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

How to Refer a Patient to the Cleveland Clinic Brain Tumor InstituteMembers of the Brain Tumor Institute are available for consultation 24 hours a day, seven days a week. Their goal is to see patients with diagnosed or suspected brain tumors within 24 to 48 hours.

216.445.8971 or 800.553.5056, ext. 58971 (weekdays 8 a.m. to 5 p.m.) for consultations and/or hospital admission.

216.444.2200 (nights and weekends). Ask for neuro-oncology staff or the chief neurosurgical or neurological resident on

call. For pediatric patients, ask for the chief pediatric neurological resident on call.

Patient appointment line:

216.445.8971 or 800.223.2273, ext. 58971

Clinical trials information:

Toll-free 866.223.8100 (Cancer Answer Line)

Cleveland Clinic Florida (Weston):

954.659.5000

For details about the Brain Tumor Institute, please visit clevelandclinic.org/braintumor

06-BTI-003

Brain Tumor Institute2005 Annual Report prepared by Gene H. Barnett, M.D., Chairman

A team approach to individualized care

III Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Table of Contents01 Letter from Chairman

02 Executive Summary

02 Invited Lectures

03 Educational Activity

04 Support and Grants

05 Membership

05 Recruitment

06 Research

07 Marketing, Advertising, Media Relations

07 Expanded Services

07 Patient Education

08 Clinical Programs

14 Clinical Research

17 Laboratory Research

26 Publications

33 Appendix A – Adult and Pediatric Clinical Trials

38 Appendix B – Charts and Statistics

39 Appendix C – Articles

44 Faculty

On the Cover: High power photomicrograph of macrophage (stained with green) showing red quantum dots phagocytized inside lysomes within the cells. These cells carry the QDots into the tumors, allowing them to be identified with optical imaging.

2005 Annual Report A team approach to individualized care �

Established in 2001, the Brain Tumor Institute (BTI) at Cleveland Clinic is among the

leading brain tumor centers in the nation. We are serving more patients than ever;

expanding our services and improving patient satisfaction; attracting world-class

physicians and scientists; making giant leaps in research and discovery; and acquiring

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

Letter from Chairman

2 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

A Team Approach

Brain Tumor Institute

Executive Summary

an increase in new patient volume of 192 percent

The vision of the BTI is fourfold:1) To provide diagnosis and comprehensive management of brain

and spinal tumors

2) To provide excellent, compassionate care to every patient

3) To advance knowledge of the causes of brain tumor develop-

ment and growth, and develop new treatment options

4) To educate the public and professionals about brain tumors

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

conducting valuable research with the goal of bringing new safe

and effective therapies to patients as quickly as possible. It is this

dedication to improving the lives of our patients and others with

brain tumors that is the cornerstone of our work.

Invited LecturesIn March 2005, the BTI hosted Morris Groves, M.D., Director of

Inpatient Services, Department of Neuro-Oncology, University of

The Cleveland Clinic BTI is a leader in the diagnosis,

treatment and research of brain tumors. Chaired by

neurosurgeon Gene Barnett, M.D., the BTI comprises a

dedicated team of specialists who share the common

goal of advancing the diagnosis, research and treatment

of brain tumors in adults and children. This group of

neurosurgeons, neuro-oncologists, medical oncologists,

neuroradiologists, radiation oncologists, neuropatholo-

gists, advanced practice nurses and nurse practitioners

collaborates on clinical management and research of

brain tumors.

This multidisciplinary approach is used to diagnose and treat

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.

2005 Annual Report A team approach to individualized care �

Texas MD Anderson Cancer Center. Dr. Groves spoke on “Anti-

Invasion 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.

Elinzano spoke on “Imaging Angiogenesis in Gliomas.” The BTI

also hosted Maciej Mrugala, M.D., from Massachusetts General

Hospital, who spoke on “Primary Central Nervous System

Lymphomas - Can we predict response to chemotherapy?”

In October, the BTI hosted Simon Lo, M.D., Assistant Professor

of Clinical Radiation Oncology from the Indiana University

Medical Center. Dr. Lo discussed “The Role of Gamma Knife

Radiosurgery in the Management of Unresectable Gross Disease

or Gross Residual Disease After Surgery in Ependymoma.”

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.”

Educational ActivitiesContinuing Medical EducationSupporting 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,

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

Country Club in Canton, Ohio, in August 2005. Michael

Vogelbaum, M.D., Ph.D., presented on Intracerebral Delivery

of Chemotherapy for Brain Tumors. Recent advances in neuro-

oncology and the possible patient benefit of Convection

Enhanced Delivery were discussed.

The BTI’s Gamma Knife Center, under the direction of John

Suh, M.D., continues to be a major thrust for the BTI. In 2005,

radiosurgeons treated the 1,500th patient since the center

opened in 1997. The BTI is one of only three centers in the world

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

in 2005, in addition to a two-day internal training course for

residents, fellows and Cleveland Clinic staff in January.

Professional EducationSponsoring 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.

to Individualized CareGamma Knife Radiosurgery Course

� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

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.

In 2005, the BTI published its first edition of outcomes. The

report is a brief summary of the department and a synopsis of its

surgical statistics and outcomes, with a comparison to published

standards and benchmarks. The outcomes booklet was mailed

to appropriate physician specialties across the country.

The BTI continues to place a high priority on hosting and

participating in physician education. In 2006, the BTI will

host two major symposia: “Contemporary Issues in Pituitary

Disease: Case-Based Management Update”, and “Cleveland

Clinic Symposium on Convection-Enhanced Drug (CED)

Delivery to the Brain,” led by an international faculty of top

CED investigators. In May 2006, the BTI will co-sponsor the

international symposium “Neuro-Oncology 2006: Current

Concepts” in Hamburg, Germany, with University Hospital

Hamburg-Eppendorf. Also in May, the BTI will host the “3rd

Brain Tumor Summit,” focusing on glioblastoma. The BTI also

will hold five Gamma Knife radiosurgery training courses for

physicians and physicists new to Gamma Knife radiosurgery.

At the end of 2005, the BTI and Case Western Reserve University

(known jointly as the Cleveland Brain Tumor Initiative) held a Brain

Tumor Biology Retreat in Cleveland to highlight emerging areas of

investigation in the area. Scientific investigators from around the

region working in such fields as cancer, neurosciences, cell growth

and migration attended the daylong conference, with the goals of

fostering interaction and encouraging collaboration.

The program consisted of a series of short talks and an interac-

tive poster session. Some of the topics included molecular

control of tumor cell migration, suppression of brain tumor

growth by agonists of the nuclear receptor PPAR gamma,

preclinical development of glioma vaccines for immunotherapy,

and tracking the migration of human glioma cells ex vivo using

quantum dots in a tissue slice model.

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

in surgical cases of 56 percent; and an increase in Gamma

Knife cases of 47 percent. BTI physicians recorded 5,964

outpatient visits and performed 930 surgical, Gamma Knife

and Novalis procedures.

Larger Market Share. The BTI has the highest market share

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.

Support and GrantsPhilanthropy. Never before now has a group of donors been

so involved with and dedicated to the long-term success and sup-

port of the Brain Tumor Institute. Because of the generosity and

involvement of our donors, the BTI is better equipped to pioneer

advanced surgical procedures, develop more accurate imaging

techniques, investigate more effective treatments and, ultimately,

save more lives than we could alone. In January 2005, James

Saporito joined our team as the Director of Development for the

Taussig Cancer Center. Also in 2005, the Brain Tumor Institute

Leadership Board expanded membership and Norma Lerner

became our Honorary Co-Chair of the Board. The Leadership

Board is instrumental in spreading the word about the important

work being conducted by BTI physicians.

Since the BTI was formed, we have secured $13.1 million in

major pledges and contributions, including three endowed chairs.

In addition, this year the BTI obtained a challenge grant for

$750,000 for Gamma Knife Research. Our donors know that

philanthropic support is crucial if we are to continue to advance

the frontier of brain tumor treatment and research. Our needs are

great. Additional philanthropic support will help sustain our

research and educational activities for years to come.

Current Funding. Ongoing funding is crucial for BTI physicians,

researchers and scientists to continue to investigate potential

brain tumor therapies that may be used for treatment in the

future. In 2005, the BTI had 15 clinical studies funded by

corporate sponsors, seven clinical studies supported by Cleveland

Clinic, and four clinical studies funded through consortia. For

example, the BTI’s award of a UO1 grant from the NCI to Dr.

Gene Barnett to support full membership in the NABTT consor-

tium means that some of these research activities receive direct

federal support and that our patients will have access to more

clinical trials, including some that are conducted at just a few

centers across the country. Also, an NIH grant awarded to

Mladen Golubic, M.D., Ph.D., a project scientist in the BTI

laboratories, continues to support his work on the study of

5-lipoxygenases inhibition as an adjuvant glioma therapy.

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.

Ali Chahlavi, M.D., of the Department of Neurosurgery and Brain

Tumor Institute received a grant award in 2005 of $40,000 from

the Neurosurgery Research and Education Foundation (NREF).

The award money will be used to study the immunosuppressive

function of glioblastoma multiforme (GBM). “New approaches

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.”

2005 Annual Report A team approach to individualized care 5

Dr. Mladen Golubic has been awarded the National Brain Tumor

Foundation’s (NBTF) 2005 Richard A. Hollow, Jr. Quality of

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,

has been selected to receive development support from the

Innovation Validation Fund. His laboratory has been granted

$30,650 to complete the proposed work for commercial develop-

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.

MembershipCleveland Clinic will host the International Blood-Brain Barrier

Disruption Consortium mid-year meeting in September 2006.

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.

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.

Clinical Research and Cutting-Edge Clinical Trials. BTI patients

may elect experimental treatments or to participate in clinical

research projects related to their diagnosis. Various chemothera-

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-

Brain Barrier Disruption Consortium (BBBD), Radiation Therapy

Oncology Group (RTOG), Southwest Oncology Group (SWOG),

American College of Surgeons Oncology Group (ACoSOG), and

Children’s Oncology Group (COG). Cleveland Clinic BTI physi-

cians serve as national principal investigators in several of the

trials conducted by these consortia.

Below are examples of projects being conducted in our clinical

research labs.

• 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. This

clinical trial, headed by Dr. Mladen Golubic, is the first comple-

mentary and alternative medicine trial launched by the BTI. Dr.

Golubic received NCI funding for this project. This trial seeks to

reduce the degree of edema around brain tumors, a common

and often debilitating aspect of brain cancer.

• 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

tumor resection. CED allows this large molecule, which otherwise

would be excluded from the brain by the blood-brain barrier,

to reach tumor cells in the brain.

• A Phase I/II Study Utilizing the PEC Intraoperative Radiotherapy

Device for the Treatment of a Resected Solitary Brain Metasta-

sis. 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

immediately, while sparing the rest of the brain from radiation.

• Phase 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

of GBM cells. This study follows initial encouraging data reported

by Dr. Michael Vogelbaum in his trial of erlotinib for recurrent

GBM. The study is headed by Dr. David Peereboom.

• 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.

• Phase III Trial comparing Whole Brain Radiation Therapy versus

Whole Brain Radiation Therapy plus Efaproxiral for Women with

Brain Metastases from Breast Cancer. Dr. Suh is the PI for this

international phase III trial of a novel radiosensitizer.

• 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.

� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

BTI clinical investigators continually are developing various

experimental treatment protocols for brain tumor and neuro-

oncology patients. At the BTI’s Center for Translational Therapeu-

tics (CTT), directed by Dr. Michael Vogelbaum, preclinical testing

of the most promising anticancer agents into Phase I and II

clinical trials is under way, giving brain tumor patients more

therapeutic treatment options.

Testing of new agents involves evaluating the toxicity and efficacy

of these compounds in the laboratory and in animals that have

brain tumors. We also are investigating the optimal route of

delivery of these drugs.

Because many new therapeutic agents cannot penetrate the

central nervous system, center researchers are exploring

alternative delivery methods. In addition to investigating the

efficacy of oral delivery, researchers evaluate the efficacy of the

agents when delivered intracerebrally – directly into the brain –

via a specialized neurosurgical technique called convection-

enhanced delivery (CED).

The staff at the CTT is focused on translating these preclinical

results into Phase I and II clinical trials - giving the brain tumor

patient more therapeutic treatment options by broadening the

horizon of potential tools we may use to manage this deadly disease.

The CTT has started research projects with several pharmaceuti-

cal 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, 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.

Other projects are focused on developing methods to improve

immune response to gliomas (in collaboration with Dr. James

Finke), understanding the role of NFkB in regulating glioma cell

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 enhance-

ment 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 develop-

ment. 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

formation and exploring new therapeutic developments for brain

tumor treatments. One example of the promising research being

conducted by BTI physicians is Dr. Robert Weil’s research on

proteomics, which involves analyzing the human genome at

the protein level – the point at which most diseases manifest

themselves. See Appendix C for details.

Below are examples of the projects being conducted in the

basic research labs.

• Developing immunotherapy for malignant glioma using

vaccines formed by fusing tumor cells with dendritic cells

(Dr. Gregory Plautz).

• The tumor antigen profile of brain tumor stem cells is being

characterized to determine whether there are common glioma

antigens, which would make it possible to develop a standard-

ized glioma vaccine (Dr. Gregory Plautz).

• The ability of dendritic cell/tumor cell fusion vaccines and

adoptive transfer of tumor-sensitized T cells to cure established

brain tumors is being tested in mouse models as a prelude to

future clinical trials (Dr. Gregory Plautz).

• Genetic alterations and biological characterization of

primary cell cultures derived from malignant gliomas

(Dr. Olga Chernova).

• Genetic alterations in GBMs (loss or gain of 19q, 1p and other

novel alterations) and their correlations with patient survival

(Dr. Olga Chernova).

• Development of a clinical assay for detection of deletions

in CDKN2A, ARF, PTEN and p53 genes in gliomas

(Dr. Olga Chernova).

• Genotyping arrays as a prognostic tool: glioma model

(Dr. Olga Chernova).

• Distinct alteration of chromosome 1p in astrocytic and

oligodendrocytic tumors (Dr. Olga Chernova).

• An in-vitro and in-vivo model altering GBM immunosuppression

to enhance immunotherapy (Drs. Ali Chahlavi and James Finke).

Research taking place at Cleveland Clinic allows BTI physicians a greater understanding of the mechanisms of brain tumors.

2005 Annual Report A team approach to individualized care �

• NAD(P)H autofluorescence in cell death - NADH and NADPH

are pyridine nucleotides that function as electron donors in

oxidative phosphorylation ( Dr. Steven Toms).

• Role of optical nanocrystals (quantum dots) in molecular

and cancer imaging (Dr. Steven Toms).

Hundreds of basic and clinical cancer research projects are under

way here at any given time, and numerous papers are presented

annually at national and international meetings regarding

research results.

Marketing. Many marketing initiatives have been instituted to

create awareness of the BTI in 2005. Because brain tumor

patients are information savvy and seek out the latest in medical

options for their condition, the BTI Web site is a particularly

important marketing tool. Focus in 2005 has been on increasing

the presence of the Web site among the Overture (Yahoo! and

MSN) and Google search engines. The content has been optimized

to increase the natural rankings of the Web site. The BTI has also

purchased brain tumor-related words on a pay-per-click basis to

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.

Advertising. Newspaper print advertising for the Gamma Knife

Center has been expanded to the following markets: Akron/

Canton, Ashtabula, Sandusky, Toledo and Warren, Ohio. The

goal of our advertising is to increase awareness and, ultimately,

patient visits to the BTI. A BTI ad appeared in the Ohio regional

issue of Women’s Day magazine. Return on investment will be

measured for these initiatives, and this information will be used

to plan advertising for 2006.

BTI in the News. In December 2004, a high profile international

athlete was treated with Gamma Knife radiosurgery at the BTI,

for which we were able to obtain media exposure on television, in

print and on the Web. Cleveland Clinic researchers Gene Barnett

and Damir Janigro received a U.S. patent for technology they

developed to measure damage to a person’s blood-brain barrier

that may help detect new brain tumors through a simple blood

test. See Appendix I for details.

Expanded Services. BTI patients can access neuro-oncology

services not only at Cleveland Clinic’s main campus, but also at

Cleveland Clinic’s west side community hospitals (Lakewood,

Lutheran and Fairview). Additionally, Dr. Gene Barnett sees

patients in consult at the Ashtabula County Medical Center

on the far east side.

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

as access to BTI protocols through the Moll Cancer Center at

Fairview Hospital and at Lakewood Hospital.

BTI physicians work closely with neurosurgeons in Cleveland

Clinic Florida to provide services for patients. Out-of-state

patients can take advantage of the Clinic’s Medical Concierge

program, a complimentary service that offers facilitation and

coordination of multiple medical appointments; access to

discounts on airline tickets and hotels, when available; help

in making hotel reservations or housing accommodations; and

arrangement of leisure activities.

BTI and Gamma Knife Center specialists also see patients from

out of the country. The special requirements of international

patients are handled through the Cleveland Clinic International

Center. The professionals within the International Center provide

the assistance and services our international patients need to

help them feel at home while they are being treated here. We

employ a large multilingual staff, and interpreters are available

to assist patients. Our staff helps coordinate all the details of a

visit, from scheduling medical appointments and making hotel

and transportation arrangements to transferring and translating

medical records.

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

choosing between standard therapy and a clinical trial. The BTI’s

Glen Stevens, D.O., Ph.D., and Kathy Lupica, M.S.N., C.N.P., as

well as marketing associate Kristin Swenson, made information

available to patients. The BTI also sponsored a similar event for

patients and their families at the ABTA’s regional patient meeting

in Dallas, Texas, in November.

The BTI participated in the Cleveland Clinic Medical Miracles

television show in fall 2005. The Strength of the Human Spirit II

follows four patients who were diagnosed with different forms

of cancer and chronicles their lives before diagnosis, during

treatment and throughout their efforts to maintain a normal life.

The episode featured a female patient of the BTI whose breast

cancer metastasized to her brain and was treated with Gamma

Knife radiosurgery. The BTI also partnered with an online support

group, the Pituitary Network Association (PNA), which is an

international nonprofit organization for patients with pituitary

tumors and disorders, their families, loved ones, and the

physicians and health care providers who treat them.

Serving as a Program Model. The success of the BTI can be

measured not only by the advances made toward patient care

at Cleveland Clinic, but also by the way in which these advances

impact the treatment of brain tumor patients everywhere.

National and International interest in the BTI model of organiza-

tion is high, serving as a model for other brain tumor programs

around the country and world.

� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Clinical Neuro-Oncology Neuro-oncologists, medical oncologists, neurosurgical oncologists,

radiation oncologists, neuro-pathologists, neuroradiologists and

BTI nurses attend daily clinics and twice-weekly tumor boards.

This cooperative approach, proven in more than a decade of use,

provides for consensus management plans that are individualized

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.

Members of the team also provide long-term surveillance and

medical management of patients.

Cutting-edge experimental treatments include use of targeted

immunotoxins delivered by convection-enhanced delivery and

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 manage-

ment of brain tumors.

Methods for both surgical and nonsurgical treatments of life-

threatening 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

Brain Tumor Institute

Clinical Programs

Physicians from several different specialties within the BTI meet weekly to discuss each patient’s case and collaborate on treatment options.

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

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

conventionally.

• Intra-arterial Chemotherapy with or without Blood-Brain

Barrier Disruption (BBBD) – a procedure by which cancer-

fighting agents are delivered to the brain through the blood

stream with or without opening the normal barriers that

may prevent those drugs from entering the brain.

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

techniques, microsurgery, endoscopic surgery, computer-assisted

rehearsal of surgery, intraoperative MRI, radiation implants and

radiosurgery. The development of precision surgical navigation

systems in the late 1980s and early 1990s by the Cleveland

Clinic’s Center for Computer-Assisted Neurosurgery allows for

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 cutting-

edge 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 conven-

tional 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

2005 Annual Report A team approach to individualized care �

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

in the corner of the room, allowing the room to be fully used for

conventional procedures. Cleveland Clinic was the fourth site in the

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.

FellowshipsIn addition to being a part of the core curriculum in Neurosurgery,

the BTI is active in other areas of postgraduate education. A two-

year fellowship – one year of basic science investigation and the

other year clinical – is offered in Neurosurgical Oncology. Dr. Dae

Kyu Lee completed his clinical Neurosurgical Oncology training,

followed by Drs. Tina Thomas and John Park. Dr. Burak Sade

continues on as the BTI skull-base fellow.

