centers across the country. Also, an NIH grant awarded to
preclinical development of glioma vaccines for immunotherapy,
Mladen Golubic, M.D., Ph.D., a project scientist in the BTI
and tracking the migration of human glioma cells ex vivo using
laboratories, continues to support his work on the study of
quantum dots in a tissue slice model.
5-lipoxygenases inhibition as an adjuvant glioma therapy.
Higher Patient Volume. Between 2001 and 2005, the BTI
experienced an increase in new patient volume of 192 percent;
an increase in outpatient visits of 250 percent; an increase
New Funding. BTI staff members are continually applying for
funding and this year submissions have tripled. Below are examples
of funding awards received by BTI staff members in 2005.
in surgical cases of 56 percent; and an increase in Gamma
Knife cases of 47 percent. BTI physicians recorded 5,964
Ali Chahlavi, M.D., of the Department of Neurosurgery and Brain
outpatient visits and performed 930 surgical, Gamma Knife
Tumor Institute received a grant award in 2005 of $40,000 from
the Neurosurgery Research and Education Foundation (NREF).
and Novalis procedures.
The award money will be used to study the immunosuppressive
Larger Market Share. The BTI has the highest market share
function of glioblastoma multiforme (GBM). “New approaches
in the “Cuyahoga County,” “21-county,” and “state of Ohio”
markets and, in 2005, increased its dominance over our closest
competitor, University Hospitals of Cleveland. Future initiatives
focus on increasing market share locally, regionally and nationally.
are requisite if malignant gliomas are to be treated successfully.
Immunotherapy has been an attractive approach in this disease;
however, due to their unsuccessful treatment so far, a second
modality that will target the immunosuppressive function of GBM
may be of greatest therapeutic relevance.”
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Dr. Mladen Golubic has been awarded the National Brain Tumor
Below are examples of projects being conducted in our clinical
Foundation’s (NBTF) 2005 Richard A. Hollow, Jr. Quality of
research labs.
Life Grant. This is a pilot study to examine whether participation
in a stress reduction program would improve quality of life for
patients with malignant brain tumors and their family caregivers.
A research project by Dr. Golubic has also been chosen for
funding by the Bakken Heart Institute.
Steven Toms, M.D., Head of the BTI’s Section of Metastatic Disease,
•P
hase 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. This
clinical trial, headed by Dr. Mladen Golubic, is the first complementary and alternative medicine trial launched by the BTI. Dr.
has been selected to receive development support from the
Golubic received NCI funding for this project. This trial seeks to
Innovation Validation Fund. His laboratory has been granted
reduce the degree of edema around brain tumors, a common
$30,650 to complete the proposed work for commercial develop-
and often debilitating aspect of brain cancer.
ment of CCF Innovations Case #04048, titled “Development of
Implantable Fiber Optic System for In Vivo Detection of Quantum
DOTS.” The funds are available as of March 1, 2005, and the
proposed date of completion for this project was February 28, 2006.
•A
Phase I Study of Convection-Enhanced Delivery (CED) of
IL13-PE38QQR Infusion After Resection Followed by Radiation
Therapy With or Without Temozolomide. Dr. Michael Vogelbaum
serves as national co-principal investigator for a clinical trial that
infuses a novel targeted cancer toxin directly into the brain after
Membership
tumor resection. CED allows this large molecule, which otherwise
Cleveland Clinic will host the International Blood-Brain Barrier
would be excluded from the brain by the blood-brain barrier,
Disruption Consortium mid-year meeting in September 2006.
to reach tumor cells in the brain.
The consortium, which comprises seven institutions, combines
basic science, research and comprehensive patient care to treat
patients with brain tumors. The consortium is researching the
effective delivery of chemotherapy by outwitting the brain’s
natural defense, the blood-brain barrier, while also protecting
cognitive function.
•A
Phase I/II Study Utilizing the PEC Intraoperative Radiotherapy
Device for the Treatment of a Resected Solitary Brain Metastasis. Dr. Steven Toms has developed a study that uses a novel
device to deliver radiation therapy directly into the surgical
cavity immediately after resection of a brain metastasis. This
strategy delivers a high dose of radiation to the tumor cavity
Recruitment. Attracting and maintaining the best physicians,
researchers and employees to the BTI team are critical to remain
one of the leading brain tumor centers in the U.S. Never before
has employee satisfaction been higher in the BTI. Planned
recruitment for 2006 includes a pediatric neuro-oncologist
and a radiation oncologist.
immediately, while sparing the rest of the brain from radiation.
•P
hase II Trial of Erlotinib with Temozolomide and Concurrent
Radiation Therapy Post-operatively in Patients with Newly
Diagnosed Glioblastoma Multiforme. This trial is designed to build
upon the therapy for patients with GBM by adding erlotinib, an
oral drug that targets a growth signaling protein on the surface
Clinical Research and Cutting-Edge Clinical Trials. BTI patients
of GBM cells. This study follows initial encouraging data reported
may elect experimental treatments or to participate in clinical
by Dr. Michael Vogelbaum in his trial of erlotinib for recurrent
research projects related to their diagnosis. Various chemothera-
GBM. The study is headed by Dr. David Peereboom.
pies and growth modifiers are among the experimental drug
protocols developed by the institute’s clinical investigators.
Cleveland Clinic brain tumor patients benefit from clinical trials
designed by Cleveland Clinic physicians as well as those
conducted in conjunction with several national and international
consortia. These groups include: New Approaches to Brain
Tumor Therapy (NABTT) CNS Consortium, International Blood-
•A
Phase I/II Trial of BMS-247550 for Treatment of Patients
with Recurrent High-grade Gliomas. This clinical trial examines
an epothilone for patients with recurrent high-grade gliomas.
Dr. David Peereboom is the PI for this national trial conducted
within the NCI-sponsored NABTT CNS Consortium.
•P
hase III Trial comparing Whole Brain Radiation Therapy versus
Brain Barrier Disruption Consortium (BBBD), Radiation Therapy
Whole Brain Radiation Therapy plus Efaproxiral for Women with
Oncology Group (RTOG), Southwest Oncology Group (SWOG),
Brain Metastases from Breast Cancer. Dr. Suh is the PI for this
American College of Surgeons Oncology Group (ACoSOG), and
international phase III trial of a novel radiosensitizer.
Children’s Oncology Group (COG). Cleveland Clinic BTI physicians serve as national principal investigators in several of the
trials conducted by these consortia.
• International Registry for CNS Atypical Teratoid/Rhabdoid
tumor. Dr. Joanne Hilden, chair of the Department of Pediatric
Hematology/Oncology at Cleveland Clinic Children’s Hospital,
founded and runs a registry for CNS Atypical Teratoid Tumor of
childhood, which generates an evidence base for the treatment
of this highly malignant tumor. Registry results were used in
part to help design the first COG clinical trial for CNS AT/RT.
2005 Annual Report
A team approach to individualized care
migration and exploring the use of a new drug that may
sensitize gliomas to temozolomide (in collaboration with
Dr. Stanton Gerson).
Basic Research. Research at Cleveland Clinic continues to
grow and prosper through recruitment of outstanding new
staff, improvement and expansion of facilities, development of
extensive infrastructure and support services, and the enhancement of education programs. Central to the success of the BTI
is advancing the care of brain tumor patients through better
understanding of the causes and mechanisms of tumor development. Basic science research efforts are focused on identifying
the genetic, cellular and molecular biology of malignant and
benign brain tumors, investigating the mechanism of tumor
Research taking place at Cleveland Clinic allows BTI physicians a greater
understanding of the mechanisms of brain tumors.
formation and exploring new therapeutic developments for brain
tumor treatments. One example of the promising research being
BTI clinical investigators continually are developing various
conducted by BTI physicians is Dr. Robert Weil’s research on
experimental treatment protocols for brain tumor and neuro-
proteomics, which involves analyzing the human genome at
oncology patients. At the BTI’s Center for Translational Therapeu-
the protein level – the point at which most diseases manifest
tics (CTT), directed by Dr. Michael Vogelbaum, preclinical testing
themselves. See Appendix C for details.
of the most promising anticancer agents into Phase I and II
Below are examples of the projects being conducted in the
clinical trials is under way, giving brain tumor patients more
basic research labs.
therapeutic treatment options.
Testing of new agents involves evaluating the toxicity and efficacy
of these compounds in the laboratory and in animals that have
•D
eveloping immunotherapy for malignant glioma using
vaccines formed by fusing tumor cells with dendritic cells
(Dr. Gregory Plautz).
brain tumors. We also are investigating the optimal route of
•T
he tumor antigen profile of brain tumor stem cells is being
delivery of these drugs.
characterized to determine whether there are common glioma
Because many new therapeutic agents cannot penetrate the
antigens, which would make it possible to develop a standard-
central nervous system, center researchers are exploring
ized glioma vaccine (Dr. Gregory Plautz).
alternative delivery methods. In addition to investigating the
efficacy of oral delivery, researchers evaluate the efficacy of the
•T
he ability of dendritic cell/tumor cell fusion vaccines and
agents when delivered intracerebrally – directly into the brain –
adoptive transfer of tumor-sensitized T cells to cure established
via a specialized neurosurgical technique called convection-
brain tumors is being tested in mouse models as a prelude to
enhanced delivery (CED).
future clinical trials (Dr. Gregory Plautz).
•G
enetic alterations and biological characterization of
The staff at the CTT is focused on translating these preclinical
results into Phase I and II clinical trials - giving the brain tumor
primary cell cultures derived from malignant gliomas
patient more therapeutic treatment options by broadening the
(Dr. Olga Chernova).
horizon of potential tools we may use to manage this deadly disease.
•G
enetic alterations in GBMs (loss or gain of 19q, 1p and other
The CTT has started research projects with several pharmaceuti-
novel alterations) and their correlations with patient survival
cal and biotechnology companies, ranging in size from small
(Dr. Olga Chernova).
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
•G
enotyping arrays as a prognostic tool: glioma model
and genetic makeup of these tumors. These drugs are targeted
(Dr. Olga Chernova).
against molecules such as EGFR, 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.
immune response to gliomas (in collaboration with Dr. James
Finke), understanding the role of NFkB in regulating glioma cell
in CDKN2A, ARF, PTEN and p53 genes in gliomas
(Dr. Olga Chernova).
to be effective against malignant gliomas, given the molecular
Other projects are focused on developing methods to improve
•D
evelopment of a clinical assay for detection of deletions
•D
istinct alteration of chromosome 1p in astrocytic and
oligodendrocytic tumors (Dr. Olga Chernova).
•A
n in-vitro and in-vivo model altering GBM immunosuppression
to enhance immunotherapy (Drs. Ali Chahlavi and James Finke).
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
•N
AD(P)H autofluorescence in cell death - NADH and NADPH
BTI physicians work closely with neurosurgeons in Cleveland
are pyridine nucleotides that function as electron donors in
Clinic Florida to provide services for patients. Out-of-state
oxidative phosphorylation ( Dr. Steven Toms).
patients can take advantage of the Clinic’s Medical Concierge
•R
ole of optical nanocrystals (quantum dots) in molecular
and cancer imaging (Dr. Steven Toms).
program, a complimentary service that offers facilitation and
coordination of multiple medical appointments; access to
discounts on airline tickets and hotels, when available; help
Hundreds of basic and clinical cancer research projects are under
in making hotel reservations or housing accommodations; and
way here at any given time, and numerous papers are presented
arrangement of leisure activities.
annually at national and international meetings regarding
research results.
BTI and Gamma Knife Center specialists also see patients from
out of the country. The special requirements of international
Marketing. Many marketing initiatives have been instituted to
patients are handled through the Cleveland Clinic International
create awareness of the BTI in 2005. Because brain tumor
Center. The professionals within the International Center provide
patients are information savvy and seek out the latest in medical
the assistance and services our international patients need to
options for their condition, the BTI Web site is a particularly
help them feel at home while they are being treated here. We
important marketing tool. Focus in 2005 has been on increasing
employ a large multilingual staff, and interpreters are available
the presence of the Web site among the Overture (Yahoo! and
to assist patients. Our staff helps coordinate all the details of a
MSN) and Google search engines. The content has been optimized
visit, from scheduling medical appointments and making hotel
to increase the natural rankings of the Web site. The BTI has also
and transportation arrangements to transferring and translating
purchased brain tumor-related words on a pay-per-click basis to
medical records.
maximize Web site traffic. Direct-mail campaigns such as mailing
the BTI annual report to neurosurgeons and neurologists across
the country and a continuous presence in Cleveland Clinic
physician and patient publications ensures information on the
BTI services is being communicated to our target markets.
Supporting Patient Education. The BTI was a proud sponsor of
the American Brain Tumor Association’s (ABTA) regional patient
meeting in July in Itasca, Ill. More than 400 patients and their
family members, health care providers and volunteers gathered
to learn about various topics, from the biology of brain tumors to
Advertising. Newspaper print advertising for the Gamma Knife
choosing between standard therapy and a clinical trial. The BTI’s
Center has been expanded to the following markets: Akron/
Glen Stevens, D.O., Ph.D., and Kathy Lupica, M.S.N., C.N.P., as
Canton, Ashtabula, Sandusky, Toledo and Warren, Ohio. The
well as marketing associate Kristin Swenson, made information
goal of our advertising is to increase awareness and, ultimately,
available to patients. The BTI also sponsored a similar event for
patient visits to the BTI. A BTI ad appeared in the Ohio regional
patients and their families at the ABTA’s regional patient meeting
issue of Women’s Day magazine. Return on investment will be
in Dallas, Texas, in November.
measured for these initiatives, and this information will be used
to plan advertising for 2006.