Clinical Radiation Neuro-OncologyRadiation oncologists, focusing on the specific problems of brain

and spinal cord tumors, offer both traditional and innovative

treatments to ensure patients have access to a number of

technologies. In 1989, the Cleveland Clinic’s Radiosurgery

Program was the first in Ohio to treat patients with state-of-the-

art noninvasive ablative therapy using a modified linear accelera-

tor. Since 1997, a number of technologies have be introduced

including Gamma Knife, intensity-modulated radiotherapy

(IMRT), intraoperative radiation therapy (IORT), brachytherapy,

and image-guided radiation therapy (IGRT). These technologies

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

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)

to train physicians new to Gamma Knife radiosurgery.

The Model �C Gamma Knife unit – the first of its kind in Ohio

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

critical structures, such as the optic nerves and chiasm, as well

as re-treat some patients who have undergone conventional

radiotherapy. In general, Gamma Knife is used for single

treatments of focused radiation that conforms to the shape

of small tumors or lesions, while Novalis delivers fractionated

conformal treatment for larger malignant or benign tumors.

Although Novalis was originally developed to treat brain tumors,

Cleveland Clinic physicians recognized its potential for treating

extracranial tumors, particularly primary and metastatic spinal

tumors that are difficult to treat due to their proximity to critical

structures. In 2006, we have plans to promote and expand the

spinal radiosurgery program.

In addition to the Gamma Knife, linear accelerators and Novalis,

we offer intraoperative radiation therapy (IORT) with the

INTRABEAM device, a 50 kVp contact unit that is placed

in the resection cavity. We have an ongoing phase II trial

evaluating the use of INTRABEAM for patients with a single

brain metastasis that has been resected. We also offer

brachytherapy using the GliaSite balloon catheter system

and have participated in several clinical trials.

Cleveland Clinic neurosurgeons continue to perfect brain tumor resection techniques, minimizing damage to delicate brain tissue.

�0 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

A number of clinical trials sponsored RTOG, NABTT and various

pharmaceutical companies are offered here. Since 1998, the

department has been a leader in radiation sensitizer trials using

motexafin gadolinium and efaproxiral. Dr. Suh is the principal

investigator for the international phase III confirmatory study

using efaproxiral. This study will enroll 360 women from North

America, South America and Europe.

Section of Metastatic DiseaseNot long ago, the diagnosis of one or more metastases to the

brain from solid organ cancer was considered a terminal event,

with treatment limited to palliative whole brain radiotherapy. As

central nervous system involvement occurs in about one fourth

of patients with such cancers, brain metastases took a terrible

human toll, being the cause of death in just a few months in

most affected patients.

Today, aggressive management, aided by a variety of effective

treatments, often can lead to indefinite or extended control of

even multiple brain metastases in patients with controlled or

limited systemic disease. At the BTI, a multidisciplinary team

of specialists, led by Dr. Steven Toms, evaluates patients and

applies one or more individualized treatments to secure control

of newly diagnosed or recurrent brain metastases.

SurgerySurgery, in addition to whole brain radiotherapy, has been shown

to be more effective than radiotherapy alone for patients with

single brain metastases. Even in patients with multiple brain

metastases, surgical resection leads to survival comparable to

those patients with single resected lesions. Pioneers in contem-

porary 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

radiotherapy, surgery in conjunction with placement of carmus-

tine wafers may thwart local recurrence. Also, BTI clinical

researchers are investigating the role of intracavitary liquid

brachytherapy and intraoperative radiotherapy after resection

with the hope of obviating the need for whole brain radiotherapy.

Today, surgery may be part of a comprehensive management

plan, where other techniques are brought to bear on additional

brain metastases not amenable to radiotherapy. Beyond

radiotherapy, staged therapy options include stereotactic

radiosurgery, intra-arterial chemotherapy with or without blood-

brain barrier disruption, and newer systemic chemotherapies.

RadiosurgeryIn many ways, brain metastases are ideally suited for treatment

with stereotactic radiosurgery such as the Gamma Knife. Lesions

are typically small and spherical, and they displace, rather than

infiltrate, normal brain tissue. Results from radiosurgery appear

comparable to those achieved by surgery with radiotherapy and

allow for effective treatment even for surgically inaccessible

tumors. Radiosurgery may also reduce the chance of leptomenin-

geal spread as a result of surgery for certain tumor types.

So-called “radio-resistant” tumor types (e.g., melanoma, renal

cell carcinoma) respond as well to stereotactic radiosurgery as

do “radio-sensitive” tumors. Neurologic morbidity is low when

dosing is prescribed at levels set by the Radiation Therapy

Oncology Group, of which Cleveland Clinic is an active member.

Cognitive side effects are minimal as the treatment is confined

to small brain regions.

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

2005 Annual Report A team approach to individualized care ��

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 radio-

surgery,” 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.

ChemotherapySystemic cancers that are chemotherapy sensitive often take

refuge in the brain, despite systemic control, as most commonly

used chemotherapies have poor penetration through the blood-

brain barrier. Management of such tumors may take several

forms. Patients with metastatic breast cancer to the brain with

tumors that are estrogen-receptor positive may respond to high-

dose tamoxifen, thereby compensating for the drug’s limited

penetration of the brain. Alternatively, temozolomide, a relatively

new orally-administered methylating agent has excellent

penetration into the brain and may be considered for some

patients. More intensive treatment includes use of chemotherapy

injected directly into the carotid vertebral arteries, at times using

hypertonic mannitol to disrupt the blood-brain barrier from

preventing active agents from reaching adequate concentrations

in brain metastases.

Small MoleculesAn exciting area of investigation is the use of small targeted

molecules to treat a variety of malignancies. As the molecular

characterization of various tumors improves, investigational drugs

that target specific molecular pathways may play an increasing

role in the management of brain metastases, and even leptomen-

ingeal disease. The use of these agents and appropriate modes of

delivery are and will continue to be a major thrust of BTI clinical

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

Knife radiosurgery and the remainder had conservative treatment.

These numbers represent one of the largest in the country for

specialized benign tumor management.

Dr. Lee, the Director of CNBT, had six articles and nine papers

accepted for publication. He currently is editing a major

landmark textbook on meningiomas consisting of 70-plus

chapters, with contributions from more than 50 international

leaders in all the basic and clinical disciplines related to

meningiomas. This book is planned for early 2007 publication.

Additionally, a three-year research grant was award to Dr. Lee

by the Integra Neurosciences Foundation for the study of dural

reconstruction following skull base and meningioma surgery.

Dr. Lee also was an invited lecturer at annual meetings of the

Korean Skull Base Society, the European Skull Base Society

and the North American Skull Base Society.

Neuro-Endocrine CenterThe Neuro-Endocrine Center has shown continuous growth since

its inception in 2002, fostered by a close working relationship

among the BTI and the departments of Endocrinology, Diabetes

and Metabolism; Neurological Surgery; Neuro-Ophthalmology;

and Radiation Oncology. The close relationship has led to the

development of highly integrated clinical care pathways, a

common pituitary tumor research database and several joint

research projects (see below).

Clinical Care PathwaysClinical 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 ActivitiesA 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

�2 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

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

acquisition and accurate three-dimensional surface localization.

All three 1.5 Tesla systems at the main campus have been

upgraded in the last year, and are located immediately adjacent

to the Gamma Knife Center. These new systems include

upgraded gradient capabilities, an extensive variety of phased

array coils and the software to perform parallel imaging tech-

niques, allowing reduce imaging time, reduce inherent MR

imaging artifacts and improve spatial resolution. One of these

1.5 Tesla systems has a wide, short bore to accommodate our

larger and claustrophobic patients, without the limitations of the

low-field open systems. A 3.0 Tesla whole-body system has

been installed at Cleveland Clinic’s Mellen Center to provide

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

and phased-array technology. The 3 Tesla system serves

as the primary magnet for functional MR studies.

Neuro-Oncology NursingNurses, physician assistants and technicians specializing in the

care of patients with brain tumors are an integral part of the BTI.

Members of the nursing and physician assistant team, which

includes Cathy Brewer, Gail Ditz, Sandra Ference, Michele Gavin,

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

opinion or when they come to the outpatient department.

Lisa Sorenson works with patients at the Cleveland Clinic main

campus, Lakewood and Fairview hospitals, as well as with the

Blood-Brain Barrier Disruption (BBBD) program.

Kathy Lupica facilitates our monthly Brain Tumor Support

Group. She also provided patients with information at the

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 retrospec-

tive 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, neuro-

ophthalmology, 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

Group), continue. These sessions are open to all interested

parties and are held the first Monday of the month in the

Department of Pathology.

Neuro-RadiologyThe Section of Magnetic Resonance Imaging at Cleveland Clinic

provides a wide array of diagnostic capabilities for routine

imaging studies as well as research projects in support of the

BTI. During the last two years, there has been a dramatic

increase in availability to high-field imaging within Cleveland

Clinic hospitals with the installation of a large number of new

magnets. This enables our patients and physicians to schedule

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

campus, and the images are transmitted digitally so they are

immediately available for comparison with prior studies on the

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

to our referring physicians. At the moment, imaging workstations

exist across Cleveland Clinic so the referring services have direct

digital access to the images.

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

preoperative planning studies at all of our facilities. At our main

campus, we also provide MR perfusion imaging, diffusion tensor

imaging, functional MRI and MR spectroscopy for more advanced

preoperative planning. Between our own MR physicists and

neuroradiology physicians, as well as our research affiliations

with Siemens Medical Systems and Massachusetts General

Hospital, we’re able to provide access to a host of new software

and hardware for the management of our patients. The most

Cleveland Clinic specialists are pioneers in developing new methods of intergrating image data with surgery

2005 Annual Report A team approach to individualized care ��

BTI’s exhibit at the ABTA’s patient meetings in Chicago, Ill.,

and Dallas, Texas, in 2005.

Nurse practitioner Sandra Ference manages patients undergoing

BBBD or intra-arterial chemotherapy.

Cathy Brewer and Carol Patton assist with patients who are

interested in participating in or who currently are involved in

research protocols.

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

Pediatric and Young Adult Brain Tumor ProgramDr. Joanne Hilden, Chair of the Department of Pediatric Hematol-

ogy/Oncology, and Dr. Bruce Cohen, BTI staff member, co-direct

the Pediatric and Adolescent Brain Tumor Program. A multidisci-

plinary brain tumor clinic for children and adolescents with brain

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.

Chemotherapy and radiation therapy are delivered under the

oversight of that team, resulting in continuity of care. The nurse

practitioner/RN team handles follow-up calls at home to ensure

the efficacy of pain control and other medical issues, which

results in fewer emergency room visits.

BTI Clinical and Clinical Research AdministrationIn 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,

which includes two surgical and one nonsurgical program.

The BTI’s clinical research infrastructure is fully integrated with

that of the Cleveland Clinic Taussig Cancer Center’s Experimental

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

Program, including IRB submissions (e.g., protocols amendments,

safety reports), protocol budget creation, nursing assignment

and study start-up. Material is dispersed from this central resource

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

Reserve University and University Hospitals of Cleveland.

This new relationship provides the opportunity to integrate

an outstanding group of cancer researchers and a large cancer

referral network at one of the nation’s most renowned hospitals

based at Cleveland Clinic, with Northern Ohio’s only National

Cancer Institute-designated Comprehensive Cancer Center

based at Case.

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.

With this integration, the Case Comprehensive Cancer Center

has strengthened its scientific programs, expanded opportunities

for disease-focused research, and enhanced access and ability

to serve the entire population of Northeast Ohio.

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.

Neuro-Oncology Nursing

�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

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.

�) 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 interna-

tional principal investigator for a large randomized trial testing

standard whole brain radiation therapy with supplemental

oxygen, with or without concurrent RSR3 (efaproxiral), in

women with brain metastases from breast cancer.

�) Intra-arterial chemotherapy with blood-brain barrier

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-

tium. Two clinical trials are available for patients with PCNSL

(newly diagnosed and recurrent), and one is available for

patients with recurrent or progressive high-grade gliomas. Drs.

Glen Stevens and David Peereboom have played an integral

role in the clinical management of the patients undergoing the

procedures. Dr. Lilyana Angelov has developed a consortium-

wide database for the tabulation of treatment results of this

procedure for patients with PCNSL. The BTI staff has contrib-

uted to the writing of protocols for the consortium as well as

making several presentations at the consortium’s annual

meetings. Several staff members also have contributed to

publication of the proceedings from this meeting.

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

organs for systemic delivery. BTI neurosurgeons are actively

enrolling patients in a clinical trial of IL13-PE38QQR for

patients with newly diagnosed GBM. Dr. Michael Vogelbaum

serves as PI for this trial.

�) Anaplastic Oligodendrogliomas – Members of the BTI have

initiated a trial with the NCI-sponsored clinical trial group

RTOG. This study, titled “A Phase II Trial of Pre-irradiation and

Clinical Protocols/ResearchBrain 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

institute’s clinical investigators. We are proud to have active

participation in the NABTT Consortium. BTI physicians serve

as protocol chairpersons for this consortium as well as others

including RTOG and the BBBD. Patients may choose to partici-

pate in multicenter management trials from these consortia as

well as the SWOG, ACoSOG or COG.

Protocols and associated clinical programs include:

�) Erlotinib Trials – The BTI initiated a Phase II trial evaluating

erlotinib for the treatment of recurrent/progressive glioblas-

toma multiforme (GBM). Erlotinib is a selective EGFR kinase

inhibitor small molecule drug, which is used in patients with

lung and pancreas cancer. The BTI has two trials for patients

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

the drug in the patient’s tumor. All research costs are being

absorbed by the BTI; Genentech is providing the drug at

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

and temozolomide for patients with newly diagnosed GBM.

The trial opened in 2004 and accrual is expected to be

complete in 2006.

A complete arrary of laboratory facilities and expertise allows us to pursue both basic science and translational research on new therapeutics

Brain Tumor Institute

Clinical Research

2005 Annual Report A team approach to individualized care �5

Concurrent Temozolomide in Patients with Newly Diagnosed

Anaplastic Oligodendrogliomas and Mixed Anaplastic

Oligoastrocytomas,” is chaired by Dr. Michael Vogelbaum;

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

of the next RTOG clinical trial for patients with anaplastic

gliomas. Another multicenter trial, initiated at Cleveland Clinic

by Dr. David Peereboom, also tests the use of chemotherapy

as initial management for patients with pure and mixed

anaplastic oligodendrogliomas. This trial is nearing completion.

�) Complementary and alternative medicine – Dr. Mladen

Golubic has received NIH funding for the first BTI trial of

complementary and alternative medicine. His trial, “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 Multi-

forme,” seeks to minimize brain edema in patients with GBM.

The above clinical trials represent only a portion of those studies

being offered by the BTI. A full listing of clinical trials is included

in the Appendix of this report.

Section of Metastatic DiseaseClinical Research ProjectsPhase I/II Study of Intraoperative Radiotherapy for Newly

Diagnosed Supratentorial Brain Metastasis Using the

“Photon Radiosurgery System”

Multicenter trial using a unique intraoperative radiotherapy device

(the “Photoelectic Cell”) to deliver radiotherapy after the resection

of brain metastases. Currently open and enrolling patients.

The Detection of Glial Tumor Margins and Intraoperative

Optical Spectroscopy

An intraoperative spectroscopy unit designed for the detection of

tumor margins in glial surgery. Currently in data acquisition phase

to improve probe algorithms prior to trials designed to test efficacy.

Radiation OncologyProject �. A Phase III, Randomized, Open-label, Comparative

Study of Standard WBRT w/O2 w/ or w/o RSR–13 in women

with Brain Metastases from Breast Cancer. The Sponsor is Allos

Therapeutics. IRB #6795. The Principal Investigator is Dr. John

Suh and this project is open.

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

project closed in 2005.

Project �. A Phase III Randomized Study of Radiation and

Temozolomide (IND #60,265) vs. Radiation Therapy & BCNU

for Anaplastic Astrocytoma and Mixed Anaplastic Oligoastrocy-

toma. The Sponsor is RTOG. IRB #3939. The Principal

Investigator is Dr. John Suh and this project is open.

Project �. Prospective study on the short-term adverse effects

from Gamma Knife radiosurgery (IRB #8078). Principal

investigator is Dr. Suh and this study is open.

Project 5. Prospective analysis of wellness for patients with non-

malignant conditions (IRB #7992). Principal investigator is Dr.

Suh and this project is open.

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.

The radiation modalities used include external beam radiation

therapy, intensity-modulated radiation therapy (IMRT), image-

guided radiation therapy (IGRT), Gamma Knife radiosurgery

and brachytherapy. In addition to brain tumor patients, Dr. Suh

also sees patients with vascular and functional disorders such as

AVM and trigeminal neuralgia who are treated with the Gamma

Knife. Dr. Suh also sees an assortment of other patients in the

Department of Radiation Oncology as the need arises.

Dr. Suh’s clinical research activities focus on enrolling patients

onto various cooperative group, in-house and pharmaceutical-

sponsored studies. He serves as the principal investigator for an

international Phase III study for women who develop brain metas-

tases from breast cancer. This trial uses an allosteric modifier of

hemoglobin, efaproxiral, to enhance oxygen delivery to hypoxic

regions. This is a confirmatory study based on the REACH study,

which he served as co-principal investigator. Dr. Suh also directs

the research efforts for the RTOG and serves as the principal

investigator for Cleveland Clinic, which is one of RTOG’s 32 full-

member institutions and was the 11th leading enroller in 2005.

Dr. Suh serves on the steering committee for the brain tumor

section of RTOG. Over the past year, he has written and

collaborated on multiple manuscripts with residents in Radiation

Oncology and Neurosurgery. He also gave numerous national

and international presentations regarding his research.

Dr. John Suh serves as the Principal Investigator on the

following IRB-approved databases:

Glioblastoma multiforme registry (IRB 6852)

Acoustic neuroma registry (IRB 6988)

Brain metastases registry (IRB 6989)

Low-grade glioma registry (IRB 6990)

Pituitary adenoma registry (IRB 6991)

Meningioma registry (IRB 7044)

Heterotopic bone registry (IRB 7045)

Gamma Knife radiosurgery patient list (IRB 7068)

Clinical Medical OncologyDr. David Peereboom’s activities related to the Brain Tumor

Institute have comprised approximately three fourths of his

clinical efforts, the remainder being connected to attending on

�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

the inpatient services of the Hematology/Oncology Teaching

Service, Consultation Service and non-BTI outpatient activities.

His clinical trial activity has included authorship and study

chair for three multicenter trials:

1) Continuous Dose Temozolomide in patients with Anaplastic

Mixed and Pure Oligodendrogliomas. This trial involves nine

centers and is the first multicenter trial authored and conduct-

ed by the Cancer Center. To date, 55 of 60 planned patients

have entered the study.

2) BMS 247550 in Recurrent High-grade Gliomas for NABTT.

This trial completed accrual in November 2005 with a

manuscript in preparation.

3) Erlotinib and Sorafenib in Recurrent High-grade Gliomas

for NABTT. This trial will open in 2006.

4) Phase I / II Pilot Study of Patients with Brain Metastasis

Secondary to Breast Cancer Treated with Methotrexate and

Carboplatin in Conjunction with BBBD, with Concurrent

Trastuzumab in HER-2 Postitive Patients for Blood-Brain

Barrier Disruption Consortium. This trial will open in 2006.

In addition, another trial, titled “Erlotinib/temozolomide/radiation

therapy for patients with newly diagnosed glioblastoma” has been

activated, and 25 of 30 planned patients have been enrolled. Dr.

Peereboom has also been active in accrual and management of

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

BBBD Consortium in the development of trials and will serve

as co-principal investigator on an upcoming breast cancer brain

metastasis trial.

Clinical Neuro-OncologyDr. Glen Stevens is the Section Head of Adult Neuro-Oncology

at the BTI and provides longitudinal management as well as

consultative services. He is co-PI of the Cleveland Clinic’s NIH-

supported NABTT program and manages day-to-day medical

activities in NABTT trials, along with research personnel in the

institute and Cleveland Clinic Cancer Center. He is active in

SWOG as well as the Blood-Brain Barrier Consortium. He also

was the local principal investigator on the GO (Glioma Outcomes)

project. Dr. Stevens often participates in the brain tumor support

group and also has an interest in the diagnosis and treatment of

neurofibromatosis in adults.