The BTI participated in the Cleveland Clinic Medical Miracles
television show in fall 2005. The Strength of the Human Spirit II
BTI in the News. In December 2004, a high profile international
follows four patients who were diagnosed with different forms
athlete was treated with Gamma Knife radiosurgery at the BTI,
of cancer and chronicles their lives before diagnosis, during
for which we were able to obtain media exposure on television, in
treatment and throughout their efforts to maintain a normal life.
print and on the Web. Cleveland Clinic researchers Gene Barnett
The episode featured a female patient of the BTI whose breast
and Damir Janigro received a U.S. patent for technology they
cancer metastasized to her brain and was treated with Gamma
developed to measure damage to a person’s blood-brain barrier
Knife radiosurgery. The BTI also partnered with an online support
that may help detect new brain tumors through a simple blood
group, the Pituitary Network Association (PNA), which is an
test. See Appendix I for details.
international nonprofit organization for patients with pituitary
Expanded Services. BTI patients can access neuro-oncology
services not only at Cleveland Clinic’s main campus, but also at
tumors and disorders, their families, loved ones, and the
physicians and health care providers who treat them.
Cleveland Clinic’s west side community hospitals (Lakewood,
Serving as a Program Model. The success of the BTI can be
Lutheran and Fairview). Additionally, Dr. Gene Barnett sees
measured not only by the advances made toward patient care
patients in consult at the Ashtabula County Medical Center
at Cleveland Clinic, but also by the way in which these advances
on the far east side.
impact the treatment of brain tumor patients everywhere.
Lilyana Angelov, M.D., continues to facilitate expansion of the
BTI’s various brain tumor programs into the western region of
Cleveland. She oversees primary and metastatic tumors, as well
National and International interest in the BTI model of organization is high, serving as a model for other brain tumor programs
around the country and world.
as access to BTI protocols through the Moll Cancer Center at
Fairview Hospital and at Lakewood Hospital.
2005 Annual Report
A team approach to individualized care
Brain Tumor Institute
Clinical Programs
session cranial stereotactic radiosurgery; Novalis System for
cranial radiosurgery in several sessions and spinal radiosurgery;
and the Peacock system for intensity-modulated radiotherapy
• Fractionated Radiotherapy – widespread exposure of the brain
and tumor to repeated low doses of radiation
• Brachytherapy – direct implantation of a radiation source
(solid or liquid) within a tumor site
• Chemotherapy/growth modifiers – traditional anti-tumor drugs
as well as new agents targeted at specific tumor molecules are
being tested
• Immunotherapy – turning the patient’s immune system against
tumor cells or using immunologically targeted toxins
• Convection-Enhanced Delivery (CED) – the slow, continuous
Physicians from several different specialties within the BTI meet weekly
to discuss each patient’s case and collaborate on treatment options.
infusion of drugs through the brain to treat certain brain tumors.
Used both in the laboratory and for patients, it permits treatment
with agents that would be too toxic to the body if delivered
Clinical Neuro-Oncology
conventionally.
Neuro-oncologists, medical oncologists, neurosurgical oncologists,
• Intra-arterial Chemotherapy with or without Blood-Brain
radiation oncologists, neuro-pathologists, neuroradiologists and
Barrier Disruption (BBBD) – a procedure by which cancer-
BTI nurses attend daily clinics and twice-weekly tumor boards.
fighting agents are delivered to the brain through the blood
This cooperative approach, proven in more than a decade of use,
stream with or without opening the normal barriers that
provides for consensus management plans that are individualized
may prevent those drugs from entering the brain.
and focused on the best mix of medical, surgical and radiotherapy
treatment of both benign and malignant tumors affecting the brain
and spinal cord. In addition to providing conventional treatments,
innovative investigational studies are available – some of these
were developed at Cleveland Clinic – and others are performed as
part of multicenter trials.
Clinical Neurosurgical Oncology
Pioneers in computer-assisted stereotactic techniques for brain
tumors since the mid-1980s, BTI surgeons have extended the
scope of operable brain tumors by using techniques such as
frame or frameless stereotaxy (surgical navigation), skull-base
Members of the team also provide long-term surveillance and
techniques, microsurgery, endoscopic surgery, computer-assisted
medical management of patients.
rehearsal of surgery, intraoperative MRI, radiation implants and
radiosurgery. The development of precision surgical navigation
Cutting-edge experimental treatments include use of targeted
systems in the late 1980s and early 1990s by the Cleveland
immunotoxins delivered by convection-enhanced delivery and
Clinic’s Center for Computer-Assisted Neurosurgery allows for
so-called “small molecule therapies” (SMTs) such as Tarceva
(an EGFR inhibitor), and an “mTOR” inhibitor. These, along with
the expanded routine use of molecular and chromosomal testing
used to guide individual patient management, help put the BTI
at the forefront of individualized care and the molecular management of brain tumors.
Methods for both surgical and nonsurgical treatments of lifethreatening tumors are advanced by medical innovations in
the following areas:
• Intraoperative MRI – navigational guidance and monitoring
tumor resection
• Stereotactic Neurosurgery – computer-guided surgery using
a three-dimensional software configuration
• Multiple Radiosurgery Options – Gamma Knife for single
smaller incisions and GPS-like guidance in the brain that have
resulted in substantial reductions of wound and neurologic
morbidity, length of surgery, hospital costs and length of stay
for many benign and malignant brain tumor surgeries. The
interest in surgical navigation continues as the Department of
Neurosurgery uses several navigation systems as well as
intraoperative imaging using ultrasound and MRI.
In 2005, the department continued the pursuit of cuttingedge technology with Odin Medical Technologies/Medtronics,
manufacturer of a compact intraoperative MRI. The device
weighs only 1,300 pounds – a fraction of the weight of conventional units. During surgery, the device is stowed below the
operative field, allowing many conventional surgical instruments
to be used. When imaging is required, the magnets are raised
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
may control lethal tumors for longer periods than conventional
radiation therapy, decrease the potential side effects of radiation
therapy and may benefit patients whose general health may not
be sufficient to withstand a protracted microsurgical procedure.
A team of personnel including neurosurgeons, radiation oncologists,
radiation physicists and radiation therapists provides treatments.
For Gamma Knife radiosurgery, a single one- to two-hour treatment
is generally required, in which 201 beams of gamma rays are
focused at multiple points throughout the target, with the aim of
matching the delivered radiation to the shape of the tumor. Thus,
the radiation’s destructive potential is concentrated in the tumor,
and fall off in adjacent tissue is exceedingly steep, minimizing
damage to tissue lying in the entry or exit pathways. Because of
this precise focusing ability, aggressive high-dose radiation can be
delivered to stabilize, shrink or destroy some lesions – even
those deep in the cerebral hemispheres or brain stem.
The past year has been a successful one for the Gamma Knife
Center. In 2005, our Gamma Knife equipment was upgraded to
the latest 4C version with software and hardware enhancements.
In 2005, 244 Gamma Knife radiosurgery cases were performed
Cleveland Clinic neurosurgeons continue to perfect brain tumor resection
techniques, minimizing damage to delicate brain tissue.
into position, flanking the patient’s head for scans that range in
time from about one to seven minutes. When not required during
surgery, the imager is placed in a magnetically shielded cage
for a number of indications, which represented our best year.
In addition, a number of papers were presented at national and
international meetings regarding the center’s results.
The Gamma Knife Center is one of three centers worldwide
certified by Elekta (the sole manufacturer of the Gamma Knife)
in the corner of the room, allowing the room to be fully used for
to train physicians new to Gamma Knife radiosurgery.
conventional procedures. Cleveland Clinic was the fourth site in the
The Model 4C Gamma Knife unit – the first of its kind in Ohio
world to have this system, and we believe that systems like it likely
are to become commonplace by the end of the decade. The device
will be upgraded to the more powerful model N20 in 2006.
The Novalis System further increases the capabilities within
radiation oncology and allows for radiosurgery and fractionated
radiosurgery treatments for neuro-oncology patients using image
guidance. This technology gives us the ability to treat lesions near
Fellowships
critical structures, such as the optic nerves and chiasm, as well
In addition to being a part of the core curriculum in Neurosurgery,
as re-treat some patients who have undergone conventional
the BTI is active in other areas of postgraduate education. A two-
radiotherapy. In general, Gamma Knife is used for single
year fellowship – one year of basic science investigation and the
treatments of focused radiation that conforms to the shape
other year clinical – is offered in Neurosurgical Oncology. Dr. Dae
of small tumors or lesions, while Novalis delivers fractionated
Kyu Lee completed his clinical Neurosurgical Oncology training,
conformal treatment for larger malignant or benign tumors.
followed by Drs. Tina Thomas and John Park. Dr. Burak Sade
Although Novalis was originally developed to treat brain tumors,
continues on as the BTI skull-base fellow.
Cleveland Clinic physicians recognized its potential for treating
extracranial tumors, particularly primary and metastatic spinal
Clinical Radiation Neuro-Oncology
Radiation oncologists, focusing on the specific problems of brain
tumors that are difficult to treat due to their proximity to critical
structures. In 2006, we have plans to promote and expand the
and spinal cord tumors, offer both traditional and innovative
spinal radiosurgery program.
treatments to ensure patients have access to a number of
In addition to the Gamma Knife, linear accelerators and Novalis,
technologies. In 1989, the Cleveland Clinic’s Radiosurgery
we offer intraoperative radiation therapy (IORT) with the
Program was the first in Ohio to treat patients with state-of-the-
INTRABEAM device, a 50 kVp contact unit that is placed
art noninvasive ablative therapy using a modified linear accelera-
in the resection cavity. We have an ongoing phase II trial
tor. Since 1997, a number of technologies have be introduced
evaluating the use of INTRABEAM for patients with a single
including Gamma Knife, intensity-modulated radiotherapy
brain metastasis that has been resected. We also offer
(IMRT), intraoperative radiation therapy (IORT), brachytherapy,
brachytherapy using the GliaSite balloon catheter system
and image-guided radiation therapy (IGRT). These technologies
and have participated in several clinical trials.
2005 Annual Report
A team approach to individualized care
A number of clinical trials sponsored RTOG, NABTT and various
radiotherapy, surgery in conjunction with placement of carmus-
pharmaceutical companies are offered here. Since 1998, the
tine wafers may thwart local recurrence. Also, BTI clinical
department has been a leader in radiation sensitizer trials using
researchers are investigating the role of intracavitary liquid
motexafin gadolinium and efaproxiral. Dr. Suh is the principal
brachytherapy and intraoperative radiotherapy after resection
investigator for the international phase III confirmatory study
with the hope of obviating the need for whole brain radiotherapy.
using efaproxiral. This study will enroll 360 women from North
Today, surgery may be part of a comprehensive management
America, South America and Europe.
plan, where other techniques are brought to bear on additional
brain metastases not amenable to radiotherapy. Beyond
Section of Metastatic Disease
radiotherapy, staged therapy options include stereotactic
Not long ago, the diagnosis of one or more metastases to the
radiosurgery, intra-arterial chemotherapy with or without blood-
brain from solid organ cancer was considered a terminal event,
brain barrier disruption, and newer systemic chemotherapies.
with treatment limited to palliative whole brain radiotherapy. As
central nervous system involvement occurs in about one fourth
Radiosurgery
In many ways, brain metastases are ideally suited for treatment
of patients with such cancers, brain metastases took a terrible
with stereotactic radiosurgery such as the Gamma Knife. Lesions
human toll, being the cause of death in just a few months in
are typically small and spherical, and they displace, rather than
most affected patients.
infiltrate, normal brain tissue. Results from radiosurgery appear
Today, aggressive management, aided by a variety of effective
comparable to those achieved by surgery with radiotherapy and
treatments, often can lead to indefinite or extended control of
allow for effective treatment even for surgically inaccessible
even multiple brain metastases in patients with controlled or
tumors. Radiosurgery may also reduce the chance of leptomenin-
limited systemic disease. At the BTI, a multidisciplinary team
geal spread as a result of surgery for certain tumor types.
of specialists, led by Dr. Steven Toms, evaluates patients and
So-called “radio-resistant” tumor types (e.g., melanoma, renal
applies one or more individualized treatments to secure control
of newly diagnosed or recurrent brain metastases.
cell carcinoma) respond as well to stereotactic radiosurgery as
Surgery
dosing is prescribed at levels set by the Radiation Therapy
Surgery, in addition to whole brain radiotherapy, has been shown
Oncology Group, of which Cleveland Clinic is an active member.
to be more effective than radiotherapy alone for patients with
Cognitive side effects are minimal as the treatment is confined
single brain metastases. Even in patients with multiple brain
to small brain regions.
do “radio-sensitive” tumors. Neurologic morbidity is low when
metastases, surgical resection leads to survival comparable to
those patients with single resected lesions. Pioneers in contemporary computer-assisted neuro-surgery, BTI neurosurgeons
routinely use minimal access techniques to remove one or more
brain metastases with minimal morbidity and short hospital
stays. For patients with recurrent or new brain metastases after
The Cleveland Clinic radiosurgery program is the oldest in Ohio,
and has been designated as only one of three centers in the world
certified by the manufacturer of the Gamma Knife to train new
users of this “gold standard” of radiosurgery. The Department of
Radiation Oncology offers training on the new Novalis system. The
Cleveland Clinic Model 4C Gamma Knife unit –
the first of its kind in Ohio
10
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
department has been designated a “center of excellence” in the
use of this image-guided technology and is one of the first sites in
the country to use Novalis especially for image-guided “spine radiosurgery,” in addition to brain tumor treatment.
Treatment with Novalis is indicated for those patients who
tumors are not ideal for Gamma Knife radiosurgery. In addition,
Novalis can be used for extracranial sites such as metastatic
spinal tumors, prostate and lung cancers. Since adding the
Novalis system to its arsenal of radiosurgery programs one year
ago, the Department has treated approximately 150 patients,
with anatomic treatment sites including the brain, spine, lung,
prostate, kidney and bone.
Knife radiosurgery and the remainder had conservative treatment.
These numbers represent one of the largest in the country for
Chemotherapy
Systemic cancers that are chemotherapy sensitive often take
specialized benign tumor management.
refuge in the brain, despite systemic control, as most commonly
Dr. Lee, the Director of CNBT, had six articles and nine papers
used chemotherapies have poor penetration through the blood-
accepted for publication. He currently is editing a major
brain barrier. Management of such tumors may take several
landmark textbook on meningiomas consisting of 70-plus
forms. Patients with metastatic breast cancer to the brain with
chapters, with contributions from more than 50 international
tumors that are estrogen-receptor positive may respond to high-
leaders in all the basic and clinical disciplines related to
dose tamoxifen, thereby compensating for the drug’s limited
meningiomas. This book is planned for early 2007 publication.
penetration of the brain. Alternatively, temozolomide, a relatively
Additionally, a three-year research grant was award to Dr. Lee
new orally-administered methylating agent has excellent
by the Integra Neurosciences Foundation for the study of dural
penetration into the brain and may be considered for some
reconstruction following skull base and meningioma surgery.
patients. More intensive treatment includes use of chemotherapy
Dr. Lee also was an invited lecturer at annual meetings of the
injected directly into the carotid vertebral arteries, at times using
Korean Skull Base Society, the European Skull Base Society
hypertonic mannitol to disrupt the blood-brain barrier from
and the North American Skull Base Society.
preventing active agents from reaching adequate concentrations
in brain metastases.
Neuro-Endocrine Center
Small Molecules
The Neuro-Endocrine Center has shown continuous growth since
An exciting area of investigation is the use of small targeted
its inception in 2002, fostered by a close working relationship
molecules to treat a variety of malignancies. As the molecular
among the BTI and the departments of Endocrinology, Diabetes
characterization of various tumors improves, investigational drugs
and Metabolism; Neurological Surgery; Neuro-Ophthalmology;
that target specific molecular pathways may play an increasing
and Radiation Oncology. The close relationship has led to the
role in the management of brain metastases, and even leptomen-
development of highly integrated clinical care pathways, a
ingeal disease. The use of these agents and appropriate modes of
common pituitary tumor research database and several joint
delivery are and will continue to be a major thrust of BTI clinical
research projects (see below).
and laboratory research.
Center for Neurofibromatosis and
Benign Tumors (CNBT)
The CNBT at Cleveland Clinic continues as a leading center in the
nation in the management of patients with benign brain tumors.
In 2005, the CNBT neurosurgeons saw over 300 new patients
with benign tumors, the two most common tumors being
meningiomas and schwannomas. More than 200 new patients
with meningiomas were seen in 2005. Of these patients,
approximately 100 underwent surgery, 20 had Gamma Knife
radiosurgery and the remaining 80 were treated conservatively.
Over 70 new patients with schwannomas were evaluated in
2005. Fifty patients had surgery, approximately 15 had Gamma
2005 Annual Report
Clinical Care Pathways
Clinical care pathways define the pre-hospital, peri-operative and
postoperative care for patients with secretory and non-secretory
pituitary tumors. The development of new pathways has decreased
patient length of stay and has likely improved outcomes.
Academic Activities
A prospective IRB-approved database has been established for
all patients with pituitary tumors seen in the Neuro-Endocrine
Center. Detailed preoperative endocrine testing, including
Cortrosyn stimulation, is routinely performed for comparison
to postoperative findings. New clinical care pathways have
eliminated the routine use of perioperative steroids, thereby
enabling the accurate determination of postoperative pituitary
adrenal activity. Several retrospective analyses have been
A team approach to individualized care
11
completed and are also in progress, including comparison of
Gamma Knife vs. IMRT for subtotally resected somatotrophic
pituitary adenomas, case review of pituicytoma and a retrospective analysis of the impact of somatostatin on the efficacy of
radiosurgery for somatotrophic adenoma.
Teaching of residents and fellows has similarly been augmented
through the establishment of the center. Endocrine residents
routinely participate in outpatient evaluation with endocrinologists
and surgeons. The vascular service junior resident spends
one day in the outpatient clinic evaluating pituitary patients.
A joint conference involving endocrinology, neurosurgery, neuroophthalmology, neuroradiology and radiation oncology is held on
the first Friday of each month, during which case presentations
and management or visiting lecturers are presented. In addition,
monthly pathology review sessions, where the pathological
findings of each patient are reviewed jointly by the pathologists,
endocrinologists and neurosurgeons (the Pituitary Interest
Cleveland Clinic specialists are pioneers in developing new methods of
intergrating image data with surgery
recent additions in this regard have been diffusion tensor
imaging, fiber tracking and functional MRI software with
prospective motion correction, real-time monitoring of the data
Group), continue. These sessions are open to all interested
acquisition and accurate three-dimensional surface localization.
parties and are held the first Monday of the month in the
All three 1.5 Tesla systems at the main campus have been
Department of Pathology.
upgraded in the last year, and are located immediately adjacent
to the Gamma Knife Center. These new systems include
Neuro-Radiology
The Section of Magnetic Resonance Imaging at Cleveland Clinic
provides a wide array of diagnostic capabilities for routine
upgraded gradient capabilities, an extensive variety of phased
array coils and the software to perform parallel imaging techniques, allowing reduce imaging time, reduce inherent MR
imaging studies as well as research projects in support of the
imaging artifacts and improve spatial resolution. One of these
BTI. During the last two years, there has been a dramatic
1.5 Tesla systems has a wide, short bore to accommodate our
increase in availability to high-field imaging within Cleveland
larger and claustrophobic patients, without the limitations of the
Clinic hospitals with the installation of a large number of new
low-field open systems. A 3.0 Tesla whole-body system has
magnets. This enables our patients and physicians to schedule
been installed at Cleveland Clinic’s Mellen Center to provide
MR imaging appointments at a site that is more convenient for
the patient and more expeditious for patient management. All of
these systems are managed centrally at Cleveland Clinic’s main
new research and imaging capabilities. This system will permit
imaging of the spine and head, as well as high-resolution
diffusion tensor imaging, multi-nuclear MR spectroscopy
campus, and the images are transmitted digitally so they are
and phased-array technology. The 3 Tesla system serves
immediately available for comparison with prior studies on the
as the primary magnet for functional MR studies.
central digital archive. Not only are the images immediately
available to our Diagnostic Neuroradiology staff, but the digital
reports and all imaging studies are also immediately available
Neuro-Oncology Nursing
to our referring physicians. At the moment, imaging workstations
Nurses, physician assistants and technicians specializing in the
exist across Cleveland Clinic so the referring services have direct
care of patients with brain tumors are an integral part of the BTI.
digital access to the images.
Members of the nursing and physician assistant team, which
includes Cathy Brewer, Gail Ditz, Sandra Ference, Michele Gavin,
Our MR machines include a large number of 1.5 and 1.0 Tesla
systems. Diagnostic imaging capabilities in our system currently
include routine imaging, diffusion imaging and high-resolution
Betty Jamison, Debra Kangisser, Kathy Lupica, Mary Miller, Carol
Patton, Rachel Perez, Sherry Soeder, Lisa Sorenson, Laural Turo,
and Carla Yoder, are often the first contact for patients seeking an
preoperative planning studies at all of our facilities. At our main
campus, we also provide MR perfusion imaging, diffusion tensor
opinion or when they come to the outpatient department.
imaging, functional MRI and MR spectroscopy for more advanced
Lisa Sorenson works with patients at the Cleveland Clinic main
preoperative planning. Between our own MR physicists and
campus, Lakewood and Fairview hospitals, as well as with the
neuroradiology physicians, as well as our research affiliations
Blood-Brain Barrier Disruption (BBBD) program.
with Siemens Medical Systems and Massachusetts General
Kathy Lupica facilitates our monthly Brain Tumor Support
Hospital, we’re able to provide access to a host of new software
and hardware for the management of our patients. The most
12
Group. She also provided patients with information at the
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
BTI Clinical and Clinical
Research Administration
In September 2005, George Lawrence, M.B.A., was appointed
Administrator of the BTI, overseeing all activities of the institute
in coordination with Dr. Gene Barnett, the Cleveland Clinic
Cancer Center, “parent” departments, Center for Clinical
Research and the Lerner Research Institute. Wendi Evanoff
manages the BTI database and Tumor Board conference, and
James Saporito coordinates philanthropic activities for the BTI.
Noreen Flowers manages the BTI’s Web site (clevelandclinic.org/
braintumor) and Martha Tobin oversees all CME activities. Kim
Blevins coordinates the Brain Tumor Fellowship Programs,
Neuro-Oncology Nursing
which includes two surgical and one nonsurgical program.
BTI’s exhibit at the ABTA’s patient meetings in Chicago, Ill.,
The BTI’s clinical research infrastructure is fully integrated with
and Dallas, Texas, in 2005.
that of the Cleveland Clinic Taussig Cancer Center’s Experimental
Nurse practitioner Sandra Ference manages patients undergoing
BBBD or intra-arterial chemotherapy.
Therapeutics Program. All clinical protocols and correspondences
are funneled into the BTI through Kathy Robinson, the BTI Study
Coordinator, and processed through the Experimental Therapeutics
Cathy Brewer and Carol Patton assist with patients who are
Program, including IRB submissions (e.g., protocols amendments,
interested in participating in or who currently are involved in
safety reports), protocol budget creation, nursing assignment
research protocols.
and study start-up. Material is dispersed from this central resource
Betty Jamison works with patients undergoing Gamma Knife
radiosurgery.
Nurse Practitioners: Sandra Ference, Kathy Lupica,
Sherry Soeder, Lisa Sorenson, Carla Yoder
Nurse Clinicians: Gail Ditz, Betty Jamison, Rachel Perez,
Laural Turo
Research Nurses: Cathy Brewer, Carol Patton
Physician Assistants: Michele Gavin, Debra Kangisser
to all appropriate parties. The BTI has two dedicated research
nurses, Cathy Brewer and Carol Patton, who manage all clinical
trials, including patient consent, monitoring and follow-up. These
nurses are part of the Experimental Therapeutics Program and are
backed up by other Experimental Therapeutic nurses. The program
oversees and manages all regulatory matters, IRB submissions and
all data collection / CRF transcription responsibilities through the
dedicated BTI Study Coordinator.
Cleveland Clinic has recently affiliated with Case Western
Pediatric and Young Adult Brain
Tumor Program
Reserve University and University Hospitals of Cleveland.
Dr. Joanne Hilden, Chair of the Department of Pediatric Hematol-
referral network at one of the nation’s most renowned hospitals
ogy/Oncology, and Dr. Bruce Cohen, BTI staff member, co-direct
based at Cleveland Clinic, with Northern Ohio’s only National
the Pediatric and Adolescent Brain Tumor Program. A multidisci-
Cancer Institute-designated Comprehensive Cancer Center
plinary brain tumor clinic for children and adolescents with brain
based at Case.
tumors takes place twice weekly. Patients can see both Drs.
Hilden and Cohen on the same day, and sedated imaging is
available. Each child has a care coordination team in place,
consisting of a physician, a nurse practitioner and a registered
nurse. Neurosurgeons are available to see patients as needed.
This new relationship provides the opportunity to integrate
an outstanding group of cancer researchers and a large cancer
The Case Comprehensive Cancer Center combines, under a single
leadership structure, the cancer research activities of the largest
biomedical research and health care institutions in Ohio – Case
Western Reserve University, Cleveland Clinic and University
Hospitals of Cleveland – into a unified cancer research center.
Chemotherapy and radiation therapy are delivered under the
With this integration, the Case Comprehensive Cancer Center
oversight of that team, resulting in continuity of care. The nurse
has strengthened its scientific programs, expanded opportunities
practitioner/RN team handles follow-up calls at home to ensure
for disease-focused research, and enhanced access and ability
the efficacy of pain control and other medical issues, which
to serve the entire population of Northeast Ohio.
results in fewer emergency room visits.
The Cleveland community has fully embraced this exceptional
opportunity to join the region’s two preeminent healthcare
delivery systems and Case, their academic partner, into a single
NCI-designated Comprehensive Cancer Center.
2005 Annual Report
A team approach to individualized care
13
Brain Tumor Institute
Clinical Research
2) Intraoperative radiation therapy for solitary brain metastases –
Dr. Steven Toms is conducting a phase I/II study utilizing a
novel method for delivering intraoperative radiation therapy
(INTRABEAM) for the treatment of a resected solitary brain
metastasis. This method allows the precise delivery of
radiation therapy directly into the tumor cavity and allows
the patient with a solitary resectable brain metastasis to
postpone the need for whole brain radiation.
3) Radiosensitizers for metastatic disease to the brain –
The BTI remains active in using novel radiation sensitizers to
augment the effect of radiotherapy on primary and secondary
(i.e., metastatic) tumors. Dr. John Suh serves as the international principal investigator for a large randomized trial testing
standard whole brain radiation therapy with supplemental
A complete arrary of laboratory facilities and expertise allows us to pursue
both basic science and translational research on new therapeutics
oxygen, with or without concurrent RSR3 (efaproxiral), in
women with brain metastases from breast cancer.