Pediatric Neuro-OncologyDrs. Bruce H. Cohen and Joanne Hilden lead the Pediatric and

Adolescent Brain Tumor Program. Dr. Cohen is an internationally

known pediatric neuro-oncologist. He is active in many clinical

research activities including serving as Chairman of CCG-99703C

Infant Brain Tumor Study, Children’s Cancer Group; Chairman

of Low-Grade Astrocytoma Discipline Committee, Children’s

Oncology Group; a member of the Brain Tumor Strategy

Committee, Children’s Oncology Group; and a member of

the Professional Advisory Board, The Gathering Place.

Dr. Hilden, Chair of Pediatric Oncology, participates in two brain

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

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.

2005 Annual Report A team approach to individualized care ��

Dr. Gene Barnett, Chairman of the Brain Tumor Institute,

and Dr. Robert Weil serve as co-directors of Neuro-oncology

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 neurosur-

geon Steven A. Toms, M.D., M.P.H., on proteomics research.

Although the field of proteomics is still in its infancy, the BTI is

committed to pursuing this field of research.

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 high-

throughput 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

relevant publications published or in press:

�. Gliomas and Glioblastomas.Li et al, details our continuing work in protein profiling of brain

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

Brain Tumor Institute

Laboratory Research

Implantable osmotic pumps are used to deliver drugs to the brain

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.

Vogel TW, Zhuang Z, Vortmeyer AO, Furuta M, Lee YS, Zeng W,

Oldfield EH, Weil RJ. Protein and protein pattern differences

between glioma cell lines and glioblastoma multiforme. Clinical

Cancer Research, 11: 3624-3632, 2005. [PMID: 15897557]

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].

Zeng W, Navaratne K, Prayson RA, Weil RJ. Aurora B expres-

sion correlates with aggressive behavior in glioblastoma

multiforme. In press, J Clin Pathol, 2006

2. Using novel technologyWith 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

systems, another unique and simple method to use visible light

to identify individual tumor cells, and avoid normal brain cells

and white matter, which may help guide us to more extensive but

safer surgical procedures.

Sinha TK, Miga MI, Cash DM, Galloway RL, Weil RJ. Intraopera-

tive 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

�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

deformations using a laser range scanner. IEEE Transactions on

Medical Imaging, 24: 767-81, 2005. [PMID: 15959938]

Toms SA, Lin WC, Weil RJ, Johnson MD, Jansen ED, Mahadevan-

Jansen A. Intraoperative optical spectroscopy identifies infiltrating

gliomas margins with high sensitivity. Neurosurgery 57 [ONS

Suppl 3]: 382-291, 2005. [PMID: 16234690].

Lin WC, Mahadevan-Jansen A, Johnson MD, Weil RJ, Toms SA.

In vivo optical spectroscopy detects radiation damage in brain

tissue. Neurosurgery, 57: 518-525, 2005. [PMID: 16145531]

�. Brain metastasis, especially from breast cancerAnother interest is the development of metastasis to the central

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

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

histologically, is the strongest marker yet identified.

Weil RJ. CNS Metastases. In: Sid Gilman, Editor-in-chief,

Neurobiology of Disease, San Diego: Elsevier, 2006.

Weil RJ, Palmieri D, Bronder JL, Stark AM, Steeg PS. Breast

cancer metastasis to the central nervous system. American

Journal of Pathology, 167: 913-920, 2005. [PMID: 16192626]

Weil RJ, Lonser RR. Selective Excision of Metastatic Brain

Tumors Originating in the Motor Cortex with Preservation of

Function. Journal of Clinical Oncology, 23: 1209-17. 2005.

[PMID: 15718318]

Hicks DG, Short SM, Prescott NL. Tarr Sm, Coleman KA, Yoder

BJ, Crowe JP, Choueiri TK, Dawson AE, Pettay J, Budd GT,

Tubbs RR, Seitz R, Ross D, Weil RJ. Breast cancers with brain

metastasis are more likely to be estrogen receptor negative,

express the basal cytokeratin CK 5/6 and over-express HER2 and

EGFR. In press, American Journal of Surgical Pathology, 2006.

�. microRNA and mRNA.Finally, in Vatolin et al., we describe a new area of interest,

micro RNA. This paper describes a potentially novel and

universal method to figure out how these micro RNAs work

and influence normal RNA function.

Micro RNAs (miRNAs) are a unique class of small, non-coding

RNA gene whose final product is an approximately 22 nucleotide

(nt) functional RNA molecule. They appear to be critical regulators

of numerous targets genes. miRNAs act in at least one of two

ways: by binding complimentary sites on target mRNAs to induce

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

found that a small RNA identified in the nematode C. elegans, lin-

4, regulated another gene, lin-14, through direct interactions with

lin-4 mRNA. Since then, investigations have revealed a rich

tapestry of short RNA activities, which suggests that miRNAs

play a potentially vast and pivotal role in the regulation of many

eukaryotic genes, with diverse effects in apoptosis, development,

gene imprinting, metabolism, and tumorigenesis. For example,

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-

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

precursors are made (which bind their targets with near-perfect

complimentarity), bio-informatic prediction models for eukaryotic

miRNAs and their targets have proven less informative.

To overcome some of these barriers, we recently developed a

novel method that detects intact miRNA-mRNA complexes in

eukaryotic cells. First, we use reverse transcription of cytoplas-

mic extract to increase the length of a miRNA by extending it

with cDNA on the template of a target mRNA. This step

minimizes non-specific annealing in a second round of reverse

transcription, which in turn creates cDNA molecules (“miRNA

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.

Vatolin S, Navaratne K, Weil RJ. A novel method to detect

functional miRNA targets. Journal of Molecular Biology 358(4):

983-996, 2006. [PMID: 16564540.]

Most recently, Brain Tumor Institute laboratory researchers

have conducted groundbreaking genomics work focused on the

molecular basis of chemotherapy resistance in gliomas, which

has led to the development of a number of clinically useful

diagnostic tests for brain tumor patients. Ongoing basic

research involves the study of three novel genes in pediatric and

adult brain tumors and the development of an implantable

optical spectroscopy unit to provide clinicians with immediate

feedback on the efficacy of chemotherapy.

2005 Annual Report A team approach to individualized care ��

Role of Optical Nanocrystals (Quantum Dots) in

Molecular and Cancer Imaging – Quantum dots are

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 tomogra-

phy as well as optical imaging. Coreshell zinc sulfide-

cadmium selenide quantum dots were studied in

magnetic resonance and computed tomography

phantoms. In addition, the Qdots were injected

into rat brain using convection-enhanced delivery,

intravenously to co-localize with rat brain tumor

models, and studied with CT and MRI. Data suggests

that current formulations of Qdots are phagocytized

by macrophages and co-localize with brain tumors

in vivo after IV injection. Phantoms and CED imaging

of animals show that Qdots may be imaged with CT,

but not MRI, suggesting that quantum dots have the

potential to function as multimodal imaging platforms

in vivo.

Steven Toms, M.D., directs the Section of Metastatic

Disease for the BTI and devotes the majority of his

clinical operating time on intraoperative monitoring,

awake craniotomy techniques and intraoperative

ultrasound.

Current translational research involves identifying and developing

new compounds that are directed against targets relevant to

malignant gliomas.

Center for Translational Therapeutics“Translating Novel Therapies for Malignant Brain Tumors from the Bench to the Bedside”The cornerstone of the BTI is the Center for Translational

Therapeutics. Directed by Dr. Michael Vogelbaum, aggressive

preclinical testing of the most promising anticancer agents is

under way. One goal of the center is to accelerate the lengthy

and expensive process of testing new drugs targeted against

brain tumors and to safely move them into clinical trials as

quickly as possible, for the benefit of patients.

Physicians, researchers and scientists involved in this center

work with both pharmaceutical companies and other medical

institutions to identify, obtain and test new compounds. The

center’s multi-million dollar efforts, including an international

search for all potential brain tumor-relevant therapies, have

yielded several promising agents for testing.

Testing of new agents involves evaluating the toxicity and efficacy

of these compounds in the laboratory and in animals that have

brain tumors. In addition, we also are investigating the optimal

route of delivery of these drugs.

Because many new therapeutic agents cannot penetrate the

central nervous system, center researchers are exploring

alternative delivery methods. In addition to investigating the

efficacy of oral delivery, researchers evaluate the efficacy of the

agents when delivered intracerebrally – directly into the brain –

via a specialized neurosurgical technique called convection-

enhanced delivery (CED).

The staff of the center is focused on translating these preclinical

results into Phase I and II clinical trials – giving the brain tumor

patient more therapeutic treatment options by broadening the

horizon of potential tools we may use to manage this deadly disease.

The CTT has started research projects with a number of pharmaceu-

tical and biotechnology companies, ranging in size from small

startup firms to some of the largest publicly traded companies.

What these companies have in common are novel drugs that are

close to or are in clinical trial and which are rationally designed to

be effective against malignant gliomas given the molecular and

genetic makeup of these tumors. These drugs are targeted against

molecules such as EGFR, VEGFR, Fas/Apo2, mTOR/Akt, Jak/STAT3

and Raf-1 kinase. Our first translational clinical trial is with Tarceva/

OSI-774, a selective EGFR kinase inhibitor small molecule drug.

CTT Staff Include:Director: Michael A. Vogelbaum, M.D., Ph.D.

Project Scientist: Baisakhi Raychaudhuri, Ph.D.

Technical Assistant: Hamid Daneshvar

Section of Metastatic Disease“Optical Adjuncts to Brain Tumor Therapy” NAD(P)H Autofluorescence in Cell Death – NADH and

NAD(P)H are pyridine nucleotides that function as electron

donors in oxidative phosphorylation. The pyridine nucleotides

also function as antioxidants in mitochondria and serve as major

intracellular fluorophores in their reduced states. Our long-term

goal is to design optical sensors to gauge the effectiveness of

chemotherapeutic drugs by measuring changes in NAD(P)H

fluorescence. We hypothesize that NAD(P)H fluorescence

declines prior to apoptotic cell death. We have observed that

1) the NAD(P)H fluorescence emission peak from UV wavelength

excitation is lost during a variety of insults, including hyperther-

mia, sodium azide poisoning and chemotherapy; 2) mass

spectrometry of cell lysates treated with chemotherapy shows

NAD(P)H losses that parallel cellular fluorescence declines; and

3) the decline in cellular fluorescence precedes nuclear conden-

sation and cell viability loss during apoptosis. Based upon these

observations, we are submitting grants to examine the role of

NAD(P)H in apoptosis, focusing upon changes in fluorescence

signal that may be used to detect cell and tissue viability.

20 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Molecular Genetics and Molecular Neuro-OncologyDr. Olga Chernova leads or participates in projects one through

five, while Dr. Mladen Golubic does so for projects six and seven.

Project �. Genetic alterations and biological characterization of

primary cell cultures derived from malignant gliomas. The initial

objectives of this project were a) finding conditions for establish-

ing short-term primary cultures from glial tumors that would

serve as a model for studies of glial tumors; b) establish a

method for fast and reliable evaluation of homogeneity of tumor

culture that would allow monitoring of culture content in different

growth conditions since variable contamination with normal cells

represented a problem. In a course of the work, we found that

modified medium used for propagation of normal neural stem

cells allow selective isolation of tumor cells in primary culture.

A genotyping assay was established, which allows semi-quantita-

tive evaluation of the homogeneity of the cultures. The growing

interest to the role of the stem cells in tumorigenesis prompted

a characterization of the origin and differentiation status of the

cultured tumor cells in collaboration with Dr. Robert Miller. Using

a set of antibodies detecting several neural stem cells markers, at

least two types of glioma cultures, which may potentially originate

from different pools of the neural stem cells, have been identified.

Analysis of tumorigenic potential of these primary tumor cultures

in nude mice is in progress.

Growing interest in stem cells in brain tumors resulted in two

collaborative projects with Cleveland Clinic researchers: (1) a

collaboration with Dr. Gregory Plautz to develop a vaccine for

brain tumors resulted in submission of RO1 NIH proposal; (2)

a collaboration with Drs. Jaharul Haque and Michael Vogelbaum

to study signal transduction pathways and gene expression in

brain tumor stem cells.

Project 2. Genetic alterations in GBMs (loss or gain of ��q, �p

and other novel alterations) and their correlations with patient

survival. Several recently published initial observations indicate

that numerical alterations in chromosomes 1p and 19q may be

predictive of clinical response or survival of patients with GBM.

To confirm and expand these initial observations, well-controlled

groups of 34 patients with newly diagnosed GBMs treated at

Cleveland Clinic and demonstrated either long (>20 months) or

short (between three and nine months) survival were selected.

Ten LOH markers distributed along 1p arm and 4 markers along

19q arm were used. Preliminary data indicate that both types of

allelic imbalance, loss or gain, of 1p and/or 19q could be found

in GBM tumors and occur in both groups of patients. However,

to complete this study, the same tumors should be analyzed

using FISH or multiplex PCR techniques to discriminate true

losses of chromosomes from their gains. Forty percent of the

specimens were analyzed by FISH at the Molecular Pathology

lab. The rest of the specimens are currently studied using

multiplex PCR assays for 1p and 19q. A recently developed

MLPA technique for multiplex PCR analysis of 1p/19q is being

used. This part of the study is in progress.

As an extension of this project, Drs. Chernova, Weil (BTI) and

Wigler (Cold Spring Harbor Laboratory) collaborated. Dr. Wigler

developed a high-density microarray-based comparative genomic

hybridization assay for analysis of numerical alterations in

genomic DNA. Using a set of six DNAs from long-term and

short-term surviving patients with GBM, preliminary data

was obtained that indicates the assay is extremely sensitive

and was able to identify novel regions of alterations.

Project �. Development of a clinical assay for detection of

deletions in CDKN2A, ARF, PTEN and p5� genes in gliomas.

We have developed a semi-quantitative assay for detection of

gene deletions based on multiplex PCR. The goal of the project

is development, validation and introduction of this prognostic

assay to the clinical laboratory. This assay will also be impor-

tant for the “Genotyping Arrays” project as a part of validation

of the array data.

Project �. Genotyping arrays as a prognostic tool: glioma

model. This project is a collaboration with Cleveland BioLabs

and the microarray manufacturing company Nimblegen. The aim

of the project is to develop a genotyping microarray-based assay

that will identify alterations in chromosome copy number and

allelic imbalances in critical chromosomal regions, as well as

mutations in genes that have prognostic significance in glial

tumors and predict response to therapy. Amended STTR

proposal had been resubmitted to the NIH in October 2005.

Project 5. Distinct alteration of chromosome �p in astrocytic

and oligodendrocytic tumors. The extent of 1p deletion in low-

and high-grade gliomas using LOH analysis was characterized.

The results indicate that oligodendroglial tumors almost uniformly

demonstrate very large deletions of 1p arm. Conversely, GBMs

have only partial deletions affecting the terminal part of 1p. This

data indicate that (1) only large deletions on 1p are associated

with positive prognosis (need to perform more statistical

analysis), and (2) partial 1p deletions in GBM are not associated

with positive prognosis (see also GBM survival project).

Project �. Role of Eicosanoids in Glioblastoma Tumorigenesis.

Eicosanoids are special type of fats produced in the human

body from diet-derived fats by the action of enzymes called

cyclooxygenases (COX-1 and COX-2) and lipoxygenases.

We have determined that 5-lipoxygenase (5-LO), an enzyme

that stimulates inflammation, is aberrantly overexpressed in

malignant brain tumors, anaplastic astrocytoma and GBM.

The two main interconnected aspects of this project are (1)

to investigate the expression of other eicosanoid enzymes of

the 5-LO pathway in the GBM tumor tissue and measure

eicosanoids in the blood of patients with GBM; and (2) to

explore novel ways to inhibit 5-LO and COX-2, the two main pro-

inflammatory enzymes that are aberrantly overexpressed in GBM.

To inhibit 5-LO, we are examining the use of Boswellic acids.

2005 Annual Report A team approach to individualized care 2�

Boswellic acids are naturally found in the gum resin exudate from

the Boswellia serrata (frankincense) tree. The herbal preparation

from B. serrata will be used in combination with a low-fat diet as

an adjuvant therapy for patients with GBM in a clinical study (see

Project 6. Molecular characterization of genes that are modulated

by Boswellic acids in GBM cells currently is in progress. The

levels of eicosanoids are measured not only in blood of patients

with GBM, but also in tumor tissue specimens that were surgically

removed. The goal of this collaborative study with Dr. Robert

Newman from the MD Anderson Cancer Center is to correlate

levels of eicosanoids in tumor tissue and blood with clinical

outcomes of patients with GBM.

To suppress the aberrantly overactive COX and 5-LO enzymes in

GBM cells, we are investigating the potential anticancer effects of

an anti-inflammatory herbal preparation (Zyflamend, by New

Chapter, Inc.). It consists of standardized extracts from 10 different

spices (including turmeric, ginger, rosemary and oregano) and

medicinal herbs. We have shown that Zyflamend induces

programmed cell death of GBM cells in vitro and inhibits produc-

tion of eicosanoids in surgically removed GBM tissue specimens.

This work is done in collaboration with Dr. Newman’s laboratory

and is supported by the research grant from New Chapter, Inc.

Recently, we identified more than 150 genes that are either

induced or suppressed in expression when GBM cells are treated

with Zyflamend. Currently, the functional significance of two of

those genes is being investigated further. The obtained results

were presented at the Annual Research Conference of the

American Institute for Cancer Research in Washington, D.C., in

July 2005, and at the 2nd International Conference of the Society

for Integrative Oncology in San Diego, Calif., in November 2005.

Project �. 5-Lipoxygenase Inhibition as an Adjuvant Glioma

Therapy A two-year clinical study supported by a grant from

the National Institutes of Health is currently in progress.

This study builds on knowledge obtained in this laboratory and

from clinical experience by German investigators. The primary

objective is to determine whether a suppression of pro-inflamma-

tory enzymes, including 5-LO, by a combination of an herbal

formulation and a diet can reduce brain swelling caused by GBM.

As brain swelling often causes symptoms, possible effects on

quality of life and survival of patients with GBM will also be

examined. Patients with a newly diagnosed GBM after surgical

removal of the tumor and radiation therapy will be randomly

assigned to two groups. The patients in the intervention group

will use a B. serrata herbal preparation (containing naturally

occurring inhibitors of 5-LO enzyme) in combination with a low-fat

vegan diet as an adjuvant to their main treatment. The control

group will eat a diet according to the guidelines by the American

Cancer Society, also as an adjuvant to their main treatment.

Molecular Biology of Brain Tumors Dr. Andrei Gudkov has established a facility aimed at identifica-

tion of molecular targets and development of target-based

therapies for treatment of brain cancer, based on an integrated

technological platform that includes: 1) gene target identification

based on the combination of novel functional genomic approach-

es with global gene expression profiling and advanced bioinfor-

matics and 2) identification of bioactive compounds with the

desired properties, using small molecule screening facility,

followed by pharmacological optimization of primary hits.

Dr. Gudkov is applying the established technology pipeline to the

generation of a genetic database and identification of candidate

genes associated with brain tumor development and progression,

with specific focus on tumor suppressor genes, drug sensitivity/

resistance genes and diagnostic markers. The aims of this work

are to: 1) identify and test prospective therapeutics among secreted

or membranal protein products of identified disease-specific genes;

2) develop high throughput technology of isolation of new anticancer

therapeutics by screening chemical libraries for prospective gene-

or pathway-specific drugs based on the discovered genes; and 3)

develop diagnostic assays that will grade tumor type and stage

of progression, facilitate selection of optimal therapy, provide an

accurate and reliable prognosis, and initiate a broad program of

clinical validation based on the selected combinations of candidate

disease-specific genes. This effort has already resulted in identifica-

tion of two prospective anticancer treatment molecular targets

that are currently being used for small molecule screening. A small

molecule inhibitor of multidrug resistance with a new mechanism

of activity associated with MRP1 and other multidrug transporters,

4H10, capable of sensitizing glioma cells to a variety of anticancer

agents has been isolated.

The initial stages of this project were funded by a Finding the

Cures for Glioblastoma Award and by the Technology Action

Fund of Ohio Award.