4) Intra-arterial chemotherapy with blood-brain barrier
Clinical Protocols/Research
Brain tumor and neuro-oncology patients may elect experimental
treatments or to participate in clinical research projects related
to their diagnosis. Various chemotherapies and growth modifiers
are among the experimental drug protocols developed by the
disruption (BBBD) for primary central nervous system
lymphoma (PCNSL) and other tumors – This program, in
its fourth year, has become a mainstay of the treatment and
research of patients with PCNSL at Cleveland Clinic. The BTI
actively enrolls patients on clinical trials of the BBBD Consor-
institute’s clinical investigators. We are proud to have active
tium. Two clinical trials are available for patients with PCNSL
participation in the NABTT Consortium. BTI physicians serve
(newly diagnosed and recurrent), and one is available for
as protocol chairpersons for this consortium as well as others
patients with recurrent or progressive high-grade gliomas. Drs.
including RTOG and the BBBD. Patients may choose to partici-
Glen Stevens and David Peereboom have played an integral
pate in multicenter management trials from these consortia as
role in the clinical management of the patients undergoing the
well as the SWOG, ACoSOG or COG.
procedures. Dr. Lilyana Angelov has developed a consortium-
Protocols and associated clinical programs include:
wide database for the tabulation of treatment results of this
1) Erlotinib Trials – The BTI initiated a Phase II trial evaluating
procedure for patients with PCNSL. The BTI staff has contrib-
erlotinib for the treatment of recurrent/progressive glioblas-
uted to the writing of protocols for the consortium as well as
toma multiforme (GBM). Erlotinib is a selective EGFR kinase
making several presentations at the consortium’s annual
inhibitor small molecule drug, which is used in patients with
meetings. Several staff members also have contributed to
lung and pancreas cancer. The BTI has two trials for patients
publication of the proceedings from this meeting.
with GBM. The first trial, for patients with recurrent disease, is
being performed under an individual investigator IND assigned
to Dr. Michael A. Vogelbaum. This trial utilizes pre-operative
treatment followed by resection or biopsy followed by further
treatment, thereby providing valuable data on the activity of
5) Convection-enhanced delivery of immunotoxins – This
program uses the slow, continuous infusion of an immunotoxin
(IL13-PE38QQR) targeted to recurrent malignant glioma. This
technique has the potential to deliver agents that otherwise
cannot be delivered to the brain or that are too toxic to other
the drug in the patient’s tumor. All research costs are being
organs for systemic delivery. BTI neurosurgeons are actively
absorbed by the BTI; Genentech is providing the drug at
enrolling patients in a clinical trial of IL13-PE38QQR for
no cost. A total of 60 patients will be enrolled in this trial.
Encouraging responses with low toxicity have been seen, and
this trial is accruing well. Another trial, directed by Dr. David
Peereboom, investigates the use of erlotinib with radiotherapy
patients with newly diagnosed GBM. Dr. Michael Vogelbaum
serves as PI for this trial.
6) Anaplastic Oligodendrogliomas – Members of the BTI have
and temozolomide for patients with newly diagnosed GBM.
initiated a trial with the NCI-sponsored clinical trial group
The trial opened in 2004 and accrual is expected to be
RTOG. This study, titled “A Phase II Trial of Pre-irradiation and
complete in 2006.
14
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Concurrent Temozolomide in Patients with Newly Diagnosed
for Anaplastic Astrocytoma and Mixed Anaplastic Oligoastrocy-
Anaplastic Oligodendrogliomas and Mixed Anaplastic
toma. The Sponsor is RTOG. IRB #3939. The Principal
Oligoastrocytomas,” is chaired by Dr. Michael Vogelbaum;
Investigator is Dr. John Suh and this project is open.
other BTI study chairs include Dr. John Suh (Radiation
Oncology) and Dr. David Peereboom (Medical Oncology).
This study has completed accrual and the data are currently
being analyzed. Dr. Vogelbaum is involved in the development
Project 4. Prospective study on the short-term adverse effects
from Gamma Knife radiosurgery (IRB #8078). Principal
investigator is Dr. Suh and this study is open.
of the next RTOG clinical trial for patients with anaplastic
Project 5. Prospective analysis of wellness for patients with non-
gliomas. Another multicenter trial, initiated at Cleveland Clinic
malignant conditions (IRB #7992). Principal investigator is Dr.
by Dr. David Peereboom, also tests the use of chemotherapy
Suh and this project is open.
as initial management for patients with pure and mixed
anaplastic oligodendrogliomas. This trial is nearing completion.
7) Complementary and alternative medicine – Dr. Mladen
Dr. Suh’s primary clinical activities focus on the use of radiation
therapy and Gamma Knife radiosurgery to treat adult and
pediatric patients with benign and malignant brain tumors.
Golubic has received NIH funding for the first BTI trial of
The radiation modalities used include external beam radiation
complementary and alternative medicine. His trial, “Phase
therapy, intensity-modulated radiation therapy (IMRT), image-
II Randomized Evaluation of 5-Lipoxgenase Inhibition by
guided radiation therapy (IGRT), Gamma Knife radiosurgery
Dietary and Herbal Complementary and Alternative Medicine
and brachytherapy. In addition to brain tumor patients, Dr. Suh
Approach Compared to Standard Dietary Control as an
also sees patients with vascular and functional disorders such as
Adjuvant Therapy in Newly Diagnosed Glioblastoma Multi-
AVM and trigeminal neuralgia who are treated with the Gamma
forme,” seeks to minimize brain edema in patients with GBM.
Knife. Dr. Suh also sees an assortment of other patients in the
The above clinical trials represent only a portion of those studies
Department of Radiation Oncology as the need arises.
being offered by the BTI. A full listing of clinical trials is included
Dr. Suh’s clinical research activities focus on enrolling patients
in the Appendix of this report.
onto various cooperative group, in-house and pharmaceuticalsponsored studies. He serves as the principal investigator for an
Section of Metastatic Disease
international Phase III study for women who develop brain metas-
Clinical Research Projects
hemoglobin, efaproxiral, to enhance oxygen delivery to hypoxic
tases from breast cancer. This trial uses an allosteric modifier of
Phase I/II Study of Intraoperative Radiotherapy for Newly
regions. This is a confirmatory study based on the REACH study,
Diagnosed Supratentorial Brain Metastasis Using the
which he served as co-principal investigator. Dr. Suh also directs
“Photon Radiosurgery System”
the research efforts for the RTOG and serves as the principal
Multicenter trial using a unique intraoperative radiotherapy device
investigator for Cleveland Clinic, which is one of RTOG’s 32 full-
(the “Photoelectic Cell”) to deliver radiotherapy after the resection
member institutions and was the 11th leading enroller in 2005.
of brain metastases. Currently open and enrolling patients.
Dr. Suh serves on the steering committee for the brain tumor
The Detection of Glial Tumor Margins and Intraoperative
section of RTOG. Over the past year, he has written and
Optical Spectroscopy
collaborated on multiple manuscripts with residents in Radiation
An intraoperative spectroscopy unit designed for the detection of
Oncology and Neurosurgery. He also gave numerous national
tumor margins in glial surgery. Currently in data acquisition phase
and international presentations regarding his research.
to improve probe algorithms prior to trials designed to test efficacy.
Radiation Oncology
Dr. John Suh serves as the Principal Investigator on the
following IRB-approved databases:
Glioblastoma multiforme registry (IRB 6852)
Project 1. A Phase III, Randomized, Open-label, Comparative
Acoustic neuroma registry (IRB 6988)
Study of Standard WBRT w/O2 w/ or w/o RSR–13 in women
Brain metastases registry (IRB 6989)
with Brain Metastases from Breast Cancer. The Sponsor is Allos
Low-grade glioma registry (IRB 6990)
Therapeutics. IRB #6795. The Principal Investigator is Dr. John
Pituitary adenoma registry (IRB 6991)
Suh and this project is open.
Meningioma registry (IRB 7044)
Project 2. Phase II study of tamoxifen with induction of
chemical hypothyroidism as an adjunct to XRT in glioblastoma.
IRB #4473. The principal investigator was Dr. Suh and this
Heterotopic bone registry (IRB 7045)
Gamma Knife radiosurgery patient list (IRB 7068)
project closed in 2005.
Clinical Medical Oncology
Project 3. A Phase III Randomized Study of Radiation and
Institute have comprised approximately three fourths of his
Temozolomide (IND #60,265) vs. Radiation Therapy & BCNU
2005 Annual Report
Dr. David Peereboom’s activities related to the Brain Tumor
clinical efforts, the remainder being connected to attending on
A team approach to individualized care
15
Clinical Neuro-Oncology
the inpatient services of the Hematology/Oncology Teaching
Service, Consultation Service and non-BTI outpatient activities.
Dr. Glen Stevens is the Section Head of Adult Neuro-Oncology
His clinical trial activity has included authorship and study
at the BTI and provides longitudinal management as well as
chair for three multicenter trials:
consultative services. He is co-PI of the Cleveland Clinic’s NIH-
1) Continuous Dose Temozolomide in patients with Anaplastic
supported NABTT program and manages day-to-day medical
Mixed and Pure Oligodendrogliomas. This trial involves nine
activities in NABTT trials, along with research personnel in the
centers and is the first multicenter trial authored and conduct-
institute and Cleveland Clinic Cancer Center. He is active in
ed by the Cancer Center. To date, 55 of 60 planned patients
SWOG as well as the Blood-Brain Barrier Consortium. He also
have entered the study.
was the local principal investigator on the GO (Glioma Outcomes)
2) BMS 247550 in Recurrent High-grade Gliomas for NABTT.
project. Dr. Stevens often participates in the brain tumor support
This trial completed accrual in November 2005 with a
group and also has an interest in the diagnosis and treatment of
manuscript in preparation.
neurofibromatosis in adults.
3) Erlotinib and Sorafenib in Recurrent High-grade Gliomas
Pediatric Neuro-Oncology
for NABTT. This trial will open in 2006.
4) Phase I / II Pilot Study of Patients with Brain Metastasis
Drs. Bruce H. Cohen and Joanne Hilden lead the Pediatric and
Secondary to Breast Cancer Treated with Methotrexate and
Adolescent Brain Tumor Program. Dr. Cohen is an internationally
Carboplatin in Conjunction with BBBD, with Concurrent
known pediatric neuro-oncologist. He is active in many clinical
Trastuzumab in HER-2 Postitive Patients for Blood-Brain
research activities including serving as Chairman of CCG-99703C
Barrier Disruption Consortium. This trial will open in 2006.
Infant Brain Tumor Study, Children’s Cancer Group; Chairman
In addition, another trial, titled “Erlotinib/temozolomide/radiation
of Low-Grade Astrocytoma Discipline Committee, Children’s
therapy for patients with newly diagnosed glioblastoma” has been
Oncology Group; a member of the Brain Tumor Strategy
activated, and 25 of 30 planned patients have been enrolled. Dr.
Committee, Children’s Oncology Group; and a member of
Peereboom has also been active in accrual and management of
the Professional Advisory Board, The Gathering Place.
patients on in-house clinical trials (e.g., Erlotinib for recurrent
GBM), NABTT trials (Talampanel with radiation/temozolomide for
newly diagnosed GBM; EMD121974 with radiation/temozolomide
for newly diagnosed GBM; Sorafenib for recurrent GBM) BBBD
Consortium trials, and RTOG trials (e.g., RTOG 9402).
Another area of active clinical and investigative work is with the
Blood-Brain Barrier Consortium. Dr. Peereboom is the Director of
the Blood-Brain Barrier Disruption program and has been active
as an attending physician for procedures and post-procedure
inpatient care of patients receiving intra-arterial chemotherapy
with or without BBBD. In addition, he has consulted for the
tumor committees for the Children’s Oncology Group (high-grade
primitive neuro-ectodermal tumors, and CNS teratoid/rhabdoid
tumors (AT/RT)).
There are 12 ongoing protocols for brain tumors open for
pediatric brain tumor patients, including a protocol for Atypical
Teratoid / Rhabdoid tumors, a very rare and aggressive pediatric
tumor. A national registry for children diagnosed with Atypical
Teratoid / Rhabdoid tumor (AT/RT) has been established by Dr.
Joanne Hilden. The registry, which collects therapy data and
outcomes, can be accessed from our Children’s Hospital Web site
BBBD Consortium in the development of trials and will serve
as co-principal investigator on an upcoming breast cancer brain
metastasis trial.
Dr. Hilden, Chair of Pediatric Oncology, participates in two brain
at clevelandclinic.org/childrenshospital. The registry site includes
references and information about AT/RT and how to register
patients. A manuscript reporting therapy and outcomes of the
registry was published in the Journal of Clinical Oncology. Three
protocols for biology studies that collect brain tumor specimens
for molecular and cytogenetic studies are open.
The departments of Pediatric Hematology/Oncology and Pediatric
Neurology hold a combined pediatric brain tumor clinic every
Tuesday and Thursday in the Pediatric Hematology/Oncology
area. A multidisciplinary team provides evaluation, treatment
and continuing care for children and adolescents diagnosed with
tumors of the brain or spinal cord.
16
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Brain Tumor Institute
Laboratory Research
potential promise. Years of testing by this group and others will
lie ahead, but it is very interesting. Dr. Weil was honored to be
invited to write this review.
Zeng et al describes one of the proteins that we have identified in
protein profiling, aurora B, which appears to be a marker of more
aggressive GBMS. We are looking a greater numbers of tumors
now to see if this remains true in a larger series, but it is very
provocative.
Li J, Zhuang Z, Akimoto H, Vortmeyer AO, Park DM, Furuta
M, Lee YS, Oldfield EH, Zeng W, Weil RJ. Proteomic profiling
distinguishes astrocytomas of increasing malignancy and
identifies differential tumor markers. Neurology 66: 733-736,
2006. [PMID: 16534112]. Supplemental material is available
at:http://www.neurology.org/cgi/content/full/66/5/733/DC1.
Implantable osmotic pumps are used to deliver drugs to the brain
Vogel TW, Zhuang Z, Vortmeyer AO, Furuta M, Lee YS, Zeng W,
Oldfield EH, Weil RJ. Protein and protein pattern differences
Dr. Gene Barnett, Chairman of the Brain Tumor Institute,
between glioma cell lines and glioblastoma multiforme. Clinical
and Dr. Robert Weil serve as co-directors of Neuro-oncology
Cancer Research, 11: 3624-3632, 2005. [PMID: 15897557]
Research. Current tumor research focuses on several areas
including molecular genetics, apoptosis, engineering,
immunology, progenitor cells and the blood-brain barrier.
Dr. Weil, Associate Director of Basic Laboratory Research,
currently is directing research in proteomics in one of the four
primary Brain Tumor Institute labs. Prior to his joining
Cleveland Clinic, he collaborated with Cleveland Clinic neurosurgeon Steven A. Toms, M.D., M.P.H., on proteomics research.
Schwartz SA, Weil RJ, Thompson RC, Shyr Y, Moore JH, Toms SA,
Johnson MD, Caprioli RM. Proteomic-based prognosis of brain
tumor patients using direct-tissue MALDI mass spectrometry.
Cancer Research, 65: 7674-7681, 2005. [PMID: 16140934].
Weil, RJ. Glioblastoma Multiforme – Treating a Deadly Tumor
with Both Strands of RNA. PLoS Med. 2006 Jan;3(1):e31.
Epub 2005 Dec 6. No abstract available. [PMID: 16323974].
Although the field of proteomics is still in its infancy, the BTI is
Zeng W, Navaratne K, Prayson RA, Weil RJ. Aurora B expres-
committed to pursuing this field of research.
sion correlates with aggressive behavior in glioblastoma
The members of the Weil laboratory focus on four discrete areas,
including work on identifying novel genes and targets in
gliomagenesis; using new technologies, such as novel navigation
systems for brain navigation and brain tumor imaging and highthroughput proteomics methodologies; identifying novel
mechanisms that promote metastasis of systemic cancers to the
central nervous system (CNS); and developing novel methods to
identify and characterize microRNA targets. The following
paragraphs detail the work carried out in the past year with
multiforme. In press, J Clin Pathol, 2006
2. Using novel technology
With colleagues at Vanderbilt, who developed the system, we have
been able to demonstrate that a simple, inexpensive, portable
system, laser range scanning, can be used to assess, in real time,
brain shift and deformation in the operating room setting.
Toms et al and Lin et al, which are collaborations with the Toms
lab here at CCF, describes the utility of optical spectroscopy
relevant publications published or in press:
systems, another unique and simple method to use visible light
1. Gliomas and Glioblastomas.
and white matter, which may help guide us to more extensive but
Li et al, details our continuing work in protein profiling of brain
safer surgical procedures.
tumors. This is very time consuming, laborious work, one tumor
at a time, but is very rewarding in terms of getting greater
understanding of how these tumor may develop, progress, and
respond to therapy, especially with respect to finding new targets.
PLOS Medicine paper is a review of Glioblastomas (GBMs) and
an editorial on a new method developed in the lab that shows
2005 Annual Report
to identify individual tumor cells, and avoid normal brain cells
Sinha TK, Miga MI, Cash DM, Galloway RL, Weil RJ. Intraoperative cortical surface characterization using laser-range scanning:
preliminary results. In press, Neurosurgery, 2006.
Sinha TK, Dawant BM, Duay V, Cash DM, Weil RJ, Thompson
RC, Weaver KD, Miga MI. A method to track cortical surface
A team approach to individualized care
17
deformations using a laser range scanner. IEEE Transactions on
of numerous targets genes. miRNAs act in at least one of two
Medical Imaging, 24: 767-81, 2005. [PMID: 15959938]
ways: by binding complimentary sites on target mRNAs to induce
Toms SA, Lin WC, Weil RJ, Johnson MD, Jansen ED, MahadevanJansen A. Intraoperative optical spectroscopy identifies infiltrating
gliomas margins with high sensitivity. Neurosurgery 57 [ONS
cleavage or by repressing translation from the target mRNAs. Over
the past fifteen years it has become increasingly evident that
these and other small RNAs exert an additional layer of gene
control beyond the traditional regulators. In 1993, two groups
Suppl 3]: 382-291, 2005. [PMID: 16234690].
found that a small RNA identified in the nematode C. elegans, lin-
Lin WC, Mahadevan-Jansen A, Johnson MD, Weil RJ, Toms SA.
4, regulated another gene, lin-14, through direct interactions with
In vivo optical spectroscopy detects radiation damage in brain
lin-4 mRNA. Since then, investigations have revealed a rich
tissue. Neurosurgery, 57: 518-525, 2005. [PMID: 16145531]
tapestry of short RNA activities, which suggests that miRNAs
3. Brain metastasis, especially from breast cancer
eukaryotic genes, with diverse effects in apoptosis, development,
play a potentially vast and pivotal role in the regulation of many
Another interest is the development of metastasis to the central
gene imprinting, metabolism, and tumorigenesis. For example,
nervous system, especially from breast cancer. Weil et al is a
review article that serves as a state-of the art review to provide
some background for this problem. About 200,000 new cases of
breat cancer develop yearly in the United States, and from10-15%
of these patients will be expected to develop a brain metastasis.
In some subgroups, such as women who over-express the HER-2
receptor, the risk may be 2-3 times greater than the average.
However, one of the difficulties is that at present, it is usually only
after the CNS metastasis has developed that these lesions are
miRNAs are believe to constitute at least 1% of the genes in
animals; are highly conserved across a wide range of species; and
mutations in the proteins required for miRNA genesis and function
impair normal development or are lethal.
In spite of their ubiquity, exact functions have been ascribed to
only a handful of the hundreds of known miRNAs. At first, most
miRNAs were identified by arduous cloning and sequencing efforts.
Beyond the complexity of the methods, low-abundance species or
those found in only a specific cell type were difficult to character-
treated. However, recently, as we have outlined in a new article
by Hicks et al, we have identified a new set of markers—found in
the original breast cancer--that may be a useful tool in finding out
which women are more likely to develop a brain metastasis. This
marker, cytokeratin 5/6, in association with basaloid features
ize. Several bioinformatics approaches have been developed to
predict novel miRNAs. Complimenting these techniques, additional
bioinformatics methods were created to validate the predictions
and to identify potential mRNA targets. However, unlike in plants,
where larger and more individually distinctive miRNA hairpin
histologically, is the strongest marker yet identified.
precursors are made (which bind their targets with near-perfect
Weil RJ. CNS Metastases. In: Sid Gilman, Editor-in-chief,
complimentarity), bio-informatic prediction models for eukaryotic
Neurobiology of Disease, San Diego: Elsevier, 2006.
miRNAs and their targets have proven less informative.
Weil RJ, Palmieri D, Bronder JL, Stark AM, Steeg PS. Breast
To overcome some of these barriers, we recently developed a
cancer metastasis to the central nervous system. American
Journal of Pathology, 167: 913-920, 2005. [PMID: 16192626]
novel method that detects intact miRNA-mRNA complexes in
eukaryotic cells. First, we use reverse transcription of cytoplasmic extract to increase the length of a miRNA by extending it
Weil RJ, Lonser RR. Selective Excision of Metastatic Brain
Tumors Originating in the Motor Cortex with Preservation of
with cDNA on the template of a target mRNA. This step
Function. Journal of Clinical Oncology, 23: 1209-17. 2005.
minimizes non-specific annealing in a second round of reverse
[PMID: 15718318]
transcription, which in turn creates cDNA molecules (“miRNA
Hicks DG, Short SM, Prescott NL. Tarr Sm, Coleman KA, Yoder
BJ, Crowe JP, Choueiri TK, Dawson AE, Pettay J, Budd GT,
signatures”) of 12-14 nucleotides in length, long enough for
sequencing and analysis. The miRNA molecules we detect have
been confirmed in miRNA database searches and are functional.
Tubbs RR, Seitz R, Ross D, Weil RJ. Breast cancers with brain
Vatolin S, Navaratne K, Weil RJ. A novel method to detect
metastasis are more likely to be estrogen receptor negative,
express the basal cytokeratin CK 5/6 and over-express HER2 and
functional miRNA targets. Journal of Molecular Biology 358(4):
EGFR. In press, American Journal of Surgical Pathology, 2006.
983-996, 2006. [PMID: 16564540.]
4. microRNA and mRNA.
Most recently, Brain Tumor Institute laboratory researchers
have conducted groundbreaking genomics work focused on the
Finally, in Vatolin et al., we describe a new area of interest,
molecular basis of chemotherapy resistance in gliomas, which
micro RNA. This paper describes a potentially novel and
has led to the development of a number of clinically useful
universal method to figure out how these micro RNAs work
diagnostic tests for brain tumor patients. Ongoing basic
and influence normal RNA function.
research involves the study of three novel genes in pediatric and
Micro RNAs (miRNAs) are a unique class of small, non-coding
adult brain tumors and the development of an implantable
RNA gene whose final product is an approximately 22 nucleotide
optical spectroscopy unit to provide clinicians with immediate
(nt) functional RNA molecule. They appear to be critical regulators
feedback on the efficacy of chemotherapy.
18
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Current translational research involves identifying and developing
new compounds that are directed against targets relevant to
malignant gliomas.
Section of Metastatic Disease
“Optical Adjuncts to Brain Tumor Therapy”
NAD(P)H Autofluorescence in Cell Death – NADH and
Center for Translational Therapeutics
“Translating Novel Therapies for Malignant Brain
Tumors from the Bench to the Bedside”
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
The cornerstone of the BTI is the Center for Translational
goal is to design optical sensors to gauge the effectiveness of
Therapeutics. Directed by Dr. Michael Vogelbaum, aggressive
chemotherapeutic drugs by measuring changes in NAD(P)H
preclinical testing of the most promising anticancer agents is
fluorescence. We hypothesize that NAD(P)H fluorescence
under way. One goal of the center is to accelerate the lengthy
declines prior to apoptotic cell death. We have observed that
and expensive process of testing new drugs targeted against
1) the NAD(P)H fluorescence emission peak from UV wavelength
brain tumors and to safely move them into clinical trials as
excitation is lost during a variety of insults, including hyperther-
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.
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 condensation 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.
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
Role of Optical Nanocrystals (Quantum Dots) in
route of delivery of these drugs.
Molecular and Cancer Imaging – Quantum dots are
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 convectionenhanced delivery (CED).
optical nanocrystals whose use in in vitro and in vivo
molecular imaging is exploding. In comparison with
organic fluorophores, quantum dots exhibit desirable
properties such as multi-wavelength fluorescence
emission, excellent brightness and resistance to
photobleaching. Their electron-dense metallic cores
suggest they may have utility in computed tomography as well as optical imaging. Coreshell zinc sulfide-
The staff of the center is focused on translating these preclinical
cadmium selenide quantum dots were studied in
results into Phase I and II clinical trials – giving the brain tumor
magnetic resonance and computed tomography
patient more therapeutic treatment options by broadening the
phantoms. In addition, the Qdots were injected
horizon of potential tools we may use to manage this deadly disease.
into rat brain using convection-enhanced delivery,
The CTT has started research projects with a number of pharmaceutical 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.
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
CTT Staff Include:
Director: Michael A. Vogelbaum, M.D., Ph.D.
Project Scientist: Baisakhi Raychaudhuri, Ph.D.
Technical Assistant: Hamid Daneshvar
2005 Annual Report
intravenously to co-localize with rat brain tumor
clinical operating time on intraoperative monitoring,
awake craniotomy techniques and intraoperative
ultrasound.
A team approach to individualized care
19
Molecular Genetics and Molecular
Neuro-Oncology
MLPA technique for multiplex PCR analysis of 1p/19q is being
used. This part of the study is in progress.
Dr. Olga Chernova leads or participates in projects one through
As an extension of this project, Drs. Chernova, Weil (BTI) and
five, while Dr. Mladen Golubic does so for projects six and seven.
Wigler (Cold Spring Harbor Laboratory) collaborated. Dr. Wigler
Project 1. Genetic alterations and biological characterization of
hybridization assay for analysis of numerical alterations in
primary cell cultures derived from malignant gliomas. The initial
objectives of this project were a) finding conditions for establishing short-term primary cultures from glial tumors that would
developed a high-density microarray-based comparative genomic
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
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
and was able to identify novel regions of alterations.
Project 3. Development of a clinical assay for detection of
deletions in CDKN2A, ARF, PTEN and p53 genes in gliomas.
We have developed a semi-quantitative assay for detection of
gene deletions based on multiplex PCR. The goal of the project
modified medium used for propagation of normal neural stem
is development, validation and introduction of this prognostic
cells allow selective isolation of tumor cells in primary culture.
A genotyping assay was established, which allows semi-quantitative evaluation of the homogeneity of the cultures. The growing
assay to the clinical laboratory. This assay will also be important for the “Genotyping Arrays” project as a part of validation
interest to the role of the stem cells in tumorigenesis prompted
of the array data.
a characterization of the origin and differentiation status of the
Project 4. Genotyping arrays as a prognostic tool: glioma
cultured tumor cells in collaboration with Dr. Robert Miller. Using
model. This project is a collaboration with Cleveland BioLabs
a set of antibodies detecting several neural stem cells markers, at
and the microarray manufacturing company Nimblegen. The aim
least two types of glioma cultures, which may potentially originate
of the project is to develop a genotyping microarray-based assay
from different pools of the neural stem cells, have been identified.
that will identify alterations in chromosome copy number and
Analysis of tumorigenic potential of these primary tumor cultures
allelic imbalances in critical chromosomal regions, as well as
in nude mice is in progress.
mutations in genes that have prognostic significance in glial
tumors and predict response to therapy. Amended STTR
Growing interest in stem cells in brain tumors resulted in two
proposal had been resubmitted to the NIH in October 2005.
collaborative projects with Cleveland Clinic researchers: (1) a
collaboration with Dr. Gregory Plautz to develop a vaccine for
Project 5. Distinct alteration of chromosome 1p in astrocytic
brain tumors resulted in submission of RO1 NIH proposal; (2)
and oligodendrocytic tumors. The extent of 1p deletion in low-
a collaboration with Drs. Jaharul Haque and Michael Vogelbaum
and high-grade gliomas using LOH analysis was characterized.
to study signal transduction pathways and gene expression in
The results indicate that oligodendroglial tumors almost uniformly
brain tumor stem cells.
demonstrate very large deletions of 1p arm. Conversely, GBMs
Project 2. Genetic alterations in GBMs (loss or gain of 19q, 1p
have only partial deletions affecting the terminal part of 1p. This
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
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).
predictive of clinical response or survival of patients with GBM.