Blood-Brain Barrier, Tumor Markers and Human Gliomas Project Previous attempts in this and other laboratories have failed to

achieve growth of a variety of malignant brain tumors consis-

tently in vitro, perhaps due to the non-physiological conditions

that traditional tissue culture provides. We are attempting to

grow malignant brain tumors (oligodendroglioma and glioblas-

toma) under so-called “dynamic conditions” in a 3-D tissue

culture apparatus where glia-endothelial co-culturing promotes

the establishment of a physiologic blood-brain barrier. When

a blood-brain barrier is formed, we position either solid or

disassociated tumors in the abluminal chamber in direct

proximity to normal glia (astrocytes). We will initially study the

ability of these human tumors to grow under dynamic conditions.

Genotyping and tumor mass determinations will be used to evalu-

ate similarity of growth patterns in vitro vs. in vivo. We also

propose to examine direct vs. indirect drug resistance of the

tumor by injecting chemotherapeutic agents either directly into

the abluminal site or intraluminally, where a blood-brain barrier

separates the “blood compartment” from the brain tumor itself.

22 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Another focus of this laboratory is to determine the role of S100

as a potential tumor marker. We are examining changes in S100

level with blood-brain barrier disruption and its correlation with

metastatic and glioma tumor burden. Related projects by Dr. Yan

Xu are examining phospholipid antibodies as a potential tumor

marker. Other markers of deranged p53 mechanisms and small

molecule modulators of blood-brain barrier function are evaluated

by Dr. Andrei Gudkov.

Immunology and Immunotherapy

New approaches are requisite if malignant gliomas are to be

treated successfully. Immunotherapy is an attractive approach in

this disease; however, this form of treatment has not been very

successful clinically. Growing evidence suggests that the poor

response to immunotherapy is likely due to the inability of current

therapeutic approaches to adequately reverse immune suppres-

sion. It is been well-documented that patients with gliomas are

characterized by systemic immune dysfunction, as demonstrated

by impaired cell-mediated immunity, lymphopenia and inability

Table �. Members of the Division of Pathology and Laboratory Medicine Actively Participating in Molecular Neuropathology

Project as of 9/30/05.

NeuropathologistsRichard Prayson, M.D. Specimen diagnosis. Validation of immunohistochemistry reagents Susan Staugaitis, M.D., Ph.D. Specimen diagnosis. Liaison among Pathology Laboratories and Clinicians for Molecular

Neuropathology test development and interpretation. Maintenance of Pathology Glioma Database. Consultant for BTI database.

MolecularGenetic PathologistsRaymond Tubbs, D.O. Director of Molecular Genetic Pathology Laboratory. Supervision of FISH. Review

of FISH results with technologists.Supervision research and development of array- based hybridization assays.

Ilka Warshawsky, M.D., Ph.D. Supervision DNA extraction, PCR based assay development, review of validated PCR based assays.

Gary W. Procop, M.D., Review of FISH results with technologists. James R. Cook, M.D., Marek Skacel, M.D.

Molecular Pathology TechnologistsJames Pettay, M.T. (ASCP), Supervisor, CLIA Compliance Molecular Genomic Laboratory

Marybeth Hartke, B.S., M.T.(ASCP) Development and validation of FISH Assays. Performance of FISH analyses

Kelly Simmerman, M.T. (ASCP), Performance of FISH analyses Karen Keslar, M.S., Rosemary Neelon, B.S.

Tissue Procurement TechnologistsJessica Krimmel, B.S., Transport and processing of blood and tissues from OR. Communications Barbara Bekebrede, B.S., with BTI Specimen Bank Technologists. Jessica Roman, B.S., Carrie Nedbalski

Immunohistochemistry TechnologistsGloria Willis-Eppinger, H.T.(ASCP) Lab Coordinator

Renata Klinkosz, B.S., M.T., Sectioning blocks for immunohistochemistry and genotyping, development and performance of Kathy Maresco, B.S., M.T.(ASCP), immunohistochemistry assays Michelle Wayman, B.S., H.T.(ASCP), Derek Mangalindan, B.S., M.T.

Reference LaboratoryMary Ann Kannenberg, B.S., M.T.(ASCP) Manager, Laboratory Services

(Reference Laboratory).

Kathy Leonhart, Client Services (Marketing)

Laboratory Information SystemsDale Duca Lead Systems Analyst. Contact for development of mechanisms for ordering and reporting test

results in CoPath, transfer to hospital information systems (LastWord, Epic, searches of CoPath for transfer of info to BTI database.

2005 Annual Report A team approach to individualized care 2�

Table 2: Summary of Molecular Genotyping Tests available during Reposting

Period 10/1/04 – 9/30/05.

Test Target specimens Status of test

FISH for 1p/19q All gliomas “FISH for 1p/19q” ordered as a single procedure within CCF and through CCF Reference Laboratory. 1p and 19q may also be ordered individually.

EGFR FISH High grade gliomas Orderable clinical test within CCF and through CCF Reference Laboratory. Tests are also performed on low grade gliomas of CCF patients and billed to research accounts.

1p LOH by PCR Performed upon request to characterize, Orderable clinical test within CCF and through CCF in greater detail, genetic alterations on Reference Laboratory. Chromosome 1p

19q LOH by PCR Performed upon request to characterize, CCF Technical Validation nearly completed. in greater detail, genetic alterations Two tests performed. on Chromosome 19q

TP53 sequencing Upon request on selected anaplastic Orderable clinical test within CCF and through CCF (exons 5-8) oligodendrogliomas. Immunohistochemistry Reference Laboratory. for p53 (>50% of cells positive) is predictive of mutation in most cases.

Table �. Numbers of Molecular Genotyping tests performed by Specimen Class*.

Specimen Class FISH FISH FISH �p LOH ��q LOH TP5� SEQ Totals for �p for ��q for EGFR** by PCR by PCR

Routine Surgical 83 83 73 3 2 0 244 (SX)

Surgical Outside 11 11 5 0 0 0 27 Review (SO)

Surgical Reference 11 7 2 0 0 0 20 Lab Consult (SRC)

Procedure Only 106 106 0 1 0 0 213 (PRS)

Totals 2�� 20� �0 � 2 0 50�

* Specimen Classes SX and SO are patients treated by BTI Physicians.** Numbers to not include approximately 13 tests performed on low grade gliomas of CCF patients and billed to research accounts.

680 surgical procedures were performed in 2005

2� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

to mount delayed-type hypersensitivity reaction. Indeed some

of the immune suppression is likely related to the fact that a

higher percentage of T cells from glioma patients are undergoing

apoptosis as compared to T cells from healthy individuals. It is

important at this time to not only focus on boosting the immune

response to GBM but also to include a second arm in the

therapeutic strategy that will prevent the immune cells from

undergoing tumor-induced immune suppression. Previously we

showed that GBMs mediate immune suppression via promoting

T-cell death through receptor-dependent and receptor-indepen-

dent apoptotic pathways.

Recently we reported that gangliosides produced by GBM

lines contribute to the induction of T-cell apoptosis, since the

glucosylceramide synthase inhibitor PPPP significantly reduced

the abilities of all four GBM apoptogenic lines to kill lymphocytes

(Chahalvi A, et al. Cancer Research 2005). HPLC and mass-

spectroscopy demonstrated that GM2, GD3 and GD1a were

expressed by all four apoptogenic GBM-lines, but not by the two

GBMs lacking activity. The expression of GM2, GD3, GD2 and

GM1 has been recently demonstrated by immunostaining of

GBM lines with antibodies specific for each of these gangliosides.

To define the relative contribution that each of these gangliosides

makes to the tumor-induced killing of T cells, antibodies specific to

each of the gangliosides were added to co-culture of T cells and

CCF-52 cells. The antibodies or isotype control Ig was added at

the beginning of the cultures. These studies revealed that anti-

GM2 antibody was most effective at blocking T cell apoptosis,

while anti-GM1 displayed modest activity, and antibodies to GD2

and GD3 were ineffective. Thus, GM2 expressed by CCF-52 plays

an important role in promoting T-cell apoptosis. These studies are

being repeated using the other GBM lines, CCF4 and U87.

Additional supporting data demonstrating that GM2 is apopto-

genic for T cells was provided by transfecting CCF-52 tumor

cells with siRNA for GM2 synthase. Such treatment causes a

significant reduction in the expression of GM2 that is observed

within 24 hours and lasts for over 72 hours. RT-PCR analysis of

mRNA from these transfected cells revealed that messenger RNA

for GM2 synthase was reduced within 12 hours, with optimal

suppression occurring at 48 hours. The reduction in GM2 expres-

sion following transfection with siRNA for GM2 synthase was

selective since there was no decrease in the expression levels

of GM1 and GD3. Most important, the loss of GM2 expression

coincided with a reduction (50 percent) in the ability of CCF-52

to induce apoptosis in normal T lymphocytes. Similar studies are

planned for the other GBM lines.

Recent findings suggest GM2, which is produced by the CCF-52

cell line, is shed into the supernatant, where it can then bind T

cells. Immunofluorescence staining with anti-GM2 antibodies

demonstrated that T cells from normal individuals do not express

detectable GM2. However, after a one- to two-day incubation of

these T cells with conditioned medium from cultured CCF-52

cells, GM2 was detected by anti-GM2 antibody staining. The

expression of GM2 coincided with the appearance of apoptosis in

the T cells exposed to CCF-52 supernatant but not T cells cultured

in media alone. Similar findings were observed when T cells from

normal donors were co-cultured with a monolayer of CCF-52 cells.

We are now interested in analyzing T cells from GBM patients to

determine whether a portion of these cells are GM2 positive and

whether the presence of GM2+ T cell correlates with increased

levels of GM2 in patient plasma and with T-cell apoptosis.

We are currently testing whether the iron chelator/antioxidant

desferoxamine (DFO) is able to protect T cells in rats that bear the

syngenic transplantable tumor, S635. Previously, we showed that

in vitro DFO can protect T-cells from apoptosis induced by isolated

GBM gangliosides and GBM cell lines by 45 to 85 percent. New

studies show that administration of DFO via an implantable pump

can significantly reduce the percentage of apoptotic T cells that are

present in the peripheral blood and tumor. We are in the process

of testing whether DFO administration will enhance the antitumor

activity of adoptively transferred T cells derived from the draining

lymph nodes of S636-bearing mice.

Cerebrovascular Research Center Dr. Damir Janigro leads the Cerebrovascular Research Center

in cooperation with Dr. Luca Cucullo.

Alternating current electrical stimulation enhanced chemotherapy:

a novel strategy to bypass multidrug resistance in tumor cells.

BMC Cancer. 2006 Mar 17;6(1):72 PMID: 16545134

Tumor burden can be pharmacologically controlled by inhibiting

cell division and by direct, specific toxicity to the cancerous tissue.

Unfortunately, tumors often develop intrinsic pharmacoresistance

mediated by specialized drug extrusion mechanisms such as P-

glycoprotein. As a consequence, malignant cells may become

insensitive to various anticancer drugs. Recent studies have shown

that low intensity, very low frequency electrical stimulation by

alternating current (AC) reduces the proliferation of different tumor

cell lines by a mechanism affecting potassium channels while

intermediate frequencies interfere with cytoskeletal mechanisms of

cell division. The aim of the present study is to test the hypothesis

that permeability of several MDR1 over-expressing tumor cell lines

to the chemotherapeutic agent doxorubicin is enhanced by low

frequency, low intensity AC stimulation.

We grew human and rodent cells (C6, HT-1080, H-1299, SKOV-

3 and PC-3), which over-expressed MDR1 in 24-well Petri

dishes equipped with an array of stainless steel electrodes

connected to a computer via a programmable I/O board.

We used a dedicated program to generate and monitor the

electrical stimulation protocol. Parallel cultures were exposed

for three hours to increasing concentrations (1, 2, 4, and 8 m)

of) M doxorubicin following stimulation to 50 Hz AC (7.5 mA)

or MDR1, inhibitor XR9576. Cell viability was assessed by

determination of adenylate kinase (AK) release. The relationship

between MDR1 expression and the intracellular accumulation

2005 Annual Report A team approach to individualized care 25

of doxorubicin as well as the cellular distribution of MDR1

was investigated by computerized image analysis immunohisto-

chemistry and Western blot techniques.

By using a variety of tumor cell lines, we show that low frequen-

cy, low intensity AC stimulation enhances chemotherapeutic

efficacy. This effect was due to an altered expression of intrinsic

cellular drug resistance mechanisms. Immunohistochemical,

Western blot and fluorescence analysis revealed that AC not only

decreases MDR1 expression but also changes its cellular distribu-

tion from the plasma membrane to the cytosol. These effects

synergistically contributed to the loss of drug extrusion ability

and increased chemosensitivity.

In the present study, we demonstrate that low frequency, low

intensity alternating current electrical stimulation drastically

enhances chemotherapeutic efficacy in MDR1 drug-resistant

malignant tumors. This effect is due to an altered expression

of intrinsic cellular drug resistance mechanisms. Our data

strongly support a potential clinical application of electrical

stimulation to enhance the efficacy of currently available

chemotherapeutic protocols.

Surgical EngineeringWork in this area was led by Dr. Barnett and Eric LaPresto

and focused on two areas: (1) Development of a brain image

processing program capable of fusing up to 64 sets of images

(CT, MRI, PET, DTI, etc) and correlating location and intensity of

any given point (voxel) over time. This program has moved into

frequent clinical use to fuse low-resolution imaging (such as PET)

with MRI, as well as new modalities such as MR and CT blood

volume imaging. It also has proved useful showing trends in

tumor size over time. (2) Ongoing development of the BTI

research/clinical database – a secure repository of clinical

information, imaging, pathology and results of molecular

investigations in a Web-accessible, IRB-approved format.

IL-�� Induction of Glioma ApoptosisDr. Martha Cathcart directs work in this laboratory that has been

defining the relevant IL-13 receptors in several cell types and

identifying the downstream signal transduction cascades. Her lab

is interested in understanding the IL-13-mediated induction of

apoptosis, the regulation of IL-13 signal transduction pathways

and the regulation by receptor composition. To date Dr. Cath-

cart’s laboratory has identified the heterodimeric receptor

molecules, IL-13Ra1 and IL-4 receptor. They associate with

activated Jak family members, Jak2 and Tyk2. These tyrosine

kinases then phosphorylate Stats 1, 3, 5 and 6. Stats 1 and 3

are also phosphorylated on serine 727 in an IL-13-dependent

manner. Recent studies indicate the Stat serine phosphorylation

is regulated by both p38 MAP kinase as well as PKCd. Her

laboratory is interested in understanding the alternative signal

transduction pathways utilized in normal cells versus glioblas-

toma cells to further understand IL-13 induction of apoptosis.

Recent data indicate the existence of a novel signalosome

complex that is induced by IL-13 and contains Src kinase, p38

MAP kinase, PKCd and Stat3. Each of these molecules has been

shown to be required for 15-lipoxygenase expression, which

appears to regulate apoptosis.

Molecular Pathology of Gliomas: “Glioma Genotyping”Reporting period: 10/1/04 through 9/30/05

During the past reporting period, it was decided that the initiative

for development of tests for possible translation into the clinical

laboratory would begin in the research labs of the BTI. Once the

research laboratories concluded that a specific test was feasible

on biopsy and surgical specimens, and the clinicians indicated

that the results of such tests would be used in treatment

planning, Dr. Susan Staugaitis would bring the test proposal to

the clinical laboratory for prioritization in their test implementa-

tion schedule and assist in coordinating efforts for technical

validation, ordering and reporting.

Several improvements for glioma genotyping ordering and execution

have occurred in the past reporting period. All glioma genotyping

tests are now ordered directly within the Pathology Information

System, CoPATH. This streamlines the process and permits

retrieval of test information for annual reports and other operational

purposes. Microdissection of samples for DNA extraction and LOH

was transferred to the technologists in the Immunohistochemistry

Laboratory. This laboratory performs the microdissection for colon

cancer microsatellite analysis by the same techniques as the glioma

specimens and permits adequate volume to maintain expertise in

the technique by several technologists.

Transcription Factors and Brain Tumors Dr. Michael Vogelbaum directs work in this laboratory. Patients

with malignant gliomas continue to have a very poor prognosis

despite multiple new approaches to their treatment. In particular,

most of these tumors are resistant to DNA-damaging treatments,

including radiation therapy and most standard forms of chemo-

therapy. A growing body of evidence supports the hypothesis that

aberrant activation of key transcription factors is critical for the

development and progression of these tumors. A greater under-

standing of the biology of these transcription factors should help

us develop new, more effective therapeutic modalities.

In collaboration with Dr. Jaharul Haque, Institute’s Department

of Cancer Biology, we have found two transcription factors,

STAT3 and NF-kB, which are aberrantly constitutively activated

in malignant gliomas. Activation of these transcription factors

results in resistance to chemotherapy and/or radiation therapy,

and stimulates tumor cell invasion. The mechanisms underlying

constitutive activation of these transcription factors are being

actively investigated, and we are investigating methods to

reverse the biological effects mediated by these factors.

Together we have received a research grant from the National

Cancer Institute and additional submissions are planned.

2� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Paper Published or In PressBatra PS, Citardi MJ, Lee JH, Bolger W, Roh HJ, Lanza DC. Endoscopic resection of sinonasal malignancies: A preliminary Report. Am J of Rhinology. 2005. In press.

Batra PS, Citardi MJ, Worley S, Lee JH, Lanza DC. Resection of anterior skull base tumors: Comparison of combined traditional and endoscopic techniques. Am J of Rhinology 2005; 19:521-528.

Chahlavi A, Rayman P, Richmond AL, et al. Glioblastomas Induce Apoptosis of T Lymphocytes By Two Distinct Pathways Involving Gangliosides and CD70. Cancer Research 2005; 65(12):5428-38.

Chahlavi A, Staugaitis SM, Yahya R, Vogelbaum MA. Intracranial collision tumor mimicking an octreotide-SPECT positive and FDG-PET negative meningioma. J Clin Neurosci 2005; 12(6):720-3.

Chao ST, Lee SY, Borden LS, Joyce MJ, Krebs VE, Suh JH. External beam radiation helps prevent heterotopic bone formation in patients with history of heterotopic ossification. J Arthroplasty 2005. In press.

Chao ST, Joyce MJ, Suh JH. Treatment of heterotopic ossification. Orthoped 2005. In press.

Chen PG, Lee SY, Barnett GH, Vogelbaum MA, Saxton JP, Fleming PA, Suh JH. Use of the RTOG RPA classification system and predictors for survival in 19 women with brain metastases from ovarian cancer. Cancer 2005. In press.

Chen PG, Lee SY, Barnett GH, Vogelbaum MA, Saxton JP, Fleming PA, Suh JH. Use of the Radiation Therapy Oncology Group recursive partitioning analysis classification system and predictors of survival in 19 women with brain metastases from ovarian carcinoma. Cancer 2005; 104(10):2174-80.

Cohen BH. Altered States of Conscious-ness. In: Maria BL. Current Management in Child Neurology, 3rd Edition. BE Decker, Hamilton, Ontario, Canada. 2005; 551-562.

Cohen BH. Mitochondrial Cytopathies. In: Maria BL. Current Management in Child

Neurology, 3rd Edition. BE Decker, Hamilton 2005; 551-562.

Doolittle ND, Abrey LE, Blyer WA, et al. New frontiers in translational research in neuro-oncology and the blood-brain-barrier: report of the tenth annual blood-brain barrier consortium meeting. Clinical Cancer Research 2005; 11:421-8.

Dreicer R, Byzova T, Plow E, Klein E, Peereboom D, Elson P. Phase II trial of GM-CSF + thalidomide in patients with androgen-independent metastatic prostate cancer. Urol Oncol 2005; 23:82-6.

Farag E, Deboer G, Cohen BH, Niezgoda J. Metabolic acidosis due to propofol infusion. [comment]. Anesthesiology. 2005; 102(3):697-8.

Farray D, Ahluwalia M, Cohen B, et al. Pre-irradiation 9-Amino [20s] camptoth-ecin (9-AC) in patients with newly diagnosed glioblastoma multiforme. Invest New Drugs. 2005 Aug 2.

Fritz M, Sade B, Wood B, Lee JH. Benign fibrous histiocytoma of the pterigopala-tine fossa with intracranial extension. Acta Neurochirurgica date. 2005 Feb 25. In press.

Hartsell WF, Scott CB, Watkins Bruner D, et al. Phase III randomized trial of 8 Gy in 1 fraction vs. 30 Gy in 10 fractions for palliation of painful bone metastases: Analysis of RTOG 97-14. J Natl Ca Inst 2005. In press.