To confirm and expand these initial observations, well-controlled
Project 6. Role of Eicosanoids in Glioblastoma Tumorigenesis.
groups of 34 patients with newly diagnosed GBMs treated at
Eicosanoids are special type of fats produced in the human
Cleveland Clinic and demonstrated either long (>20 months) or
body from diet-derived fats by the action of enzymes called
short (between three and nine months) survival were selected.
cyclooxygenases (COX-1 and COX-2) and lipoxygenases.
Ten LOH markers distributed along 1p arm and 4 markers along
We have determined that 5-lipoxygenase (5-LO), an enzyme
19q arm were used. Preliminary data indicate that both types of
that stimulates inflammation, is aberrantly overexpressed in
allelic imbalance, loss or gain, of 1p and/or 19q could be found
malignant brain tumors, anaplastic astrocytoma and GBM.
in GBM tumors and occur in both groups of patients. However,
The two main interconnected aspects of this project are (1)
to complete this study, the same tumors should be analyzed
to investigate the expression of other eicosanoid enzymes of
using FISH or multiplex PCR techniques to discriminate true
the 5-LO pathway in the GBM tumor tissue and measure
losses of chromosomes from their gains. Forty percent of the
eicosanoids in the blood of patients with GBM; and (2) to
specimens were analyzed by FISH at the Molecular Pathology
explore novel ways to inhibit 5-LO and COX-2, the two main pro-
lab. The rest of the specimens are currently studied using
inflammatory enzymes that are aberrantly overexpressed in GBM.
multiplex PCR assays for 1p and 19q. A recently developed
To inhibit 5-LO, we are examining the use of Boswellic acids.
20
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Boswellic acids are naturally found in the gum resin exudate from
therapies for treatment of brain cancer, based on an integrated
the Boswellia serrata (frankincense) tree. The herbal preparation
technological platform that includes: 1) gene target identification
from B. serrata will be used in combination with a low-fat diet as
based on the combination of novel functional genomic approach-
an adjuvant therapy for patients with GBM in a clinical study (see
es with global gene expression profiling and advanced bioinfor-
Project 6. Molecular characterization of genes that are modulated
matics and 2) identification of bioactive compounds with the
by Boswellic acids in GBM cells currently is in progress. The
desired properties, using small molecule screening facility,
levels of eicosanoids are measured not only in blood of patients
followed by pharmacological optimization of primary hits.
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.
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
To suppress the aberrantly overactive COX and 5-LO enzymes in
are to: 1) identify and test prospective therapeutics among secreted
GBM cells, we are investigating the potential anticancer effects of
or membranal protein products of identified disease-specific genes;
an anti-inflammatory herbal preparation (Zyflamend, by New
2) develop high throughput technology of isolation of new anticancer
Chapter, Inc.). It consists of standardized extracts from 10 different
therapeutics by screening chemical libraries for prospective gene-
spices (including turmeric, ginger, rosemary and oregano) and
or pathway-specific drugs based on the discovered genes; and 3)
medicinal herbs. We have shown that Zyflamend induces
develop diagnostic assays that will grade tumor type and stage
programmed cell death of GBM cells in vitro and inhibits produc-
of progression, facilitate selection of optimal therapy, provide an
tion of eicosanoids in surgically removed GBM tissue specimens.
accurate and reliable prognosis, and initiate a broad program of
This work is done in collaboration with Dr. Newman’s laboratory
clinical validation based on the selected combinations of candidate
and is supported by the research grant from New Chapter, Inc.
disease-specific genes. This effort has already resulted in identifica-
Recently, we identified more than 150 genes that are either
tion of two prospective anticancer treatment molecular targets
induced or suppressed in expression when GBM cells are treated
that are currently being used for small molecule screening. A small
with Zyflamend. Currently, the functional significance of two of
molecule inhibitor of multidrug resistance with a new mechanism
those genes is being investigated further. The obtained results
of activity associated with MRP1 and other multidrug transporters,
were presented at the Annual Research Conference of the
4H10, capable of sensitizing glioma cells to a variety of anticancer
American Institute for Cancer Research in Washington, D.C., in
agents has been isolated.
July 2005, and at the 2nd International Conference of the Society
for Integrative Oncology in San Diego, Calif., in November 2005.
Project 7. 5-Lipoxygenase Inhibition as an Adjuvant Glioma
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.
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-inflammatory 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.
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 consistently in vitro, perhaps due to the non-physiological conditions
that traditional tissue culture provides. We are attempting to
grow malignant brain tumors (oligodendroglioma and glioblastoma) 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 evaluate similarity of growth patterns in vitro vs. in vivo. We also
Molecular Biology of Brain Tumors
propose to examine direct vs. indirect drug resistance of the
Dr. Andrei Gudkov has established a facility aimed at identifica-
the abluminal site or intraluminally, where a blood-brain barrier
tion of molecular targets and development of target-based
2005 Annual Report
tumor by injecting chemotherapeutic agents either directly into
separates the “blood compartment” from the brain tumor itself.
A team approach to individualized care
21
Another focus of this laboratory is to determine the role of S100
New approaches are requisite if malignant gliomas are to be
as a potential tumor marker. We are examining changes in S100
treated successfully. Immunotherapy is an attractive approach in
level with blood-brain barrier disruption and its correlation with
this disease; however, this form of treatment has not been very
metastatic and glioma tumor burden. Related projects by Dr. Yan
successful clinically. Growing evidence suggests that the poor
Xu are examining phospholipid antibodies as a potential tumor
response to immunotherapy is likely due to the inability of current
marker. Other markers of deranged p53 mechanisms and small
therapeutic approaches to adequately reverse immune suppres-
molecule modulators of blood-brain barrier function are evaluated
sion. It is been well-documented that patients with gliomas are
by Dr. Andrei Gudkov.
characterized by systemic immune dysfunction, as demonstrated
by impaired cell-mediated immunity, lymphopenia and inability
Immunology and Immunotherapy
Table 1. Members of the Division of Pathology and Laboratory Medicine Actively
Participating in Molecular Neuropathology
Project as of 9/30/05.
Neuropathologists
Richard 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 Pathologists
Raymond Tubbs, D.O.Director of Molecular Genetic Pathology Laboratory. Supervision of FISH. Review
of FISH results with technologists.Supervision research and development of arraybased 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.,
James R. Cook, M.D.,
Marek Skacel, M.D.
Review of FISH results with technologists.
Molecular Pathology Technologists
James Pettay, M.T. (ASCP), Supervisor,
Molecular Genomic Laboratory
CLIA Compliance
Marybeth Hartke, B.S., M.T.(ASCP)
Development and validation of FISH Assays. Performance of FISH analyses
Kelly Simmerman, M.T. (ASCP), Karen Keslar, M.S.,
Rosemary Neelon, B.S.
Performance of FISH analyses
Tissue Procurement Technologists
Jessica Krimmel, B.S., Barbara Bekebrede, B.S.,
Jessica Roman, B.S.,
Carrie Nedbalski
Immunohistochemistry Technologists
Gloria Willis-Eppinger, H.T.(ASCP)
Renata Klinkosz, B.S., M.T., Kathy Maresco, B.S., M.T.(ASCP), Michelle Wayman, B.S., H.T.(ASCP),
Derek Mangalindan, B.S., M.T.
Transport and processing of blood and tissues from OR. Communications
with BTI Specimen Bank Technologists.
Lab Coordinator
Sectioning blocks for immunohistochemistry and genotyping, development and performance of
immunohistochemistry assays
Reference Laboratory
Mary Ann Kannenberg, B.S., M.T.(ASCP)Manager, Laboratory Services
(Reference Laboratory).
Kathy Leonhart,
Client Services (Marketing)
Laboratory Information Systems
Dale DucaLead 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.
22
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Table 2: Summary of Molecular Genotyping Tests available during Reposting
Period 10/1/04 – 9/30/05.
Test
Target specimens
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.
Status of test
EGFR FISH
High grade gliomasOrderable 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, in greater detail, genetic alterations on Chromosome 1p
Orderable clinical test within CCF and through CCF
Reference Laboratory.
19q LOH by PCR
Performed upon request to characterize, in greater detail, genetic alterations on Chromosome 19q
CCF Technical Validation nearly completed. Two tests performed.
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 3. Numbers of Molecular Genotyping tests performed by Specimen Class*.
Specimen Class
FISH for 1p
FISH
for 19q FISH 1p LOH 19q LOH for EGFR**
by PCR
by PCR
TP53 SEQ
Totals
Routine Surgical
(SX)
83
83
73
3
2
0
244
Surgical Outside Review (SO)
11
11
5
0
0
0
27
Surgical Reference Lab Consult (SRC)
11
7
2
0
0
0
20
Procedure Only (PRS)
106
106
0
1
0
0
213
Totals
211
207804
2
0
504
* 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
2005 Annual Report
A team approach to individualized care
23
to mount delayed-type hypersensitivity reaction. Indeed some
expression of GM2 coincided with the appearance of apoptosis in
of the immune suppression is likely related to the fact that a
the T cells exposed to CCF-52 supernatant but not T cells cultured
higher percentage of T cells from glioma patients are undergoing
in media alone. Similar findings were observed when T cells from
apoptosis as compared to T cells from healthy individuals. It is
normal donors were co-cultured with a monolayer of CCF-52 cells.
important at this time to not only focus on boosting the immune
We are now interested in analyzing T cells from GBM patients to
response to GBM but also to include a second arm in the
determine whether a portion of these cells are GM2 positive and
therapeutic strategy that will prevent the immune cells from
whether the presence of GM2+ T cell correlates with increased
undergoing tumor-induced immune suppression. Previously we
levels of GM2 in patient plasma and with T-cell apoptosis.
showed that GBMs mediate immune suppression via promoting
T-cell death through receptor-dependent and receptor-indepen-
We are currently testing whether the iron chelator/antioxidant
desferoxamine (DFO) is able to protect T cells in rats that bear the
dent apoptotic pathways.
syngenic transplantable tumor, S635. Previously, we showed that
Recently we reported that gangliosides produced by GBM
in vitro DFO can protect T-cells from apoptosis induced by isolated
lines contribute to the induction of T-cell apoptosis, since the
GBM gangliosides and GBM cell lines by 45 to 85 percent. New
glucosylceramide synthase inhibitor PPPP significantly reduced
studies show that administration of DFO via an implantable pump
the abilities of all four GBM apoptogenic lines to kill lymphocytes
can significantly reduce the percentage of apoptotic T cells that are
(Chahalvi A, et al. Cancer Research 2005). HPLC and mass-
present in the peripheral blood and tumor. We are in the process
spectroscopy demonstrated that GM2, GD3 and GD1a were
of testing whether DFO administration will enhance the antitumor
expressed by all four apoptogenic GBM-lines, but not by the two
activity of adoptively transferred T cells derived from the draining
GBMs lacking activity. The expression of GM2, GD3, GD2 and
lymph nodes of S636-bearing mice.
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
Cerebrovascular Research Center
Dr. Damir Janigro leads the Cerebrovascular Research Center
in cooperation with Dr. Luca Cucullo.
CCF-52 cells. The antibodies or isotype control Ig was added at
Alternating current electrical stimulation enhanced chemotherapy:
the beginning of the cultures. These studies revealed that anti-
a novel strategy to bypass multidrug resistance in tumor cells.
GM2 antibody was most effective at blocking T cell apoptosis,
BMC Cancer. 2006 Mar 17;6(1):72 PMID: 16545134
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.
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-
Additional supporting data demonstrating that GM2 is apopto-
glycoprotein. As a consequence, malignant cells may become
genic for T cells was provided by transfecting CCF-52 tumor
insensitive to various anticancer drugs. Recent studies have shown
cells with siRNA for GM2 synthase. Such treatment causes a
that low intensity, very low frequency electrical stimulation by
significant reduction in the expression of GM2 that is observed
alternating current (AC) reduces the proliferation of different tumor
within 24 hours and lasts for over 72 hours. RT-PCR analysis of
cell lines by a mechanism affecting potassium channels while
mRNA from these transfected cells revealed that messenger RNA
intermediate frequencies interfere with cytoskeletal mechanisms of
for GM2 synthase was reduced within 12 hours, with optimal
cell division. The aim of the present study is to test the hypothesis
suppression occurring at 48 hours. The reduction in GM2 expres-
that permeability of several MDR1 over-expressing tumor cell lines
sion following transfection with siRNA for GM2 synthase was
to the chemotherapeutic agent doxorubicin is enhanced by low
selective since there was no decrease in the expression levels
frequency, low intensity AC stimulation.
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.
We grew human and rodent cells (C6, HT-1080, H-1299, SKOV3 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.
Recent findings suggest GM2, which is produced by the CCF-52
We used a dedicated program to generate and monitor the
cell line, is shed into the supernatant, where it can then bind T
electrical stimulation protocol. Parallel cultures were exposed
cells. Immunofluorescence staining with anti-GM2 antibodies
for three hours to increasing concentrations (1, 2, 4, and 8 m)
demonstrated that T cells from normal individuals do not express
of) M doxorubicin following stimulation to 50 Hz AC (7.5 mA)
detectable GM2. However, after a one- to two-day incubation of
or MDR1, inhibitor XR9576. Cell viability was assessed by
these T cells with conditioned medium from cultured CCF-52
determination of adenylate kinase (AK) release. The relationship
cells, GM2 was detected by anti-GM2 antibody staining. The
between MDR1 expression and the intracellular accumulation
24
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
of doxorubicin as well as the cellular distribution of MDR1
Recent data indicate the existence of a novel signalosome
was investigated by computerized image analysis immunohisto-
complex that is induced by IL-13 and contains Src kinase, p38
chemistry and Western blot techniques.
By using a variety of tumor cell lines, we show that low frequency, 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 distribution 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 Engineering
Work 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
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 implementation 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
investigations in a Web-accessible, IRB-approved format.
despite multiple new approaches to their treatment. In particular,
IL-13 Induction of Glioma Apoptosis
including radiation therapy and most standard forms of chemo-
most of these tumors are resistant to DNA-damaging treatments,
Dr. Martha Cathcart directs work in this laboratory that has been
therapy. A growing body of evidence supports the hypothesis that
defining the relevant IL-13 receptors in several cell types and
aberrant activation of key transcription factors is critical for the
identifying the downstream signal transduction cascades. Her lab
development and progression of these tumors. A greater under-
is interested in understanding the IL-13-mediated induction of
standing of the biology of these transcription factors should help
apoptosis, the regulation of IL-13 signal transduction pathways
us develop new, more effective therapeutic modalities.
and the regulation by receptor composition. To date Dr. Cathcart’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 glioblastoma cells to further understand IL-13 induction of apoptosis.
2005 Annual Report
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.
A team approach to individualized care
25
Brain Tumor Institute
Publications
Paper Published
or In Press
Batra 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 Consciousness. 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
26
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-brainbarrier: report of the tenth annual bloodbrain 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.
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.
Farray D, Ahluwalia M, Cohen B, et al.
Pre-irradiation 9-Amino [20s] camptothecin (9-AC) in patients with newly
diagnosed glioblastoma multiforme. Invest
New Drugs. 2005 Aug 2.
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.
Fritz M, Sade B, Wood B, Lee JH. Benign
fibrous histiocytoma of the pterigopalatine fossa with intracranial extension.
Acta Neurochirurgica date. 2005 Feb
25. In press.
Lee JH, Krishnaney AA, Steinmetz MP,
Lee DK. Intracranial Meningiomas. In:
Barnett GH, ed. Computer-Assisted Neurosurgery. 2005. 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
Cleveland Clinic
Lee JH, Steinmetz M, Krishaney A, Lee
DK. Intracranial Meningiomas. In: Barnett
G, Roberts D, Maciunas R, eds. ComputerAssisted Surgical Navigation in Neurosurgery. 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 distinguishes 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, 57:518525, 2005.
Lo SS, Chang EL, Suh JH. Stereotactic
radiosurgery with and without whole-brain
Brain Tumor Institute
clevelandclinic.org/braintumor
radiotherapy for newly diagnosed brain
metastases. Expert Rev Neurotherapeutics. 2005; 5(4):487-495.
Lonser RR, Buggage R, Weil, RJ.
Malignant cerebellar swelling in a patient
with neuro-Behçet’s disease. J Neurosurgery: 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 melanocytoma 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 Management 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 Neurosurgeon, 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 Technologies. In: Barnett G, Roberts D, Maciunas
R, Peereboom DM, eds. ComputerAssisted 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
2005 Annual Report
genetic changes in hereditary and sporadic
pituitary adenomas detected by comparative 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 hemangiopericytoma. 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): 675682.
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 deformations 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; 129:415416.
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 efaproxiral 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 Management. 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.
A team approach to individualized care
27
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-Lindauassociated 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):81724.
Weil RJ, Lonser RR, Quezado MM. Skull
and brain metastasis from tibial osteosarcoma. 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
Book Chapters
Abstracts
Barnett GH. Image-Guided Needle Biopsy.
In: Advanced Techniques in Image-Guided
Brain and Spine Surgery. Thieme
Publisher. 2005. In press.
Angelov L. The use if tissue equivalent
Super Stuff Bolus ™
Barnett GH. Intraoperative MRI. Contemporary 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 NeuroOncology. 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. ComputerAssisted Neurosurgery. Ontario, Canada: BC
Decker, Hamilton; 2005. In preparation.
Barnett, GH, Maciunas R, Roberts D, eds.
Computer-Assisted Neurosurgery. Ontario,
Canada; BC Decker Publishing Co; 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.
Barnett GH, ed. High Grade Gliomas:
Diagnosis and Treatment. Totawa, NY;
Humana Press. 2005, In preparation.
Vogelbaum M and Kanner A. Intraoperative MRI. In: Barnett G, Maciunas R,
Roberts D, Marcel Dekker, eds. ComputerAssisted Neurosurgery. New York, NY: Inc.
Publishers; 2005. In press.
Prayson, RA, Angelov, L, Barnett, GH.
Mixed Neuronal-Glial Tumors. In: Berger,
MS, Prados, M.D., eds. Textbook of
Neuro-Oncology Philadelphia, PA; Elsevier
Saunders; 2005: 222-226.
28
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.
Cleveland Clinic
material to treat skull metastases with
Gamma Knife Radiosurgery. 7th International 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 temozolomide 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 acromegaly. 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 BMS247550 for patients with recurrent highgrade 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.
Brain Tumor Institute
clevelandclinic.org/braintumor
Usmani A, Makdissi A, Hamrahian A,
Reddy S, Weil R, et al. Hypothalamicpituitary-adrenal axis testing using a
twenty-five microgram Cotrosyn stimulation 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.
Presentations
Barnett GH. Gamma Knife Planning,
Stereotactic Frame Application, Gamma
Knife Shot Strategy, AVM Planning, Wizard
Software. Cleveland Clinic Gamma Knife
Course, Cleveland, OH; Jan 2005.
Barnett GH. Surgery for Gliomas.
Cleveland Clinic Neuro-oncology Symposium, Lake Buena Vista, FL; Jan 2005.
Barnett GH. Moderator: Gliomas II.
Cleveland Clinic Neuro-oncology Symposium, Lake Buena Vista, FL; Jan 2005.
Barnett GH. Stereotactic Frame Application, 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 Intraoperative 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.
Barnett GH. Stereotactic Navigation,
Cleveland Clinic Neurosurgery Resident
Lecture; May 2005.
Barnett GH. Stereotactic Frame Application, Introduction to Planning System,
Gamma Knife Shot Strategy, AVM
Planning. Cleveland Clinic Gamma Knife
Course, Cleveland, OH; June 2005.
Lee DK, Lee JH. Surgical management of
tentorial meningiomas. Oral presentation:
Korean Skull Base Society Annual
Meeting, Seoul, Korea; December 2005.
2005 Annual Report
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, Interdisciplinary SBS Conference, Cleveland Clinic,
Cleveland, OH; March 2005.
Lee JH, Sade B, Park BJ. A novel ‘CLASS’
algorithm for patient selection in meningioma 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 Metastases. 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 Neurooncology Symposium: Current Concepts
Emerging Medical Therapies for Highgrade 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 Temozolomide: 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 Metastases. 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.
A team approach to individualized care
29
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 Radiotherapy. 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 International Neuro-oncology Symposium.
Cleveland, OH; Aug 2005.
Toms SA. Optical Imaging in NeuroOncology: 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
30
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 phagocytized by macrophages and detect
experimental malignant glioma. International Association for Nanotechnology;
November 2005.
Usmani A, Makdissi A, Hamrahian A,
Reddy S, Weil RJ, Faiman C. Hypothalamic-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. Platform presentation: RNAi course; Cold
Spring Harbor Laboratory; September 28October 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 Convectionenhanced Delivery. Snowmass, CO;
February 2005.
Vogelbaum MA. Tumor Margin Dose
Affects Local Control Following Stereotactic 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-Irradiation and Concurrent Temozolomide in
Patients with Newly Diagnosed Anaplastic
Oligodendrogliomas and Mixed Anaplastic
Oligodendrogliomas. ASCO, 2005.
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 Symposium. 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 BloodBrain-Barrier and Drug Resistance Genes.
Cleveland, OH; March 2005.
Weil, RJ. CNS Metastases in Women with
Breast Cancer: Challenges and Opportunities. 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 Neurooncology 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, Management of low-grade gliomas: current
strategies and dilemmas. CNS Annual
Meeting. Boston, MA; October 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.
Manuscripts Submitted
Vogelbaum MA, Mazzone P, Masaryk T, et
al. Low serum S100 levels in patients with
Barnett G and Thomas T. Imaged-Guided
Surgery. In: Black P, ed. Neurosurgical
Cleveland Clinic
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.
Brain Tumor Institute
clevelandclinic.org/braintumor
Oncology.
Barnett GH, Park J. Craniopharyngioma.
In: Ragahaven, ed. Textbook of Uncommon 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 oligodendrogliomas 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. SpringerVerlag, 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
2005 Annual Report
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. Submitted.
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 metastases. 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, Peereboom 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.
A team approach to individualized care
31
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 tumorigenesis and progress. Meningiomas. SpringerVerlag, London. In review.
Krishnaney A, Steinmetz MP, Golubic M,
Lee JH. Meningioma location is associated 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 meningothelial. 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: Nonwatertight 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. SpringerVerlag, London. In review.
Quan AL, Ross JS, Lee SY, et al. Prognostic implication of multicentric and
multifocal disease in patients with glioblastoma 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 influencing early outcome in meningioma
surgery. In progress.
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 preparation.
Toms SA, Daneshvar H, Nelms J,
Muhammed O, Jackson H, Vogelbaum
MA, Bruchez M. Optical Detection of Brain
Tumors Using Quantum Dots. In preparation.
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 preparation.
Sade B, Prayson R, Lee JH. Giosarcoma
with infratemporal fossa extension. Journal
of Neurosurgery. In review.
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.
Sajja R, Barnett GH, Lee SY, et al. Gamma
Knife radiosurgery for newly diagnosed
and recurrent intracranial meningiomas. In
progress.
Toms SA, Yuan S, Miller DW, Muhammed
O, Tasch J, Williams BRG. Identification of
an alternate splice of hSLK, hSLKS. In
preparation.
Siomin V, Toms SA. En bloc resection of
skull base metastasis is achievable with
good clinical outcomes. In preparation.
Ugokwe K, Toms SA. Renal Cell Carcinoma Brain Metastases. Renal Cell
Carcinoma. In preparation.
Vogelbuam M. Small Molecule Agents.
High-Grade Gliomas. Diagnosis and
Treatment.
32
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
Brain Tumor Institute
Appendix A – Clinical Trials
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 Protocols
IV 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
Thrombocytopenia
Eligibility: Histologically confirmed
high-grade glioma, age 18-75.
Study Design: Phase II,
multi-institutional trial
Contact: Glen Stevens, D.O., Ph.D.,
216.445.1787
AP23573 in Progressive or Recurrent
Malignant Glioma
Description: A Phase I Sequential
Ascending Dose Trial of AP23573 in
Patients with Progressive or Recurrent
Malignant Glioma
Eligibility: 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 recurrence or relapse. Age >= 18.
Study Design: Phase I, multi-institutional
Contact: TEMPORARILY NOT ACCEPTING PATIENTS
Contact: David Peereboom, M.D.,
216.445.6068
Celecoxib & Anticonvulsants
for Newly Diagnosed GBM’s undergoing Radiation Therapy
Description: 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 radiographic evidence of recurrence.
Study Design: Internal, Phase II
Contact: Michael Vogelbaum, M.D.,
Ph.D., 216.444.856
ACOSOG Z0300 (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
Erlotinib with Temozolomide & Radiation
for Newly Diagnosed GBM
BMS (Recurrent Malignant Glioma)
Description: 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
Description: A Phase I/II Study of BMS24755A 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
2005 Annual Report
progressive or recurrent following radiation
therapy ± chemotherapy. Patients with
previous low-grade glioma who progressed after radiotherapy +/- chemotherapy 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 Multiforme 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 progressed after radiotherapy +/- chemotherapy 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
A team approach to individualized care
33
RTOG-9813
(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 9803 (Gliadel and
O6-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 9901 (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 9809 (Col-3 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 S0001: Upfront Treatment for
Newly Diagnosed GBMs
Description: Randomization to Radiation
therapy + O6-BG + BCNU vs. Radiation
+ BCNU Alone
Study Design: Phase III SWOG study
Eligibility: Newly diagnosed GBM, KPS >60
Contact: CURRENTLY NOT
ACCEPTING PATIENTS
IL-13
Description: Pre-Operative IL13PE38QQR 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 oligoastrocytoma (excludes glioma of know grade
or “pure” oligodendroglioma). Patients with
34
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-13
Description: Phase I study of convectionenhanced delivery (CED) of IL13PE38QQR 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 specimen. Diagnosis must be consistent with
either GBM, AA or mixed OA.
Contact: Mike Vogelbaum, M.D.,
216.444.5381
IL-13
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 +/- RSR13 in Women
with Brain Metastases from
Breast Cancer
Description: 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 radiographically confirmed metastases to the brain.