Hughes G, Lee JH, Ruggieri P. Cystic lesions of the petrous apex. In: Clinical Otology, 3rd Edition (Hughes & Pensak, editors). Thieme, NY, 2005. In press.

Kanner AA, Staugaitis SM, Castilla EA, et al. The Impact of Genotype on the Outcome in Oligodendroglioma: Validation of the loss of chromosome arm 1p as a factor of importance in clinical decision making. J Neurosurgery. March 2006. In press.

Kanner A, Vogelbaum M. Intraoperative MRI. In Computer Assisted Neurosurgery. Barnett GH, Robert D, Maciunas R, eds. 2005. In press.

Kelly TW, Prayson RA, Barnett GH, Stevens GHJ, Cook JR, Hsi ED. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue arising

in the lateral ventricle: case report and literature review. American J of Surg Path. 2005. In press.

Komaki R, Swan R, Ettinger DS, et al. Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) Protocol 97-12. Int J Radiol Oncol Biol Phys 2005; 62:342-350.

Latif T, Wood L, Connell C, et al. Phase II Study of Oral Bis (aceto) Ammine Dichloro (cyclohexamin) Platium (IV) (JM-216, BMS-182751) given Daily x 5 in Hormone Refractory Prostate Cancer. Invest New Drugs 2005; 23:79-84.

Lee JH, Evans JJ, Steinmetz MP, Krishnaney AA. Surgical Technique for Removal of Clinoidal Meningiomas. In: Badie B, ed. Neurosurgical Operative Atlas, 2nd ed. Neuro-Oncology. Thieme, NY: 2005. In press.

Lee JH, Krishnaney AA, Steinmetz MP, Lee DK. Intracranial Meningiomas. In: Barnett GH, ed. Computer-Assisted Neuro-surgery. 2005. In press.

Lee JH, Steinmetz M, Krishaney A, Lee DK. Intracranial Meningiomas. In: Barnett G, Roberts D, Maciunas R, eds. Computer-Assisted Surgical Navigation in Neurosur-gery. 2005. In press.

Lee JH, Sade B, Choi E, Prayson R, Golubic M. Midline skull base and spinal meningiomas are predominantly of the meningothelial histologic subtype. J Neurosurgery. In press.

Lee JH, Tobias S, Kwon, JT, Sade B, Kosmorsky G. Wilbrand’s knee: Does it exist? Surgical Neurology. In press.

Lin WC, Mahadevan-Jansen A, Weil RJ, Johnson M, Toms SA. Intraoperative optical spectroscopy accurately distin-guishes radiation necrosis versus recurrent tumor in vivo. Neurosurgery. In press.

Lin WC, Mahadevan-Jansen A, Johnson MD, Weil RJ, Toms SA. In vivo optical spectroscopy detects radiation damage in brain tissue. Neurosurgery, 57:518-525, 2005.

Lo SS, Chang EL, Suh JH. Stereotactic radiosurgery with and without whole-brain

Brain Tumor Institute

Publications

2005 Annual Report A team approach to individualized care 2�

radiotherapy for newly diagnosed brain metastases. Expert Rev Neurotherapeu-tics. 2005; 5(4):487-495.

Lonser RR, Buggage R, Weil, RJ. Malignant cerebellar swelling in a patient with neuro-Behçet’s disease. J Neurosur-gery: Pediatrics. 2005;103: 292.

Mahelas TJ, Lee JH. Neurosarcoidosis: A cause of compressive, infiltrative optic neuropathy. Ocular Surgery News. 2005; 23 (18):64-66.

Mangels KJ, Johnson MD, Weil RJ. Thoracic intermediate-grade melanocy-toma mimicking meningioma. Brain Pathology. 2005. In press.

Mason A, Toms SA, Hercbergs A. Biological Response Modifiers. In: Barnett GH, ed. Malignant Gliomas. 2005. In press.

Moulder S, Johnson D, Toms SA. Metastatic breast cancer. In: Sawaya R ed. Intracranial Metastases: Current Manage-ment Strategies. Armonk; NY: Futura Publishing Co. In press.

Nathoo N, Cavusoglu M, Vogelbaum M, Barnett G. In Touch with Robotics: Neurosurgery for the future. Neurosurgery. March 2005; 56(3):237-242.

Nathoo N, Chalavi A, Barnett GH, Toms SA. Pathobiology of Brain Metastasis. Journal of Clinical Pathology. 2005; 58:237-42.

Nathoo, N, Lautzenheiser F, Barnett GH. George W. Crile, Ohio’s First Neurosur-geon, and his relationship with Harvey Cushing. Journal Neurosurgery. 2005; 103: 378-386.

Nathoo N, Prayson R, Bodnar J, Vargo L, et al. 5-Lipoxygenase is Overexpressed in High-Grade Astrocytomas. Neurosurgery. May 2005. In press.

Nathoo N, Steiner C, Barnett G, Roberts D. Surgical Navigation System Technolo-gies. In: Barnett G, Roberts D, Maciunas R, Peereboom DM, eds. Computer-Assisted Neurosurgery. Chemotherapy in Brain Metastases. Neurosurg Suppl. Nov 2005.

Nathoo N, Nair D, Phillips M, Vogelbaum MA. Mapping prosody: correlation of functional magnetic resonance imaging with intraoperative electrocorticography recordings in a patient with a right-sided temporooccipital glioma. Case illustration. J Neurosurg. 2005; 103(5):930.

Pack SD, Qin LX, Pak E, Wang Y, Ault DO, Mannan P, Jaikumar J, et al. Common

genetic changes in hereditary and sporadic pituitary adenomas detected by compara-tive genomic hybridization (CGH). Genes, Chromosomes, and Cancer. 2005; 43(1):72-82.

Quan AL, Barnett GH, Lee SH, Vogelbaum MA, Toms SA, Staugaitis SM, Prayson RA, et al. Epidermal Growth Factor Receptor Amplification Does Not Have Prognostic Significance In Patients With Glioblastoma Multiforme. International Journal of Radiation Oncology. June 1, 2005.

Rahaman SO, Vogelbaum MA, Haque SJ. Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13R{alpha}2. Cancer Research. 2005; 65(7):2956-63.

Rahaman SO, Vogelbaum MA, Haque SJ. Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13R (alpha)2. Cancer Research. 2005; 65(7):2956-63.

Robinson CG, Prayson RA, Hahn JF, Kalfas IH, Whitfield MD, Lee SY, Suh JH. Long-term survival and functional status of patients with low-grade astrocytomas of the spinal cord. Int J Radiat Oncol Biol Phys. 2005; 63:91-100.

Sade B, Evans JJ, CY Kweon, Lee JH: Enhanced carotico-oculomotor triangle following anterior clinoidectomy: an anatomic morphometric study. Skull Base Surgery. 2005; 15: 157-162.

Sade B, Lee JH: Outcome following meningioma surgery: A personal series of 600 cases. Meningiomas. Springer-Verlag, London. In review.

Sade B, Lee JH, Lee DK. Postoperative psychosis and depression following removal of a giant skull base hemangio-pericytoma. Surgical Neurology. In press.

Sajja R, Barnett GH, Lee SY, Stevens GHJ, Lee J, Suh JH. Intensity-modulated radiation therapy (IMRT) for newly diagnosed and recurrent intracranial meningiomas: the Cleveland Clinic Foundation experience. Technol Cancer Res Treat. December 2005; 4(6): 675-682.

Schwartz SA, Weil RJ, Thompson RC, et al. Proteomic-based prognosis of brain tumor patients using direct-tissue MALDI mass spectrometry. Cancer Research. 2005; 65:7674-7681. (co-senior author).

Sinha TK, Dawant BM, Duay V, et al. A method to track cortical surface deforma-tions using a laser range scanner. IEEE

Transactions on Medical Imaging. 2005; 24:767-81.

Siomin V, Barnett G. Brain Biopsy and Related Procedures. In: Barnett G, Roberts D, Maciunas R., eds. Computer Assisted Neurosurgery. 2005. In press.

Siomin, V., Angelov, L., Liang, L.,Vogelbaum, M.A. Results of a Survey of Neurosurgical Practice Patterns Regarding the Prophylactic Use of anti-EpilepsDrugs in Patients with Brain Tumors. J. Neurooncol. 2005 Sep; 74(2):211-5.

Solares CA, Fakhri S, Batra PS, Lee JH, Lanza DC. Trans-nasal endoscopic resection of lesions of the clivus: a preliminary report. Laryngoscope. 2005; 115:1917-1922.

Song JK, Weil RJ. An unusual cause of acromegaly. Archives of Pathology & Laboratory Medicine. 2005; 129:415-416.

Spencer A, Lee JH, Prayson RA. Optic nerve choristoma: A case report and review of the literature. Ann. of Diagnostic Path. 2005; 9:348-354, 2005.

Steinmetz MP, Krishnaney AA, Lee DK, Lee JH. Convexity Meningiomas. In: Badie b, ed. Neurosurgerical Operative Atlas 2nd Edition. Neuro-Oncology. New York; NY: Thieme 2005. In press.

Stevens G. General Consideration. In: Barnett GH. High-grade Gliomas. Totowa; NJ: Humana Press. 2005. In press.

Stevens GHJ. Antiepileptic Drug Use in Patients with Brain Tumors. Profiles in Seizure Management. 2005; 4:4-9.

Stevens GHJ. Antiepileptic therapy in patients with central nervous system malignancies. In: Lesser G, ed. Current Treatment Options in Oncology. 2005. In press.

Suh JH, Stea B, Nabid N, et al. Results from a phase 3 study evaluating efaproxi-ral as an adjunct to whole brain radiation therapy for the treatment of patients with brain metastases. J Clin Oncol. 2005. In press.

Tobias S, Kim CH, Kosmorsky G, Lee JH. Clinoidal Meningiomas. Surgical Manage-ment. 2005. In press.

Tobias S, Kim CH, Sade B, Lee JH. Benign neuromuscular choristoma of the trigeminal nerve in an adult. Acta Neurochir. 2005. In press.

Toms SA, Lin WC, Weil RJ, Johnson MD, Jansen ED, Mahadevan-Jansen A.

2� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Intraoperative optical spectroscopy identifies infiltrating gliomas margins with high sensitivity. Neurosurgery. 2005; 57 [ONS Suppl 3]: 382-291.

Ugokwe K, Nathoo N, Prayson R, Barnett GH. Trigeminal nerve schwannoma with ancient change. Journal Neurosurgery. 2005; 102;1163-1165.

Vogel TW, Brouwers FM, Lubensky IA, et al. Differential expression of erythropoietin and its receptor in von Hippel-Lindau-associated and MEN type 2-associated pheochromocytomas. Journal of Clinical Endocrinology and Metabolism. 2005; 90:3747-3751.

Vogel TW, Zhuang Z, Vortmeyer AO, et al. Protein and protein pattern differences between glioma cell lines and glioblastoma multiforme. Clinical Cancer Research. 2005; 11:3624-3632.

Vogelbaum MA. Convection-enhanced Delivery for the Treatment of Malignant Gliomas: Symposium Review. Journal of Neuro-oncology. 2005; 73(1):57-69.

Vogelbaum MA, Masaryk T, Mazzone P, et al. S100beta as a predictor of brain metastases. Cancer. 2005; 104(4):817-24.

Weil RJ, Lonser RR, Quezado MM. Skull and brain metastasis from tibial osteosar-coma. J Clinical Oncology. 2005; 23:4226-4229.

Weil RJ, Lonser RR. Selective Excision of Metastatic Brain Tumors Originating in the Motor Cortex with Preservation of Function. Journal of Clinical Oncology. 2005; 23:1209-17.

Weil RJ, Palmieri D, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. American Journal of Pathology. 2005; 167:913-920.

Books Barnett, GH, Maciunas R, Roberts D, eds. Computer-Assisted Neurosurgery. Ontario, Canada; BC Decker Publishing Co; 2005. In preparation.

Barnett GH, ed. High Grade Gliomas: Diagnosis and Treatment. Totawa, NY; Humana Press. 2005, In preparation.

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.

Book Chapters Barnett GH. Image-Guided Needle Biopsy. In: Advanced Techniques in Image-Guided Brain and Spine Surgery. Thieme Publisher. 2005. In press.

Barnett GH. Intraoperative MRI. Contem-porary Neurosurgery. Baltimore, MD: Williams & Wilkins. 2005. In press.

Barnett GH. Barnett GH, ed. Surgical Techniques. In: High Grade Gliomas: Diagnosis and Treatment. Totawa, NJ: Humana Press. 2005. In preparation.

Barnett GH. Molecular Classifications. In: High Grade Gliomas: Diagnosis and Treatment. Barnett GH, ed. Totawa, NJ: Humana Press. 2005. In preparation.

Barnett GH. Image-Guided Surgery. In: Neurosurgical Oncology. Black P, ed. Totawa, NJ: Humana Press. 2005. In preparation.

Cohen B. Altered States of Consciousness In: Maria BL, ed. Current Management in Child Neurology. 3rd Ed. Ontario, Canada: BE Decker, Hamilton; 2005: 551-562.

Cohen B, Nicholson C. Brainstem Gliomas. In: Schiff D, O’Neill BP, eds. Principles of Neuro-Oncology. New York, NY: McGraw-Hill; 2005: 333-342.

Cohen B. Mitochondrial Cytopathies. In: Maria BL, ed. Current Management in Child Neurology. 3rd Ed. BE Decker, Hamilton; 2005: 277-284.

Prayson R, Angelov L, Barnett GH. Mixed Neuronal-Glial Tumors. In: Berger M, Prados M, eds. Textbook of Neuro-Oncology. Philadelphia, PA: Elsevier Saunders; 2005: 30: 222-226.

Siomin V, Barnett GH. Brain Biopsy and Related Procedures. In: Barnett GH, Maciunas R, Roberts D, eds. Computer-Assisted Neurosurgery. Ontario, Canada: BC Decker, Hamilton; 2005. In preparation.

Suh JH, Barnett GH. Radiosurgery. In: Barnett GH, ed. High Grade Gliomas: Diagnosis and Treatment. Totawa, NJ: Humana Press; 2005. In preparation.

Vogelbaum M and Kanner A. Intraopera-tive MRI. In: Barnett G, Maciunas R, Roberts D, Marcel Dekker, eds. Computer-Assisted Neurosurgery. New York, NY: Inc. Publishers; 2005. In press.

Vogelbaum M and Siomin V. Image-guided Treatment of Metastatic Brain Tumors. In: Barnett G, Maciunas R, Roberts D, eds. Computer-Assisted Neurosurgery. New York, NY: Marcel Dekker Inc. Publishers; 2005. In press.

Abstracts Angelov L. The use if tissue equivalent Super Stuff Bolus ™

material to treat skull metastases with Gamma Knife Radiosurgery. 7th Interna-tional Stereotactic Radiosurgery Society Congress: Poster Presentation. Brussels, Belgium; September 2005.

Angelov L. Blood Brain Barrier Disruption and Intra-Arterial Methotrexate theray for Primary CNS Lymphoma: The Cleveland Clinic Experience. 2005 Congress of Neurological Surgeons Annual Meeting: Talk & Poster Presentation. Boston, MA; Oct 2005.

Brewer CJ, Suh JH, Stevens GHJ, et al. Phase II trial of erlotinib with temozolo-mide and concurrent radiation therapy in patients with newly-diagnosed glioblastoma multiforme. J Clin Oncol. June 1, 2005; 23(16):130S-130S Part 1 Suppl. S.

Chao ST, Barnett GH, Toms SA, et al. Salvage Stereotactic Radiosurgery Effectively Treats Recurrences from Whole Brain Radiation Therapy. ASTRO, 2005.

Fleseriuu M, Weil RJ, Prayson, Hamrahian AH. Lack of significant immunostaining for growth hormone in patients with acro-megaly. Poster presented at: 7th International Pituitary Conference, June 2005, San Diego, CA. Selected for endocrinology fellow’s research award.

Haut JS, Klaas PA, Cohen BH. Cognitive Decline in a 10-Year-Old with MELAS: Regression or Developmental Plateau? The Clinical Neuropsychologist. 2005.

Peereboom DM, Brewer C, Schiff D, et al. Phase II multicenter study of dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma. Neuro-Oncol. 2005; 7:401. (Abstract 470)

Peereboom D, Carson K, Lawson D, Lesser G, Supko J, Grossman S for The New Approaches to Brain Tumor Therapy Consortium. A phaseI/II trial of BMS-247550 for patients with recurrent high-grade gliomas. Proc Am Soc Clin Oncol. 2005; 23:129s. (Abstract 1563)

Pineyro M, Makdissi A, Hamrahian AH, et al. Poor correlation of serum alpha subunit with postsurgical pituitary MRI in patients with nonfunctional pituitary adenomas: The Cleveland Clinic Experience. Poster presented at: Endocrine Society, 87th Annual Meeting; June 2005; San Diego, CA.

2005 Annual Report A team approach to individualized care 2�

Usmani A, Makdissi A, Hamrahian A, Reddy S, Weil R, et al. Hypothalamic-pituitary-adrenal axis testing using a twenty-five microgram Cotrosyn stimula-tion test. American Academy of Clinical Endocrinologists 2005 Annual Meeting.

Weil R, DeVroom, Vortmeyer A, et al. Adeomas confined to the neurohypophysis in Cushing’s Disease. Endocrine Society 87th Annual Meeting; June 2005; San Diego, CA.

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 Sympo-sium, Lake Buena Vista, FL; Jan 2005.

Barnett GH. Moderator: Gliomas II. Cleveland Clinic Neuro-oncology Sympo-sium, Lake Buena Vista, FL; Jan 2005.

Barnett GH. Stereotactic Frame Applica-tion, Introduction to Planning System, Gamma Knife Shot Strategy, Functional Planning and Procedures, AVM Planning. Cleveland Clinic Gamma Knife Course, Cleveland, OH; April 2005.

Barnett GH. Practical Course 386/387: Non-Invasive Preoperative and Intraopera-tive Brain Mapping. American Association of Neurological Surgeons Annual Meeting, New Orleans, LA; April 2005.

Barnett GH. Moderator: Scientific Session I: Tumors, American Association of Neurological Surgeons Annual Meeting, New Orleans, LA; April 2005.

Barnett GH, Nathoo N, Lautzenheiser F. Crile: Ohio’s First Neurosurgeon and his relationship to Harvey Cushing. American Association of Neurological Surgeons Annual Meeting, New Orleans, LA; April 2005.

Barnett GH. Stereotactic Navigation, Cleveland Clinic Neurosurgery Resident Lecture; May 2005.

Barnett GH. Stereotactic Frame Applica-tion, 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.

Lee, JH. Grand Skull base surgery: basic principles: Invited Lecture: Grand Rounds, Interdisciplinary Skull Base Surgery Conference, Cleveland Clinic, Cleveland, OH; January 2005.

Lee, JH. Unique features of meningothelial meningiomas. Invited Lecture: Cleveland Clinic Neuro-Oncology Symposium, Orlando, Florida; January 2005.

Lee, JH. Meningiomas: When and when not to operate?: Invited Lecture: Mayfield Clinic/Cleveland Clinic Neuroscience Symposium, Snowmass, CO; February 2005.

Lee, JH. Twelve years of skull base surgery: the lessons learned. Invited Lecture: Mayfield Clinic/Cleveland Clinic Neuroscience Symposium, Snowmass, CO; February 2005.

Lee, JH. When and when not to operate?: Invited Lecture: Grand Rounds, Interdisci-plinary SBS Conference, Cleveland Clinic, Cleveland, OH; March 2005.

Lee JH, Sade B, Park BJ. A novel ‘CLASS’ algorithm for patient selection in menin-gioma surgery. Oral presentation: The 7th Congress of the European Skull Base Society. Fulda, Germany; May 2005.

Peereboom DM. Hematology Oncology Associates Grand Rounds State of the Art Treatment Approaches for Brain Metasta-ses. Syracuse, NY; January 2005.

Peereboom DM. Palliative Medicine Grand Rounds Multidisciplinary Management of Brain Metastases: State of the Art 2005. Cleveland, OH; January 2005.

Peereboom DM. University of Utah Neurosciences Grand Rounds New Strategies in Primary Brain Tumors. Salt Lake City, UT; April 2005.

Peereboom DM. Failure of Chemotherapy for Brain Tumors: Focus on Drug Delivery and Drug Resistance Chemotherapy for High-Grade Gliomas: Pitfalls and Possibilities. Cleveland, OH; March, 2005.

Peereboom DM. Cleveland Clinic International Neuro-oncology Symposium. Role of Chemotherapy in High-grade Gliomas. Cleveland, OH; August, 2005.

Peereboom DM. Cleveland Clinic Neuro-oncology Symposium: Current Concepts Emerging Medical Therapies for High-grade Gliomas: Where do we stand and where are we going?. Orlando, FL; January 2005.

Peereboom DM. Cleveland Clinic NeuroOncology 2005: Current Concepts.

Clinical Trials of NABTT (New Approaches to Brain Tumor Therapy) Consortium. Orlando, FL; January 2005.

Peereboom DM. World Federation of Neuro-Oncology. Phase II multicenter study of dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma. Edinburgh, UK; May 2005.

Peereboom DM. Cleveland Clinic Taussig Cancer Center ASCO Review. CNS Malignancies. Cleveland, OH; June 2005.

Peereboom DM. The Human Epidermal Growth Factor Receptor as a Target for Therapy of Solid Tumors. Akron, OH; January 2005.

Peereboom DM. Schering-Plough Oncology North America Temodar Investigator Advisory Board Meeting .Alternative Dosing Regimens for Temo-zolomide: Do they work? Atlanta, GA; February 2005.

Peereboom DM. Schering-Plough Oncology North America Temodar Investigator Advisory Board Meeting. Temozolomide for Newly Diagnosed Pure and Mixed Anaplastic Oligodendroglioma.Atlanta, GA; February 2005.

Peereboom DM. St. Luke’s Medical Center Cancer Conference

“The Human Epidermal Growth Factor Receptor as a Target for Therapy of Solid Tumors” Madison, WI; February 2005.

Peereboom DM. Blood-Brain Barrier Consortium Meeting. State of the Art Treatment Approaches for Brain Metasta-ses. Portland, OR; March 2005.

Peereboom DM. Cleveland Metro General Hospital Oncology Speaker Series. Management of Primary Brain Tumors: 2005. Cleveland, OH; April 2005.

Peereboom DM. Gliadel Wafer Investigator Meeting. Chemotherapy for Brain Metastases: State of the Art 2005. Miami, FL; June 2005.

Peereboom DM. Glioblastoma Multiforme: The Multidisciplinary Approach to Treatment. Cleveland, OH; September 2005.

Peereboom DM. Glioblastoma Multiforme: The Multidisciplinary Approach to Treatment. Peioria, IL; November 2005.

Peereboom DM. Blood-Brain Barrier Consortium Meeting. Treatment of CNS Metastases – Summary Discussion. Portland, OR; March 2005.

�0 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Peereboom DM. Blood-Brain Barrier Consortium Meeting. Conflict of Interest Management and Policy Development for the Blood-Brain Barrier Consortium. Minneapolis, MN; September 2005.

Prayson R, Barnett GH. Current Concepts in the Diagnosis of Gliomas. United States & Canadian Academy of Pathology Annual Meeting. San Antonio, TX; March 2005.

Sade B, Lee JH. Clinoidal meningiomas: Surgical outcome in 41 patients. Oral presentation, Annual Meeting, NASBS, Toronto, ON Canada; April 2005.

Suh JH. Advances in Pituitary Radiothera-py. Pituitary update conference. Lake Buena Vista, FL; Jan 2005.

Suh JH. Moderator for new therapeutic approaches for brain tumors. Cleveland Clinic Neuro-oncology Symposium. Lake Buena Vista, FL; Jan 2005.

Suh JH. Moderator for complementary medicine for brain tumors. Cleveland Clinic Neuro-oncology Symposium. Lake Buena Vista, FL; Jan 2005.

Suh JH. Overview of Brain Metastases. European Investigator’s meeting for ENRICH study. Paris, France; Feb 2005.

Suh JH. Review of RT-009 study. European Investigator’s meeting for the ENRICH study. Paris, France; Feb 2005.

Suh JH. Management of Efaproxiral toxicity. European Investigator’s meeting for the ENRICH study. Paris, France; Feb 2005.

Suh JH. Radiation Oncology. Cleveland Clinic Taussig Cancer Center National Leadership Board meeting. Cleveland, OH; June 2005.

Suh JH. Overview of Gamma Knife Radiosurgery. Cleveland Clinic Interna-tional Neuro-oncology Symposium. Cleveland, OH; Aug 2005.

Toms SA. Optical Imaging in Neuro-Oncology: New Techniques and Their Applications. 7th Neuro-oncology Update 2005; January 2005.

Toms SA. Quantum dots detect malignant glioma. Cambridge Healthtech Institute›s 6th Annual Targeted Nanodelivery for Therapeutics and Molecular Imaging; August 2005.

Toms SA. Video presentation: «Surgical resection of brain metastasis», Congress of Neurological Surgeons; October 2005.

Toms SA. Surgical Resection of Brain

Metastasis: Basic and Special Techniques. Congress of Neurological Surgeons; October 2005.

Toms SA. Quantum dots detect malignant glioma. OpticsEast; October 2005.

Toms, SA. Quantum Dots are phagocy-tized by macrophages and detect experimental malignant glioma. Interna-tional Association for Nanotechnology; November 2005.

Usmani A, Makdissi A, Hamrahian A, Reddy S, Weil RJ, Faiman C. Hypotha-lamic-pituitary-adrenal (HPA) axis testing using a twenty-five (25) microgram Cotrosyn stimulation test. Poster presented at: American Academy of Clinical Endocrinologists, Annual meeting; 2005.

Vatolin S, Navaratne K, Weil RJ. Method for detection of microRNA targets. Plat-form presentation: RNAi course; Cold Spring Harbor Laboratory; September 28-October 2, 2005.

Videtic GM, Reddy CA, Chao ST, et al. Women with Brain Metastases from Non-Small Cell Lung Cancer Live Longer than Men: An outcomes study utilizing the RTOG RPA class stratification. ESTRO, 2005.

Vogelbaum MA. Mayfield Clinic-Cleveland Clinic-Mayo Clinic Winter Neuroscience Symposium. Overview of Convection-enhanced Delivery. Snowmass, CO; February 2005.

Vogelbaum MA. Tumor Margin Dose Affects Local Control Following Stereotac-tic Radiosurgery of Brain Metastases; February 2005.

Vogelbaum MA. Radiation Therapy Oncology Group Brain Tumor Symposium. Convection-enhanced Drug Delivery; June 2005.

Vogelbaum MA, Berkey B, Peereboom D, et al. RTOG 0131: Phase II Trial of Pre-Irra-diation and Concurrent Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendrogliomas and Mixed Anaplastic Oligodendrogliomas. ASCO, 2005.

Vogelbaum MA, Sampson JH, Kunwar S, et al. Convection-enhanced delivery of cintredekin besudotox (IL13-PE38QQR) followed by radiation therapy without and with temozolomide. A phase I study in newly diagnosed malignant glioma patients. CNS, 2005.

Vogelbaum MA, Mazzone P, Masaryk T, et al. Low serum S100 levels in patients with

newly diagnosed lung cancer correlate with an absence of brain metastases on MRI. World Federation of Neuro-Oncology, 2005.

Weil RJ, DeVroom, Vortmeyer AO, Nieman L, Oldfield EH. Adenomas confined to the neuro-hypophysis in Cushing’s Disease. Poster presented at: Endocrine Society, 87th Annual Meeting; June 2005; San Diego, CA.

Weil RJ. Advances in Tumor Diagnostics: Genomics, Epigenomics, and Proteomics. Cleveland Clinic Neuro-oncology Sympo-sium. Orlando, FL; January 2005.

Weil RJ. Potential Proteomic Approaches to Analysis of Drug Resistance Proteins in Gliomas. Invited Speaker, Cleveland Clinic Foundation Cancer Center Symposium, Failure of Chemotherapy in Malignant Brain Tumors: The Roles of the Blood-Brain-Barrier and Drug Resistance Genes. Cleveland, OH; March 2005.

Weil, RJ. CNS Metastases in Women with Breast Cancer: Challenges and Opportuni-ties. Invited speaker, Molecular and Genetic Markers in Breast Cancer Working Group and the Cleveland Clinic Women’s Center. Cleveland, OH; May 2005.

Weil RJ. Pituitary Surgery and Endoscopic Approaches: Overview, Problems, and Expectations. Invited faculty member and speaker, Cleveland Clinic Foundation Neuro-Endoscopy Surgical Techniques Course. May 2005.

Weil RJ. Pituitary Surgery: Conventional and Endoscopic Approaches. Invited speaker and faculty member, Cleveland Clinic Foundation International Neuro-oncology Symposium, Cleveland Clinic Foundation. August 2005.

Weil RJ. Invited lecturer and panelist, Congress of Neurological Surgeons. Medical and Surgical Management of Seizures in patients with low-grade gliomas. Luncheon Seminar T-24, Manage-ment of low-grade gliomas: current strategies and dilemmas. CNS Annual Meeting. Boston, MA; October 2005.

Manuscripts Submitted Angelov L, Barnett GH. Awake Craniotomy and Intra-op Imaging. In Image guided Surgery (Barnett, Maciunas,Roberts eds). Marcel Dekker, Inc. New York 2005. Submitted.

Barnett G and Thomas T. Imaged-Guided Surgery. In: Black P, ed. Neurosurgical

2005 Annual Report A team approach to individualized care ��

Oncology.

Barnett GH, Park J. Craniopharyngioma. In: Ragahaven, ed. Textbook of Uncom-mon Cancer, 3rd ed. Sent to publisher August 2005.

Chahlavi A, Borsellino S, Barnett GH, Vogelbaum MA. The use of skull-implanted fiducials for computer-assisted sterotactic brain stem and posterior fossa brain biopsies. Submitted.

Chen PG, Lee SY, Barnett GH, Vogelbaum MA, Saxton JP, Fleming PA, Suh JH. Use of the RTOG RPA classification system and preditors of survival in 19 women with brain metastases from ovarian cancer. Cancer. March 16, 2005. Submitted.

Hercbergs AA, Suh JH, Toms SA, et al. Propylthiouracil-induced thyroid hormone depletion improves survival and response rates in recurrent high-grade glioma patients treated with tamoxifen. Cancer, August 2005. Submitted.

Kanner A, Marton LJ, Barnett GH, Vogelbaum MA. Targeting Polyamines. A strategy to treat brain neoplasms. 2005. In review.

Kanner A, Vogelbaum MA, Staugaitus S, Chernova O, Prayson RA, Suh JH, Lee SY, Barnett GB. Effect of allelic loss of chromosome 1p on survival in oligoden-drogliomas independent of therapy. 2005 J Neurosurg. Submitted.

Lee JH, Sade B, Choi E, Golubic M, Prayson R. Midline Skull Base and Spinal Meningiomas are Predominantly of the Meningothelial Histological Subtype. Journal of Neurosurgery. June 8, 2005. Submitted.

Lee JH, Sade B, Park BJ. Surgical Technique for Removal of Clinoidal Meningiomas. Neurosurgery for their Operative Nuances issue. June 29, 2005. Submitted.

Lee JH. Management options and basic surgical principles. Meningiomas. Springer-Verlag, London. In review.

Lee JH. Meningioma surgery: Personal philosophy. Meningiomas. Springer-Verlag, London. In review.

Lupica K, Ditz G. Nursing Considerations. In High-Grade Gliomas: Diagnosis and Treatment.

Mahmoud-Ahmed A, Suh J, Lee SY, Hamrahian A, Barnett GH, Mayberg MR. Gamma Knife Radiosurgery Induces Biochemical Cure in Patients with

Acromegaly Faster than External Beam Radiation. 2005. Submitted.

Mason A, Toms SA, Hercbergs A. Biological Modifiers. In High-grade Gliomas. Submitted.

Taban M, Cohen B, Rothner D, Traboulsi E. Association of Optic Nerve hypoplasia with Mitochondrial Cytopathies. Submit-ted.

Nathoo N, Chahlavi, A, Barnett GH, Toms, SA. Pathobiology of Brain Metastasis. 2005. Submitted.

Nathoo N, Ugokwe K, Chang A, et al. The Role of 111 indium-octreotide brain scintigraphy in the diagnosis of cranial, dural-based meningiomas. Neurosurgery. March 2005. Submitted.

Rogers LR, Rock JP, Sills AK, et al. Brain Metastasis Study Group, Shaw EG. Results of a phase II trial of GliaSite Radiation Therapy System for the treatment of newly diagnosed resected single brain metasta-ses. J Neurosurg. July 2005. Submitted.

Sajja R, Barnett GH, Lee SY, Stevens GH, Lee J, Suh JH. Intensity-Modulated Radiation Therapy (IMRT) for Newly Diagnosed and Recurrent Intracranial Meningiomas: The Cleveland Clinic Foundation Experience. International Journal Radiology Oncology, Biology, Physiology. 2005. Submitted.

Sajja R, Barnett GH, Lee SY, Vogelbaum M, Stevens G, Lee JH, Suh J. Local control of intracranial meningiomas with Gamma Knife radiosurgery: The Cleveland Clinic Foundation Experience. International Journal Radiology Oncology, Biology, Physiology. 2005. In review.

Sajja R, Barnett GH, Lee SY, Vogelbaum MA, Stevens GHJ, Lee J, Suh JH. Local control on intracranial meningiomas with gamma knife radiosurgery (GKRS): The Cleveland Clinic Foundation Experience. 2005. Submitted.

Sajja R, Barnett GH, Lee SY, Stevens GHJS, Lee JH, Suh J: Intensity-modulated radiation therapy (IMRT) for newly diagnosed and recurrent intracranial meningiomas: The Cleveland Clinic Foundation Experience. Journal Radiology Oncology, Biology, Physiology. 2005. In review.

Suh JH, Curran W, Mehta MP, et al. Predictors for survival for patients with brain metastases: results of a randomized phase III trial. Int J Radiat Oncol Biol Phys. August 2005. Submitted.

Taban M, Cohen B, Rother D, et al. Association of Optic Nerve hypoplasia with Mitochondrial Cytopathies. 2005. Submitted.

Tobias S, Kim C-H, Burak S, Staugaitis SM, Lee JH. Benign neuromuscular choristoma of the trigeminal nerve in an adult: Case report and literature review. Acta Neurochirurgica February 2005. Submitted.

Ugokwe K, Nathoo N, Prayson R, Barnett GH. Trigeminal Nerve Schwannoma with Ancient Change: Case Report and Review of the Literature. 2005. Submitted.

Vogelbaum M, Thomas T. Contemporary Investigational Treatments for Malignant Brain Tumors: Small Molecule Agents. In: Barnett GH. High-grade Gliomas: Diagnosis and Treatment. Totawa, NJ: Humana Press. 2005. Submitted.

Vogelbaum MA, Angelov L, Lee SY, Li L, Barnett GH, Suh JH. Local control of Brain Metastases by Stereotactic Radiosurgery Depends Upon the Dose to the Tumor Margin. Journal of Neurosurgery. February 2005. Submitted. (Accepted with revisions.)

Vogelbaum MA, Barnett, GH. Response of Recurrent Glioblastoma Multiforme to Tarceva (OSI774) with Subsequent Leptomeningeal Failure. 2005. Submitted.

Vogelbaum, M. A., Angelov, L., Lee, S-Y., Barnett, G.H., Suh, J.H., Factors affecting local control in patients with metastatic brain tumors treated with Gamma Knife stereotactic radiosurgery. Journal of Neurosurgery. 2005. Submitted.

WIP Angelov L, Lee SY, Barnett GH, Suh JH, Vogelbaum MA. The response to treatment of melanoma brain metastasis with stereotactic radiosurgery alone or in combination with whole brain radiation therapy. In progress.

Angelov L, Vogelbaum MA, Barnett GH, Stevens GHJ, Suh JH, Miller M, Peere-boom DM. Temozolomide therapy in the management of primary central nervous system lymphomas. In progress.

Barnett GH. High-Grade Gliomas. Diagnosis and Treatment. In progress.

Chahlavi A, Krishnany A, Nagel S, Lee JH. Aggressive and Malignant Meningiomas are Rare in the Skull Base Locations. In progress.

�2 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Chahlavi A, LaPresto E, Vogelbaum MA. Analysis of Patients with Glioblastoma Multiforme and amplified EGFR. In progress.

Chahlavi A, Park J, Staugatis S, Lee JH. Incidental Intraoperative Finding of Vestibular Nerve Heterotopia: case report. In preparation.

Golubic M, Lee JH. Emerging treatment modalities for meningiomas: Targeting the NF-2 and Ras pathways. Meningiomas. Springer-Verlag, London. In review.

Golubic M, Angelov L, Sade B, Lee JH. Molecular basis of meningioma tumorigen-esis and progress. Meningiomas. Springer-Verlag, London. In review.

Krishnaney A, Steinmetz MP, Golubic M, Lee JH. Meningioma location is associ-ated with histologic subtype and risk of aggressive behavior. Manuscript. In progress.

Krishnany A, Chahlavi A, Nagel S, Lee J. Meningiomas of the midline / paramedian skull base are predominantly meningothe-lial. In preparation.

Lee JH, Sade B, Park BJ. The «CLASS» algorithmic scale for patient selection in meningioma surgery: rationale and validity – a retrospective study. In progress.

Lee JH, Sade B. Dural reconstruction following meningioma resection: Non-watertight closure. Meningiomas. Springer-Verlag, London. In progress.

Lee JH, Sade B. Meningiomas of the central neuraxis. Unique tumors. Meningiomas. Springer-Verlag, London. In review.

Lee JH, Sade B. Surgical management of clinoidal meningiomas. Meningiomas. Springer-Verlag, London. In review.

Lee JH, Sade B. The factors influencing outcome in meningioma surgery. Meningiomas. Springer-Verlag, London. In review.

Lin WC, Mahadevan J, Chari R, Toms SA. Optics of cell and tissue viability. In preparation.

Mahelas TJ, Lee JH. Sequential visual loss from skull base neurosarcoidosis. In review.

Mason A, Barnett G. Retrospective review and case report of peritumoral malignant edema from perisagital meningiomas after gamma knife. In review.

Park BJ, Kim HK, Lee JH. Epidemiology of meningiomas. Meningiomas. Springer-Verlag, London. In review.

Quan AL, Ross JS, Lee SY, et al. Prognos-tic implication of multicentric and multifocal disease in patients with glioblas-toma multiforme. In preparation.

Sade B, Lee JH. Tuberculum sellae meningiomas: surgical management and outcome. In progress.

Sade B, Chahlavi A, Krishnaney A, Nagle S, Choi E, Lee JH. The WHO Grade II and III meningiomas are rare in the skull base and spinal locations. Neurosurgery. In review.

Sade B, Lee JH, Lee DK, Hughes GB, Prayson R. Cavernous angioma of the petrous bone. Laryngoscope. In review.

Sade B, Lee JH. Recovery of low frequency sensori-neuronal hearing loss following resection of a greater superficial petrous and nerve schwannoma. Journal of Neurosurgery. In review.

Sade B, Lee JH. Validity and utility of the ‘CLASS’ algorithmic scale. Meningiomas. Springer-Verlag, London. In review.

Sade B, Park BJ, Lee JH. The factors influ-encing early outcome in meningioma surgery. In progress.

Sade B, Prayson R, Lee JH. Giosarcoma with infratemporal fossa extension. Journal of Neurosurgery. In review.

Sajja R, Barnett GH, Lee SY, et al. Gamma Knife radiosurgery for newly diagnosed and recurrent intracranial meningiomas. In progress.

Siomin V, Toms SA. En bloc resection of skull base metastasis is achievable with good clinical outcomes. In preparation.

Spotta A, Nathoo N, Stevens GHJ, Barnett GH. Primary cranial vault lymphoma with complete occlusion of the superior saggital sinus and subgaleal extension without bone erosion: A case report and review of the literature. In preparation.

Stevens GHJ, Vogelbaum MA, Peereboom DA, Suh J, Barnett GH. Brain tumor patients and driving: special considerations regarding seizures. In preparation.

Stevens GHJ, Vogelbaum MA, Peereboom DA, Suh J, Barnett GH. Brain tumor patients and treatment of epilepsy: Is it time for a paradigm shift? The Cleveland Clinic experience for conversion of phenytoin to levatriracitam. In preparation.

Suh JH, Barnett GH, Regine WF. Role of radiosurgery for brain metastases. Principles and Practice of Stereotactic Radiosurgery.