Cleveland Clinic
Contact: John Suh, M.D., 216.444.5574
Melatonin for Brain Metastases
Description: 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 1-3
Brain Metastases
Description: 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
Oligoastrocytoma
Description: Phase II Trial of Continuous
Dose Temozolomide in Patients with
Newly Diagnosed Anaplastic Oligodendrogliomas 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 Tumors
Description: 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 Brachytherapy
Description: Phase I Brachytherapy Dose
Escalation Using the Gliasite RTS in
Newly Diagnosed Glioblastoma Multi-
Brain Tumor Institute
clevelandclinic.org/braintumor
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 Approach
Description: 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 43-9006 for Recurrent/Progressive Malignant Gliomas
Description: A Phase I Trial of Bay 439006 for Patients with Recurrent or
Progressive Malignant Glioma
Study Design: Phase I trial
Eligibility: Recurrent Anaplastic Astrocytoma, Recurrent Anaplastic Oligodendroglioma, Recurrent GBM, Recurrent
Gliosarcoma
Contact: David Peereboom, M.D.,
216.445.6068
EMD & RT for Newly Diagnosed
GBM’s
Description: A Safety Run-In/Randomized
Phase II Trial of EMD 121974 in Conjunction with Radiation Therapy in Patients
with Newly Diagnosed Glioblastoma
Multiforme NCI #: NABTT 0306
Study Design: NABTT Cooperative Phase
II Trial
Eligibility: Newly Diagnosed GBM, Newly
Diagnosed Gliosarcoma
Contact: David Peereboom, M.D.,
216.445.6068
Temozolomide for Low-grade Gliomas
Description: A Phase II Study of Temozolomide-Based Chemotherapy Regimen for
High Risk Low-Grade Gliomas
Study Design: Phase II trial
Eligibility: Low-Grade Gliomas
Contact: John Suh, M.D., 216.444.5574
Talampanel w/RT & Temozolomide
for Newly Diagnosed GBM’s
Description: A Phase II Trial of Talampanel in Conjunction with Radiation
Therapy with Concurrent and Adjuvant
Temozolomide in Patients with Newly
Diagnosed Glioblastoma Multiforme
2005 Annual Report
Study Design: Phase II Trial
Eligibility: Newly Diagnosed GBM, Newly
Diagnosed Gliosarcoma
Contact: 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 Regimen
Eligibility: 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, multiinstitutional
Contact: 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 +/- IntraOcular Chemotherapy, in Patients
with Primary CNS
Eligibility: 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-9811 (Benign Meningioma)
Description: Chemotherapy with
hydroxyurea
Study Design: Phase II, cooperative group
Eligibility: Primary, recurrent or residual
benign meningioma which is unresectable, Age >18yrs, XRT > 1 yr
Contact: CURRENTLY NOT
ACCEPTING PATIENTS
Metastasis
Zeiss INTRABEAM System
for Solitary Brain Metastasis
Description: A Phase I/II Study Utilizing
the Zeiss INTRABEAM System for the
Treatment of a Resected Solitary Brain
Metastasis
Eligibility: 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
Metastases
Description: A Randomized, DoubleBlind, Placebo-Controlled, Phase III Study
of Temozolomide or Placebo added to
Whole Brain Radiation Therapy for the
Treatment of Brain Metastases from NonSmall Cell Lung Cancer
Eligibility: 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 metastatic 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 Metastases
Description: 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 +/- RSR13 in Women with
Brain Metastases from Breast Cancer
Description: 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 radiographically confirmed metastases to the brain.
Contact: John Suh, M.D., 216.444.5574
A team approach to individualized care
35
Xcytrin for Non-Small Cell Lung
Cancer Brain Metastases
Description: 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 Metastases
Description: 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 Metastases
Study Design: RTOG Cooperative Phase
III Trial
Eligibility: Non-Small Cell Lung Cancer
with Brain Metastases
Contact: John Suh, M.D., 216.444.5574
Motexafin Gadolinium with WBRT &
SRS Boost for Brain Metastases
Description: Phase II Trial of Motexafin
Gadolinium with Whole Brain Radiation
Therapy Followed by Stereotactic
Radiosurgery Boost in the Treatment of
Patients with Brain Metastases
Study Design: Phase II trial
Eligibility: Brain Metastases
Contact: John Suh, M.D., 216.444.5574
Child and Adolescent
Protocols
Newly Diagnosed
Malignancies
Head Start III: Dose-Intensive
Chemotherapy for Children Less Than
10 Years of Age Newly Diagnosed
with Malignant Brain Tumors
Description: 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
36
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 #6140)
Description: The study represents a multiinstitutional 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.-ACNS0121: A Phase II Trial
of Conformal Radiation Therapy for
Pediatric Patients with Localized
Ependymoma, Chemotherapy Prior
to Second Surgery for Incompletely
Resected Ependymoma, and Observation for Completely Resected Differentiated, Supratentorial Ependymoma
Description: 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 ependymoma, myxopapillary ependymoma,
Cleveland Clinic
subependymoma, ependymo­blastoma, or
mixed gliomas are not eligible.)
Study Design: Phase II clinical trial with
four treatment arms, based on tumor location, 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.-ACNS0122: A Phase II Study
to Assess the Ability of Neoadjuvant
Chemotherapy +/– Second-Look Surgery
to Eliminate All Measurable Disease
Prior to Radiotherapy for NGGCT
Description: 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: endodermal 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.-ACNS0126: A Phase II Study
of Temozolomide in the Treatment of
Children with High-Grade Gliomas
Description: 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
Brain Tumor Institute
clevelandclinic.org/braintumor
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.
216.444.8407, or Bruce H. Cohen, M.D.,
216.444.9182.
C.O.G.-ACNS0331: A Study Evaluating Limited-Target Volume Boost
Irradiation and Reduced-Dose
Craniospinal Radiotherapy (18.00 Gy)
and Chemotherapy in Children with
Newly Diagnosed Standard-Risk
Medulloblastoma: A Phase III
Double-Randomized Trial
CCG-A9952: Chemotherapy for
Progressive Low-Grade Astrocytoma
in Children Less Than Ten Years Old
Description: 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.-P9934: Systemic Chemotherapy, Second-Look Surgery, and
Conformal Radiation Therapy Limited
to the Posterior Fossa and Primary
Site for Children > 8 Months and
< 3 Years with Nonmetastatic
Medulloblastoma
Description: 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.,
2005 Annual Report
Refractory / Progressive
/ Relapsed Malignancies
Description: The study compares eventfree survival rates of two chemotherapeutic 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 astrocytomas (grade 1 and 2) or other low-grade
gliomas and who have progressive disease
following surgical excision or an incomplete 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.-ACNS0226: A Phase II Study
of R115777 (Zarnestra) (NSC#
702818, IND# 58359) in Children
with Recurrent or Progressive HighGrade Glioma, Medulloblastoma/
PNET or Brainstem Glioma
Description: The protocol tests effectiveness 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 oligodendroglioma, recurrent or refractory medulloblastoma/PNET, or diffuse intrinsic brainstem
glioma. Patients must have histopathologic 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.
ADVL0421: A Phase II Study of
Oxaliplatin in Children with Recurrent
Solid Tumors
Description: 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.-P9962: A Phase II Trial of
Intrathecal Topotecan in Patients with
Refractory Meningeal Malignancies
Description: 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.-P9761: A Phase II Trial of
Irinotecan in Children with Refractory
Solid Tumors
Description: 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 histologically 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,
A team approach to individualized care
37
patients receive irinotecan 5 of every 21
days; patients demonstrating continued
response or stable disease without
significant toxicity may continue treatment. Subsequent radio­graphic evaluations would be performed every 3 months
as indicated.
Contact: CLOSED TO PATIENT ACCRUAL.
Registry
ATT/RT Registry (IRB #5181):
Central Nervous System Atypical
Teratoid/Rhabdoid Tumor Registry
Description: 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 Studies
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-B947: Protocol for Collection
of Biology Specimens for Research
Studies
Description: 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. therapeutic trial.
Contact: CLOSED TO PATIENT ACCRUAL.
CCG-B971: Molecular Biology of
Pediatric Brain Tumors
Description: 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.
CCG-B961: Prognostic Significance of
Ki-67 Proliferative Index Utilizing the
MIB-1 Antibody in Low-Grade
Gliomas in Young Children
Description: 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 CCGA9952.
Brain Tumor Institute
Appendix B – Charts & Statistics
Total Outpatient Visits
Surgical Procedures | Annualized
6500
1000
Gamma Knife Cases
Surgical Cases
3250
500
0
0
‘01
‘02
‘03
‘04
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.
38
‘01
‘05
‘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.
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
New Outpatient Visits
Patient Enrollment
500
500
Therapeutic Trials
Genetic Trials
250
250
0
0
‘01
‘02
‘03
‘04
‘05
‘01
‘02
‘03
‘04
‘05
New patient visits have increased by 192 percent since
Over the past five years, the number of patients on
2001, setting a new mark
research trials has increased from 94 to 431, or 358
of 529 visits in 2005.
percent.
Brain Tumor Institute
Appendix C – Articles
Clinic Researchers Earn Patent for
Blood-Brain Barrier Technology
Cleveland 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.”
Small Metastases 0.34
MRI FLAIR
Axial View with
Enhancement
S-100 beta levels in patient with small (top) vs. larger
brain metastases (bottom). Higher numbers indicate
greater breakdown of the blood-brain barrier.
Large Metastases 0.71
Axial View with
Enhancement
Coronal View
with Enhancement
Axial View
MRI FLAIR
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.
2005 Annual Report
A team approach to individualized care
39
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
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.
Proteomic Profiling Holds Promise
for Identifying Markers of Interest
Robert J. Weil, M.D., Associate Director of Basic Research, Brain Tumor Institute
Robert J. Weil, M.D.
Early detection of cancer is crucial for its treatment, control and prevention. Identification 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 expression 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
40
Cleveland Clinic
Brain Tumor Institute
clevelandclinic.org/braintumor
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 electrophoresis (2DGE), matrix-assisted laser desorption/ionization mass
spectrometry (MALDI-MS), surface-enhanced laser desorptionionization (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 glioblastoma 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 microdissection 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.
Figure Legends
Figure 1. 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 3. 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
2005 Annual Report
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 4. 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).
A team approach to individualized care
41
Surgical Management of Spinal
Tumors Revolutionizes Treatment
The 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 promoting this broader treatment approach for patients with metastatic spine tumors for several years. A recent study in Lancet
(2005;366(9486):643-648), in which surgery plus radiotherapy 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 interdisciplinary committee that meets regularly to discuss these cases and
plan appropriate treatment. The main candidates for consideration 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 methylmethacrylate (bone cement), Steinmann pins and pedicle screws fixation. The
patient’s pain resolved, and he remained ambulatory after surgery.
42
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.
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A Dietary and Herbal Approach to
Reducing Peritumoral Brain Edema
Cleveland 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 twopronged 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-inflammatory 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 eicosanoids 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-competitive 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.
Mladen Golubic, M.D., Ph.D.
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 World
TWO 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.
In the Cleveland Clinic study, B. serrata is combined with a lowfat 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 combination of dietary and herbal approaches as an adjuvant to standard
2005 Annual Report
A team approach to individualized care
43
*Denotes joint appointment
Brain Tumor Institute Faculty
Neurosurgery
Pediatric Oncology
Gene H. Barnett, M.D., F.A.C.S.
Kate Gowans, M.D.*
Sandra Ference, M.S.N., C.N.P.
Chairman, Brain Tumor Institute
Joanne Hilden, M.D.*
Michele Gavin, M.P.A.S., P.A.-C.
Chair, Pediatric Hematology & Oncology
Co-Director, Pediatric & Adolescent
Brain Tumor Program
Betty Jamison, R.N., B.S.N.
Michael Levien, M.D.*
Kathy Lupica, M.S.N., C.N.P.
Gregory Plautz, M.D.*
Mary Miller, R.N., B.S.N.
Jawhar Rawwas, M.D.*
Carol Patton, R.N.
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.*
Neurology
Bruce H. Cohen, M.D.*
Co-Director, Pediatric & Adolescent
Brain Tumor Program
Neuroradiology
Thomas Masaryk, M.D.*
Jeffrey S. Ross, M.D.*
Administration
Rehabilitative Medicine
Kim Blevins
Vinod Sahgal, M.D.*
Gennady Neyman, Ph.D.
Martin S. Weinhous, Ph.D.
Neuropathology
Richard Prayson, M.D.*
Susan Staugaitis, M.D., Ph.D.*
Michael Lawson, MBA
Taussig Cancer Center
Division Administrator
Gene H. Barnett, M.D.
George Lawrence IV, MBA
Chairman, Brain Tumor Institute
BTI Administrator
Nabila Bennani-Baiti, Ph.D.
Henrietta-English West
Olga Chernova, Ph.D.
Patient Access Coordinator
Peter Cohen, M.D.*
Mladen Golubic, M.D., Ph.D.
Andrei Gudkov, Ph.D.*
Radiation Oncology
Christopher Deibel, Ph.D.
Medical Secretary Work Leader
Research
Robert Miller, Ph.D.
Radiation Physics
Laural Turo, R.N., B.S.N.
Andrew Tievsky, M.D.*
Damir Janigro, Ph.D.*
Director, Gamma Knife Center
Lisa Sorenson, M.S.N., A.C.N.P.
Carla Yoder, M.S.N., C.N.P.
Head, Section of Adult Neuro-Oncology
John H. Suh, M.D.
Sherry Soeder, M.S.N., C.N.P.
Paul Ruggieri, M.D.*
Jaharul Haque, M.D.*
Roger M. Macklis, M.D.*
Debra Kangisser, P.A.-C.
Rachel Perez, R.N., B.S.N.
Glen H. Stevens, D.O., Ph.D.
Aleck Hercbergs, M.D.*
Gail Ditz, R.N., B.S.N.
Wendi Evanoff, B.A.
Noreen Flowers*
Charlotte Horner
Patient Access Coordinator
Eric LaPresto
Systems Engineer
Senior Consultant
Sally McCartney
Gregory Plautz, M.D., Ph.D.*
James Saporito
Suyu Shu, Ph.D.*
Susan Staugaitis, M.D., Ph.D.*
Steven Toms, M.D., M.P.H.
Head, Section of Metastatic Disease
Executive Director of Development
Kristin Swenson, MBA*
Marketing Associate
Martha Tobin*
Continuing Medical Education
Bruce Trapp, Ph.D.*
Sherri Wilson
Raymond Tubbs, D.O.*
Tanya Wray, MBA*
Michael A. Vogelbaum, M.D., Ph.D.
Marketing Manager
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
Cancer Center
Research Support
Joanne Civic
Robert Gerlach
Hematology & Medical
Oncology
Bryan Williams, Ph.D.*
John Pellecchia
Kathy Robinson
Brian Bolwell, M.D.*
Nursing/Physician Assistants
Cathy Brewer, R.N.
Medical Oncology
David Peereboom, M.D.
Head, Section of Medical Oncology
Patricia Weiss, R.N.
How to Refer a Patient to the Cleveland Clinic Brain Tumor Institute
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.
2005 Annual Report
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
A team approach to individualized care
45