Toms SA, Muhammed O, Damishear H, Vogelbaum MA. Computed tomography detects quantum dots in vivo. In prepara-tion.

Toms SA, Daneshvar H, Nelms J, Muhammed O, Jackson H, Vogelbaum MA, Bruchez M. Optical Detection of Brain Tumors Using Quantum Dots. In prepara-tion.

Toms SA, Konrad P, Weil RJ, Lin WC. Neurological applications of optical spectroscopy. In preparation.

Toms SA, Muhammed O, Damishear H, Vogelbaum MA. Gradient echo MRI detects quantum dots in vivo. In prepara-tion.

Toms SA, Tasch J, Muhammed O, Jackson H, Lin W-C. Decline in NAD(P)H Autofluorescence Precedes Apoptotic Cell Death from Chemotherapy. In preparation.

Toms SA, Yuan S, Miller DW, Muhammed O, Tasch J, Williams BRG. Identification of an alternate splice of hSLK, hSLKS. In preparation.

Ugokwe K, Toms SA. Renal Cell Carci-noma Brain Metastases. Renal Cell Carcinoma. In preparation.

Vogelbuam M. Small Molecule Agents. High-Grade Gliomas. Diagnosis and Treatment.

2005 Annual Report A team approach to individualized care ��

Consortia: NABTT: New Approaches Brain Tumor Therapy ACOSOG: American College of Surgeons Oncology Group BBBD: Blood-Brain Barrier Disruption RTOG: Radiation Therapy Oncology Group SWOG: South West Oncology Group COG: Children’s Oncology Group

Adult ProtocolsIV Chemotherapy for High-Grade Gliomas Description: Phase II Clinical Trial of Patients with High-Grade Glioma Treated with Intra-arterial Carboplatin-based Chemotherapy, Randomized to Treatment with or without Delayed Intravenous Sodium Thiosulfate as a Potential Chemoprotectant against Severe ThrombocytopeniaEligibility: Histologically confirmed high-grade glioma, age 18-75.Study Design: Phase II, multi-institutional trialContact: Glen Stevens, D.O., Ph.D., 216.445.1787

AP2�5�� in Progressive or Recurrent Malignant GliomaDescription: A Phase I Sequential Ascending Dose Trial of AP23573 in Patients with Progressive or Recurrent Malignant GliomaEligibility: Radiographically suspected progressive or recurrent primary malignant glioma (glioblastoma multiforme, gliosarcoma or WHO Grade 4) and must have failed standard therapy. Patients may not have received any systemic therapy for the treatment of this recur-rence or relapse. Age >= 18.Study Design: Phase I, multi-institutionalContact: TEMPORARILY NOT ACCEPT-ING PATIENTS

Erlotinib with Temozolomide & Radiation for Newly Diagnosed GBMDescription: A Phase II Trial of Erlotinib with Temozolomide & Concurrent Radiation Therapy Post-operatively in Patients with Newly Diagnosed Glioblastoma Multiforme Eligibility: Newly diagnosed glioblastoma multiforme, ≥18 years old. Study Design: Phase II internal study

Contact: David Peereboom, M.D., 216.445.6068

Celecoxib & Anticonvulsants for Newly Diagnosed GBM’s undergo-ing Radiation TherapyDescription: A Pharmacokinetic Study of the Interaction between Celecoxib & Anticonvulsant Drugs in Patients with Newly Diagnosed Glioblastoma Multiforme Undergoing Radiation Therapy (NABTT 2100) Eligibility: Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme). Age ≥18. Study Design: Pharmacokinetic cooperative group study Contact: CURRENTLY NOT ACCEPTING PATIENTS

Tarceva (Recurrent/Progressive Glioblastoma Multiforme)Description: A Phase II study of OSI-744 used alone in patients with recurrent malignant gliomas. Eligibility: Patients must be at least 18 years of age and have Histologically confirmed WHO grade IV astrocytoma (glioblastoma multiforme), with radio-graphic evidence of recurrence. Study Design: Internal, Phase II Contact: Michael Vogelbaum, M.D., Ph.D., 216.444.856

ACOSOG Z0�00 (One to Three Cerebral Metastases)Description: A Phase III Randomized Trial of the Role of Whole Brain Radiation Therapy in Addition to Radiosurgery in the Management of Patients with One to Three Cerebral Metastases Eligibility: Patient must be at least 18 years of age Study Design: ACOSOG Consortium, Phase III Contact: CURRENTLY NOT ACCEPTING PATIENTS

BMS (Recurrent Malignant Glioma)Description: A Phase I/II Study of BMS-24755A Phase I/II Study of BMS-247550 for Treatment of Patients with Recurrent Malignant Gliomas (NABTT 2111) Eligibility: Patients must be 18 years of age or older and have histologically proven malignant glioma (anaplastic astrocytoma or glioblastoma multiforme), which is

progressive or recurrent following radiation therapy ± chemotherapy. Patients with previous low-grade glioma who pro-gressed after radiotherapy +/- chemo-therapy and are biopsied and found to have a high-grade glioma are eligible. Study Design: NABTT consortium, Phase I/II Contact: David Peereboom, M.D., 216.445.6068

OXALIPATIN (Newly Diagnosed Glioblastoma Multiforme) Description: Phase I/II Trial of Oxaliplatin as Neoadjuvant Treatment in Adults with Newly Diagnosed Glioblastoma Multi-forme NABTT 9902 Eligibility: Patients must be at least 18 years of age and have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme). Study Design: NABTT consortium, Phase I/II Contact: CURRENTLY NOT ACCEPTING PATIENTS

Karenitecin (Recurrent Malignant Gliomas)Description: Phase I Evaluation of the Safety of Karenitecin in the Treatment of Recurrent Malignant Gliomas NABTT 2006 Eligibility: Patients must be 18 years of age or older and have histologically proven malignant glioma (anaplastic astrocytoma, anaplastic oliogodendroglioma or glioblastoma multiforme) which is progressive or recurrent following radiation therapy +/- chemotherapy. Patients with previous low-grade glioma who pro-gressed after radiotherapy +/- chemo-therapy and are biopsied and found to have a high-grade glioma are eligible. Study Design: NABTT consortium, Phase I Contact: CURRENTLY NOT ACCEPTING PATIENTS

Tamoxifen-Hypothyroid GBM Description: High-dose Tamoxifen in combination with reduction of thyroid hormone during and post external beam radiotherapy. Study Design: Internal study: Phase II Eligibility: Newly diagnosed GBM, Age >18yrs Contact: CURRENTLY NOT ACCEPTING PATIENTS

Brain Tumor Institute

Appendix A – Clinical Trials

�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

RTOG-���� (Anaplastic Astrocytoma) Description: Radiation with randomization to one of three chemotherapy options Study Design: RTOG-98-13, Phase I/III trial Eligibility: Anaplastic astocytoma, Age 18 yrs Contact: John Suh, M.D., 216.444.5574

NABTT ��0� (Gliadel and O�-BG for Malignant gliomas) Description: Surgical resection and placement of gliadel wafer with systemic O6BG Study Design: Phase I study Eligibility: Supratentorial malignant glioma, Age >18yrs Contact: CURRENTLY NOT ACCEPTING PATIENTS

NABTT ��0� (procarbazine for malignant gliomas)Description: oral procarbazine, 2 arm: P450 vs. non P450 inducing medications Study Design: NABTT 9901, Phase I/II study Eligibility: recurrent high-grade glioma, 3 months post XRT, only one prior chemo Contact: CURRENTLY NOT ACCEPTING PATIENTS

NABTT ��0� (Col-� for recurrent malignant gliomas) Description: Col-3 (anti-angiogenesis) for high-grade gliomas Study Design: NABTT 9809, Phase I/II trial, P450 and non P 450 arms Eligibility: recurrent high-grade glioma, 2 or less prior chemos and 3 months post XRT Contact: CURRENTLY NOT ACCEPTING PATIENTS

SWOG S000�: Upfront Treatment for Newly Diagnosed GBMsDescription: Randomization to Radiation therapy + O6-BG + BCNU vs. Radiation + BCNU Alone Study Design: Phase III SWOG study Eligibility: Newly diagnosed GBM, KPS >60Contact: CURRENTLY NOT ACCEPTING PATIENTS

IL-��Description: Pre-Operative IL13-PE38QQR Infusion in Patients with Recurrent or Progressive Supratentorial Malignant Glioma Study Design: A Phase I/II Study Eligibility: Patients must have prior histologic diagnosis of supratentorial malignant gliomas. Eligible histologies: glioblastoma multiforme, anaplastic astrocytoma, or malignant mixed oligoas-trocytoma (excludes glioma of know grade or “pure” oligodendroglioma). Patients with

clinical /radiographic diagnosis of malignant glioma may be registered pending histologic confirmation. Patients must have recurrent or progressive supratentorial tumor compared with a previous study. Patients must be > 18 years old.Contact: CURRENTLY NOT ACCEPTING PATIENTS

IL-��Description: Phase I study of convection-enhanced delivery (CED) of IL13-PE38QQR cytotoxin after resection and prior to radiation therapy with or without temozolomide in patients with newly diagnosed supratentorial malignant glioma Study Design: Phase I Eligibility: Age > 18 years old., must have undergone a gross total resection of the solid contrast-enhancing lesions(s) > 1.0 cm in diameter, must be able to have catheters placed within 14 days of tumor resection (including a planned Gross Total Resection following an initial biopsy or subtotal resection) and must have histopathologic documentation of malignant glioma from resection speci-men. Diagnosis must be consistent with either GBM, AA or mixed OA. Contact: Mike Vogelbaum, M.D., 216.444.5381

IL-��Description: Phase III Randomized Evaluation of Convection-enhanced Delivery of IL13-PE38QQR Compared to Gliadel Wafer with Survival Endpoint in Glioblastoma Multiforme Patients at First Recurrence Study Design: Phase III Eligibility: Patients with glioblastoma multiforme (GBM) at first recurrence who are considered candidates for resection and meet the specified eligibility criteria may be enrolled in the study. Contact: CURRENTLY NOT ACCEPTING PATIENTS

WBRT +/- RSR�� in Women with Brain Metastases from Breast CancerDescription: A Phase III Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy with Supplemental Oxygen, with or without Concurrent RSR13 (efaproxiral), in Women with Brain Metastases from Breast Cancer Study Design: Phase III Eligibility: Age >= 18 years old, histologically or cytologically confirmed breast cancer in women with radiographi-cally confirmed metastases to the brain.

Contact: John Suh, M.D., 216.444.5574

Melatonin for Brain MetastasesDescription: A Randomized Phase II Study of A.M. and P.M. Melatonin for Brain Metastases in RPA Class II Patients Study Design: Phase II Eligibility: Brain metastasis from histologically documented solid tumors (except germ cell tumors). Biopsy proof from the brain metastasis is preferred when clinical history and radiologic findings are equivocal. Contact: CURRENTLY NOT ACCEPTING PATIENTS

Focal Radiation for �-� Brain MetastasesDescription: A Phase II Study Utilizing Focal Radiation in Patients with 1-3 Brain Metastases Study Design: Phase II Eligibility: Have 1 to 3 newly diagnosed supratentorial metastatic brain lesions with at least one being dominant and eligible for surgical resection as visualized on enhanced MRI scan. Have histological evidence of metastatic carcinoma on intraoperative pathology (frozen section) or final pathology report. Contact: Mike Vogelbaum, M.D., Ph.D., 216.444.5381

Temozolomide for Anaplastic Oligodendrogliomas & Mixed OligoastrocytomaDescription: Phase II Trial of Continuous Dose Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendro-gliomas and Mixed Oligoastrocytoma Study Desgin: Phase II trial Eligibility: Newly Diagnosed Anaplastic Oligodendroglioma, Newly Diagnosed Mixed Anaplastic Oligodendroglioma Contact: David Peereboom, M.D., 216.445.6068

Intraoperative Optical Spectroscopy for Glial TumorsDescription: Detection of glial tumor margins with intraoperative optical spectroscopy Study Design: Internal study Eligibility: Unifocal or multifocal supratentorial glial neoplasm suspected on MRI & patient is a surgical candidate for craniotomy Contact: Steven Toms, M.D., 216.445.7303

Gliasite BrachytherapyDescription: Phase I Brachytherapy Dose Escalation Using the Gliasite RTS in Newly Diagnosed Glioblastoma Multi-

2005 Annual Report A team approach to individualized care �5

forme in Conjunction with External Beam Radiation Therapy Study Design: Phase I trial Eligibility: Newly Diagnosed GBM Contact: Michael Vogelbaum, M.D., Ph.D., 216.444.8564

Dietary & Herbal Complementary Alternative Medicine ApproachDescription: Phase II Randomized Evaluation of 5-Lipoxgenase Inhibition by Dietary and Herbal Complementary and Alternative Medicine Approach Compared to Standard Dietary Control as an Adjuvant Therapy in Newly Diagnosed Glioblastoma Multiforme Study Design: Phase II Randomized Eligibility: Newly Diagnosed GBM Contact: Mladen Golubic, M.D., Ph.D., 216.445.7641

Bay ��-�00� for Recurrent/Progres-sive Malignant GliomasDescription: A Phase I Trial of Bay 43-9006 for Patients with Recurrent or Progressive Malignant Glioma Study Design: Phase I trial Eligibility: Recurrent Anaplastic Astrocy-toma, Recurrent Anaplastic Oligodendro-glioma, Recurrent GBM, Recurrent Gliosarcoma Contact: David Peereboom, M.D., 216.445.6068

EMD & RT for Newly Diagnosed GBM’sDescription: A Safety Run-In/Randomized Phase II Trial of EMD 121974 in Conjunc-tion with Radiation Therapy in Patients with Newly Diagnosed Glioblastoma Multiforme NCI #: NABTT 0306Study Design: NABTT Cooperative Phase II TrialEligibility: Newly Diagnosed GBM, Newly Diagnosed GliosarcomaContact: David Peereboom, M.D., 216.445.6068

Temozolomide for Low-grade GliomasDescription: A Phase II Study of Temozolo-mide-Based Chemotherapy Regimen for High Risk Low-Grade GliomasStudy Design: Phase II trialEligibility: Low-Grade GliomasContact: John Suh, M.D., 216.444.5574

Talampanel w/RT & Temozolomide for Newly Diagnosed GBM’sDescription: A Phase II Trial of Talam-panel in Conjunction with Radiation Therapy with Concurrent and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma Multiforme

Study Design: Phase II TrialEligibility: Newly Diagnosed GBM, Newly Diagnosed GliosarcomaContact: David Peereboom, M.D., 216.445.6068

Lymphoma Blood-Brain Barrier Disruption (Primary Central Nervous System Lymphoma) Description: A Phase II Trial involving Patients with Recurrent PCNSL Treated with Carboplatin/BBBD, by Adding Rituxan (Rituximab), an anti-CD-20 Antibody, to the Treatment RegimenEligibility: Patients must be 18-75 yrs of age histologically confirmed Primary CNS Lymphoma as documented by brain biopsy, or cytology (analysis from CSF or vitrectomy), & CD20 positive. Study Design: Internal, Phase II, multi-institutionalContact: CURRENTLY NOT ACCEPTING PATIENTS

Blood-Brain Barrier Disruption (Primary Central Nervous System Lymphoma)Description: Combination Chemotherapy (Methotrexate, Cyclophosphamide and Etoposide Phosphate) Delivered in Conjunction with Osmotic Blood-Brain Barrier Disruption (BBBD), with Intraventricular Cytarabine +/- Intra-Ocular Chemotherapy, in Patients with Primary CNSEligibility: 16-75 years old; histologically confirmed intermediate/high-grade primary CNS lymphoma Study Design: Internal, multi-institutional Contact: Glen Stevens, D.O., Ph.D., 216.445.1787

Meningioma SWOG-���� (Benign Meningioma)Description: Chemotherapy with hydroxyurea Study Design: Phase II, cooperative group Eligibility: Primary, recurrent or residual benign meningioma which is unresect-able, Age >18yrs, XRT > 1 yr Contact: CURRENTLY NOT ACCEPTING PATIENTS

MetastasisZeiss INTRABEAM System for Solitary Brain MetastasisDescription: A Phase I/II Study Utilizing the Zeiss INTRABEAM System for the Treatment of a Resected Solitary Brain

MetastasisEligibility: Newly diagnosed supratentorial single metastatic brain tumor as visualized on enhanced MRI scan that is surgically resectable. CT scans may be substituted for MRI only for those patients in whom MRI scans cannot be safely performed. Age >= 18.Study Design: Phase I/II, internal study.Contact: Steven Toms, M.D., 216.445.7303

WBRT with Temozolomide or Placebo for Non-Small Cell Lung Cancer Brain MetastasesDescription: A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Temozolomide or Placebo added to Whole Brain Radiation Therapy for the Treatment of Brain Metastases from Non-Small Cell Lung CancerEligibility: Histologically or cytologically confirmed non-small cell lung cancer. Eligible histologies include squamous cell and adenocarcinoma (including large cell carcinoma) and non-small cell cancer not otherwise specified. A biopsy of meta-static disease in the brain is not required for study enrollment. Age >= 18.Study Design: Phase III, randomized, double-blind, placebo controlled.Contact: John Suh, M.D., 216.444.5574

Radiation therapy plus Thalidomide for Multiple Brain MetastasesDescription: A Phase III Study of Conventional Radiation Therapy Plus Thalidomide vs. Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118) Eligibility: Histopathologically confirmed extracranial primary malignancy. Age ≥18. Study Design: Phase III cooperative group study Contact: CURRENTLY NOT ACCEPTING PATIENTS

WBRT +/- RSR�� in Women with Brain Metastases from Breast CancerDescription: A Phase III Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy with Supplemental Oxygen, with or without Concurrent RSR13 (efaproxiral), in Women with Brain Metastases from Breast CancerStudy Design: Phase IIIEligibility: Age >= 18 years old, histologically or cytologically confirmed breast cancer in women with radiographi-cally confirmed metastases to the brain.Contact: John Suh, M.D., 216.444.5574

�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Xcytrin for Non-Small Cell Lung Cancer Brain MetastasesDescription: Randomized Phase III Trial of Xcytrin® (Motexafin Gadolinium) Injections for the Treatment of Brain Metastases in Patients with Non-Small Cell Lung Cancer Undergoing Whole Brain Radiation Therapy. Study Design: Phase III Randomized trial Eligibility: Non-small cell lung cancer with brain metastases Contact: CURRENTLY NOT ACCEPTING PATIENTS

WBRT & SRS +/- Temozolomide/Gefitinib for Non-Small Cell Lung Cancer & Brain MetastasesDescription: RTOG 0320: A Phase III Trial Comparing Whole Brain Radiation and Stereotactic Radiosurgery Alone Versus with Temozolomide or Gefitinib in Patients with Non-Small Cell Lung Cancer and 1-3 Brain MetastasesStudy Design: RTOG Cooperative Phase III TrialEligibility: Non-Small Cell Lung Cancer with Brain MetastasesContact: John Suh, M.D., 216.444.5574

Motexafin Gadolinium with WBRT & SRS Boost for Brain MetastasesDescription: Phase II Trial of Motexafin Gadolinium with Whole Brain Radiation Therapy Followed by Stereotactic Radiosurgery Boost in the Treatment of Patients with Brain MetastasesStudy Design: Phase II trialEligibility: Brain MetastasesContact: John Suh, M.D., 216.444.5574

Child and Adolescent Protocols

Newly Diagnosed MalignanciesHead Start III: Dose-Intensive Chemotherapy for Children Less Than �0 Years of Age Newly Diagnosed with Malignant Brain TumorsDescription: The study uses an intensified chemotherapeutic regimen for five months followed by a highly intensive single-drug treatment course and stem cell rescue with lower-dose radiation to try to increase the chance of cure for children with certain malignant brain tumors.Eligibility: Children less than 10 years (120 months) of age at time of histologic or cytologic diagnosis of malignant brain tumor who have not previously received

irradiation or chemotherapy (except corticosteroids). Patients with the following tumor types ma y be eligible: medulloblastoma, primitive neuroecto-dermal tumor, ependymoma, choroid plexus carcinoma, atypical teratoid/rhabdoid tumor, or malignant glioma. Specific criteria apply depending on brain tumor type.Study Design: Nonrandomized Phase II study with 2-stage design.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

Chemo-Radiation Therapy for CNS AT/RT (IRB #���0)Description: The study represents a multi-institutional effort to estimate activity of an aggressive multimodality (systemic and intrathecal) chemotherapeutic regimen for highly malignant atypical teratoid-rhabdoid tumors of the CNS. Treatment showed promising results in a very limited number of these extremely rare cases. Favorable study results may occasion a full-scale national trial proposal.StudyDesign: Phase II.Eligibility: Patients must be < 18 years of age. Target tumors: histologically confirmed primary intracranial CNS AT/RT or tumor that possesses the INI1 gene mutation.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182

C.O.G.-ACNS0�2�: A Phase II Trial of Conformal Radiation Therapy for Pediatric Patients with Localized Ependymoma, Chemotherapy Prior to Second Surgery for Incompletely Resected Ependymoma, and Observa-tion for Completely Resected Differ-entiated, Supratentorial EpendymomaDescription: The study attempts to define a standard for treatment of intracranial ependymoma based on tumor location, degree of resection, and histological characteristics. Treatment will fall into one of four groups. The study will include children under 3 years of age for treatment with conformal radiation.Eligibility: Patients must be > 12 months and < 21 years of age at time of enrollment. Patients must have had no prior treatment except previous surgery or corticosteroid therapy. Target tumors: histologically confirmed intracranial ependymoma. Patients with differentiated or anaplastic ependymoma are eligible. (Patients with primary spinal cord ependy-moma, myxopapillary ependymoma,

subependymoma, ependymoblastoma, or mixed gliomas are not eligible.)Study Design: Phase II clinical trial with four treatment arms, based on tumor loca-tion, degree of resection, and histology.Contact: Joanne M. Hilden, M.D., 216.444.8407 or Bruce H. Cohen, M.D., 216.444.9182.

C.O.G.-ACNS0�22: A Phase II Study to Assess the Ability of Neoadjuvant Chemotherapy +/– Second-Look Surgery to Eliminate All Measurable Disease Prior to Radiotherapy for NGGCTDescription: The protocol aims to improve progression-free survival and overall survival of children with nongerminomatous germ cell tumor through a new therapy regimen combining anticancer drugs, radiation therapy, and, based on response, “second-look” surgery and potentially stem cell transplant.Eligibility: Patients must be at least 3 years old and less than 25 years of age at diagnosis of one of the following: endoder-mal sinus tumor (yolk sac tumor), embryonal carcinoma, choriocarcinoma, immature teratoma and teratoma with malignant transformation, or mixed germ cell tumor.Study Design: Phase II. During the first 18 weeks, patients receive three-drug chemotherapy regimen for induction with subsequent status assessment. Status will direct further treatment options—conformal radiation versus second-look surgery followed by radiation or further chemotherapy.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

C.O.G.-ACNS0�2�: A Phase II Study of Temozolomide in the Treatment of Children with High-Grade GliomasDescription: The protocol tests the effectiveness of FDA-approved temozolomide combined with radiation therapy against hard-to-treat high-grade gliomal or diffuse intrinsic pontine gliomal brain tumors.Eligibility: Patients must be > 3 years of age and < 22 years of age at time of enrollment. Target tumors: anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, and diffuse intrinsic pontine gliomas. Patients with primary spinal cord malignant gliomas are also eligible. Patients with high-grade gliomas must have histologic verification of diagnosis. Metastatic disease-ineligible.Study Design: Phase II. Initially patients receive temozolomide concurrently with

2005 Annual Report A team approach to individualized care ��

radiation therapy on 42-day schedule. Four weeks after radiation therapy, patients receive temozolomide daily for 5 days, beginning a new cycle every 28 days; 10 cycles total.Contact: CLOSED TO PATIENT ACCRUAL.

C.O.G.-ACNS0���: A Study Evaluat-ing Limited-Target Volume Boost Irradiation and Reduced-Dose Craniospinal Radiotherapy (��.00 Gy) and Chemotherapy in Children with Newly Diagnosed Standard-Risk Medulloblastoma: A Phase III Double-Randomized TrialDescription: The trial seeks to reduce nervous system damage caused by radiation therapy in children diagnosed with medulloblastoma. Children at least 3 years of age to less than 8 years of age will receive craniospinal radiation dosing at a rate reduced by 25%, supplemented by moderate intensification of adjuvant chemotherapy. The study will also explore the safety of reducing boost-volume irradiation dosing from the whole posterior fossa to the tumor bed area plus a circumscribed margin by using conformal radiation.Eligibility: Patients must be at least 3 years old and less than 22 years of age when diagnosed with posterior fossa medulloblastoma.Study Design: Phase III, randomized trial.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

C.O.G.-P����: Systemic Chemothera-py, Second-Look Surgery, and Conformal Radiation Therapy Limited to the Posterior Fossa and Primary Site for Children > � Months and < � Years with Nonmetastatic MedulloblastomaDescription: The study serves as a historical control to see if the proposed chemotherapy and conformal radiation treatment plan will be more effective (in terms of one-year event-free survival rates) than the combined treatments given to children of the same age and extent of disease on the POG-9233 trial.Eligibility: Patients greater than 8 months of age and less than three years of age with primary histology diagnosis of medulloblastoma or posterior fossa primitive neuroectodermal tumor (PNET) and no evidence of metastases.Study Design: Phase III trial; no randomization.Contact: Joanne M. Hilden, M.D.,

216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

Refractory / Progressive / Relapsed MalignanciesCCG-A��52: Chemotherapy for Progressive Low-Grade Astrocytoma in Children Less Than Ten Years OldDescription: The study compares event-free survival rates of two chemotherapeu-tic regimens in children less than ten years old who have progressive or incompletely resected astrocytoma or other glioma.Eligibility: Children less than 10 years old (120 months) with low-grade astrocyto-mas (grade 1 and 2) or other low-grade gliomas and who have progressive disease following surgical excision or an incom-plete excision (< 95% or > 1.5 cm2 residual tumor) with necessity to begin treatment because of risk of neurologic impairment with progression.Study Design: Phase III trial, two randomized regimens. NF1 patients, however, will be nonrandomly assigned.Contact: CLOSED TO PATIENT ACCRUAL.

C.O.G.-ACNS022�: A Phase II Study of R��5��� (Zarnestra) (NSC# �02���, IND# 5��5�) in Children with Recurrent or Progressive High-Grade Glioma, Medulloblastoma/PNET or Brainstem GliomaDescription: The protocol tests effective-ness of investigational drug R115777 (Zarnestra) in treating recurrent malignant childhood brain tumors.Eligibility: Patients must be < 21 years of age at enrollment. Target tumors: recurrent or progressive anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglio-ma, recurrent or refractory medulloblas-toma/PNET, or diffuse intrinsic brainstem glioma. Patients must have histopatho-logic verification of diagnosis from either initial presentation or at time of recurrence except for brainstem glioma patients. Patients must have radiographically documented measurable disease and have relapsed or become refractory to conventional therapy. Patients must have life expectancy of at least 8 weeks. Patients are excluded for uncontrolled infection, allergy to azoles, or for taking enzyme-inducing anticonvulsants.Study Design: Phase II. Patients receive study drug for 21 days followed by 7-day rest period. The 28-day cycles may be

repeated for up to two years in the absence of disease progression or unacceptable toxicity.Contact: CLOSED TO PATIENT ACCRUAL.

ADVL0�2�: A Phase II Study of Oxaliplatin in Children with Recurrent Solid TumorsDescription: The study seeks to determine the response rate of various disease strata of recurrent or refractory malignant tumors of childhood to the investigational drug oxaliplatin.Eligibility: Patients must be no more than 21 years of age inclusive when originally diagnosed. The trial includes the following malignancies for the brain tumor stratum: recurrent or refractory high-grade astrocytoma, multiforme glioblastoma, low-grade astrocytoma, brain stem glioma and ependymoma.Study Design: Phase II trial.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

C.O.G.-P���2: A Phase II Trial of Intrathecal Topotecan in Patients with Refractory Meningeal MalignanciesDescription: The study seeks to determine the therapeutic activity (response rate and time to CNS progression) of intrathecal topotecan in patients with recurrent or refractory neoplastic meningitis.Eligibility: Patients must be at least 1 year of age but less than 22 years of age at study entry. Patients must have neoplastic meningitis. Patients with meningeal lymphoma or leukemia must be refractory to conventional therapy including radiation therapy (meaning 2nd or greater relapse).Study Design: Phase II trial.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

C.O.G.-P����: A Phase II Trial of Irinotecan in Children with Refractory Solid TumorsDescription: The study seeks to determine efficacy of irinotecan in treatment of refractory pediatric brain tumors.Eligibility: Children must be at least one year and no more than 21.99 years of age at original diagnosis. Patients with histologi-cally documented brain tumors who exhibit recurrent or refractory tumor growth will be eligible. Patients will be stratified based on histology into the following groups: medulloblastoma/PNET, ependymoma, brain stem glioma, other CNS tumors.Study Design: In this Phase II trial,

�� Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

500

1000

0

Surgical Procedures | Annualized

‘01 ‘02 ‘03 ‘04 ‘05

Gamma Knife Cases

Surgical Cases

The Brain Tumor Institute (BTI) continues to grow in

volume of procedures. More than 240 stereotactic

radiosurgery (Gamma Knife) and 680 surgical procedures

were performed in 2005, which is a 57 percent increase

compared with 2001.

Brain Tumor Institute

Appendix B – Charts & Statistics

3250

6500

0

Total Outpatient Visits

‘01 ‘02 ‘03 ‘04 ‘05

Total outpatient visits increased by

250 percent over the past five years,

reaching a high point of more than

5,900 visits in 2005.

patients receive irinotecan 5 of every 21 days; patients demonstrating continued response or stable disease without significant toxicity may continue treat-ment. Subsequent radiographic evalua-tions would be performed every 3 months as indicated.Contact: CLOSED TO PATIENT ACCRUAL.

RegistryATT/RT Registry (IRB #5���): Central Nervous System Atypical Teratoid/Rhabdoid Tumor RegistryDescription: The registry collects information (with patient consent) about the clinical course, treatment, and outcomes of patients with atypical teratoid/rhabdoid tumor of the CNS.Eligibility: Patients with atypical teratoid/rhabdoid tumor of the central nervous system.Contact: Joanne M. Hilden, M.D., 216.444.8407, or Bruce H. Cohen, M.D., 216.444.9182.

Biology StudiesCCG-B���: Protocol for Collection of Biology Specimens for Research StudiesDescription: The study provides a specimen accrual mechanism within C.O.G.-participating institutions for human pediatric cancer tissues.Eligibility: All patients up to and including 21 years of age who have had biology specimen(s) suspected of malignancy obtained and/or enrolled in a C.O.G. thera-peutic trial.Contact: CLOSED TO PATIENT ACCRUAL.

CCG-B���: Prognostic Significance of Ki-�� Proliferative Index Utilizing the MIB-� Antibody in Low-Grade Gliomas in Young ChildrenDescription: This biology study attempts to determine the value of the Ki-67 proliferative index utilizing the MIB-1 antibody in predicting time to progression in low-grade gliomas in young children a) following initial diagnosis and b) at time of tumor progression if surgery is performed.Eligibility: Patients entered on CCG-A9952.

Study Design: Unstained slides are sent to C.O.G. at time of study entry.Contact: Joanne M. Hilden, M.D., 216.444.8407 or Bruce H. Cohen, M.D., 216.444.9182.

CCG-B���: Molecular Biology of Pediatric Brain TumorsDescription: This biology study will correlate molecular and cytogenetic findings with outcomes on C.O.G. clinical trials.Eligibility: All patients less than 21 years of age with a primary CNS malignancy consistent with PNET/MB or ATT/RT who are entered on CCG front-line studies. Patients cannot have received any prior radiation treatment before the tissue was obtained. Study credit will be given for specimens obtained retrospectively on closed CCG studies, providing samples are adequate for analysis.Study Design: Tissue is accessed at time of study entry.Contact: CLOSED TO PATIENT ACCRUAL.

2005 Annual Report A team approach to individualized care ��

250

500

0

New Outpatient Visits

‘01 ‘02 ‘03 ‘04 ‘05

New patient visits have increased by 192 percent since

2001, setting a new mark

of 529 visits in 2005.

250

500

0

Patient Enrollment

‘01 ‘02 ‘03 ‘04 ‘05

Therapeutic Trials

Genetic Trials

Over the past five years, the number of patients on

research trials has increased from 94 to 431, or 358

percent.

Brain Tumor Institute

Appendix C – ArticlesClinic Researchers Earn Patent for Blood-Brain Barrier TechnologyCleveland Clinic researchers have received a U.S. patent for technology they developed to measure damage to a person’s blood-brain barrier. The patent covers the researchers’ work to develop a blood test capable of indicating when a person’s blood-brain barrier has been compromised, if neuronal damage exists, and when the person might be more responsive to therapies that need to reach the brain to treat tumors or other neurological disorders.

The patent was issued to Cleveland Clinic researchers Damir Janigro, Ph.D., and Gene Barnett, M.D. Dr. Janigro is a professor of molecular medicine and director of cerebrovascular research for Cleveland Clinic Lerner College of Medicine. Dr. Barnett is chairman of the Cleveland Clinic Brain Tumor Institute and professor of surgery and oncology.

“Determining the integrity of the blood-brain barrier is crucial in understanding disease states,” Dr. Janigro says. “This blood test is a quick and easy way to determine the most appropriate treatment for many different patients.”

The blood test would provide a minimally invasive alternative to painful spinal taps currently used to assess the condition of a patient’s blood-brain barrier. In addition, Dr. Janigro says, this blood test has the potential to save millions of dollars in MRI and CT scan costs.

MRI FLAIR Axial View with Enhancement

Axial View with Enhancement

Coronal View with Enhancement

Axial View MRI FLAIR

S-100 beta levels in patient with small (top) vs. larger brain metastases (bottom). Higher numbers indicate greater breakdown of the blood-brain barrier.

Small Metastases 0.��

Large Metastases 0.��

�0 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

CCF Innovations, the Cleveland Clinic’s technology transfer arm, is actively working to commercialize the technology through a license or a new company.

The work of Drs. Janigro and Barnett has shown that when a high level of S100b, a protein normally found in brain cells, is detected in the blood stream, it can signal a disruption of the blood-brain barrier. This disruption, in turn, can indicate the

Proteomic Profiling Holds Promise for Identifying Markers of InterestRobert J. Weil, M.D., Associate Director of Basic Research, Brain Tumor Institute

Early detection of cancer is crucial for its treatment, control and prevention. Identifica-tion of diagnostic and prognostic markers, as well as therapeutic targets, is a major goal in cancer research. Correlation of morphologic phenotypes of cancer with their expres-sion profile is a promising approach to detecting unique markers that can assist in the diagnosis and management of disease or serve as targets for therapy. A variety of new and powerful methods have been developed in recent years to foster these goals, including microarrays (DNA or “gene” chips).

Among recent technologic advances, proteomics (modeling of many proteins, the products of the genes, which are the source of all the action inside normal, as well as cancerous, cells) may have great potential as a facile tool to identify a number of

presence of a brain tumor or brain injury. In contrast, when an individual’s blood-brain barrier is intact or working properly, the level of S100b in the bloodstream is low or even undetectable.

“This test could prove useful in the early detection of brain tumors, particularly in patients with lung, breast or other systemic cancers where the risk of their cancer spreading to the brain is one in four,” Dr. Barnett says.

Robert J. Weil, M.D.

2005 Annual Report A team approach to individualized care ��

Figure LegendsFigure �. A schematic representation of the method of analyzing tissues with two-dimensional gel electrophoresis and identifying the unique proteins with mass spectrometry (LC/MS/MS).

Figure 2. Representative picture of the two types of GBMs with proteins common to the two types and unique to one or the other type. The boxes below show a small segment of a 2-D gel to illustrate the individual proteins.

Figure �. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) methodology. A nitrogen laser is shot at cells, and the absorption of energy leads to scattering of individual proteins, which are picked up in the mass

spectrometer and characterized. Sophisticated computer programs are used to smooth out the data, which are first studied to get information about tumor type and then compared to different tumors to detect subtle differences between tumors of the same type.

Figure �. An example of how comparing the spectra from tumors of the same type can reveal subtle differences in otherwise similar-appearing tumors of the same type, for example, gliomas. Here we see that it is possible to divide a group of patients, followed over many years, into those who are likely to do well (blue line, top) from those who are less responsive to treatment (red line, bottom).

markers of interest. Proteomic profiling to characterize the expression patterns of benign cells and to compare them with cancer cells appears to be a promising approach to identifying markers of interest.

A variety of methods, including two-dimensional gel electrophore-sis (2DGE), matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), surface-enhanced laser desorption-ionization (SELDI), and protein microarrays, have been utilized to study normal and cancer cells, as well as a selection of body fluids, such as blood, saliva and urine, to look for changes that predict the presence of cancer. In the study of gliomas, we have focused recently on two methods, 2DGE and MALDI-MS.

Gliomas are the most common primary brain tumors of adults, with a yearly incidence of approximately 25,000 cases in the United States. The most common form of glioma is the glioblas-toma multiforme (GBM), an aggressive and malignant tumor. Despite decades of research on tumor biology and treatment, patients with GBMs continue to have a poor prognosis, with a median survival of one year following aggressive surgical and adjuvant therapy. GBMs account for an estimated 2.5 percent of all cancer deaths in the United States, and treating these tumors remains a high priority for researchers and clinicians.

2DGE protein identification and proteomic profiling methods have seen considerable technological improvements since 2DGE was first used to analyze gliomas in the 1980s. 2DGE analysis is an effective method to identify proteins involved in human disease. Despite its potential, however, many proteomic methodologies are limited by the complexity of cancer tissues, where a mixture of neoplastic and non-neoplastic cells can hamper the effort to acquire a pure tumor cell signature. In addition, heterogeneity among tumor types at a single site can increase the complexity of proteomics and other gene expression approaches.

Further refinements in gene expression and protein profiling were realized with the more recent development of selective tissue microdissection, which enables the procurement of pure populations of cells of interest. In concert with colleagues at the National Institutes of Health, we used selective tissue microdis-section of primary tumor samples to study a group of GBMs.

Two types of GBMs have previously been described: de novo or primary GBMs, which typically arise in older individuals, and secondary or progressive GBMs, which arise several years after the first manifestation of a lower grade glioma, typically found in younger patients.

We used selective tissue microdissection to procure pure populations of glioblastoma cells and analyzed them by 2DGE. In each case, the protein expression patterns could be classified into one of two groups, which coincided with the clinical distinction of primary or secondary. Unique expression of a number of proteins was identified on a large scale between members of the primary or secondary tumors. We isolated and sequenced some of these proteins and identified several proteins known or suspected in gliomas and/or other cancers. In addition, we identified several proteins not previously known to be expressed in normal brain and glial tissue or to be a part of gliomagenesis.

In a second study, in collaboration with colleagues at the National Institutes of Health and Vanderbilt University, we used a direct-tissue protein profiling approach to tumor analysis using mass spectrometry (MALDI-MS) to correlate protein patterns obtained directly from tumor biopsies with patient survival trends. MALDI is not only a powerful method to confirm the diagnosis of a brain tumor, but it also can be used to “crunch” a tremendous amount of information to distinguish between people with the same type of tumor—for example, a GBM—and to identify protein patterns that predict different survival trends.

Both of these types of protein studies, along with others, can be used to improve diagnosis; identify prognostic markers in tumors and other tissues and fluids, like the blood; and, in the future, serve as useful adjuncts for predicting response to treatment and overall outcome.

These studies are still in their infancy; not just technologically, but also as predictive tools. These and other methods will be developed and studied in the Brain Tumor Institute in a larger group of patients, where their uses and limitations will become better understood.

�2 Cleveland Clinic Brain Tumor Institute clevelandclinic.org/braintumor

Surgical Management of Spinal Tumors Revolutionizes TreatmentThe days of a single therapeutic approach to all metastatic spine tumors are coming to a close.

For more than 20 years, external beam radiation has been the standard of care for patients with these tumors. Now the paradigm is shifting to surgical treatment prior to radiation as a better option for many patients, a strategy that Cleveland Clinic physicians Steven Toms, M.D., M.P.H., and Edward Benzel, M.D., believe offers significant advantages.

“There is compelling evidence that aggressive management of these tumors, including radiosurgery or surgical resection and decompression, followed by radiotherapy to sterilize the tumor bed, improves pain control and ambulation, preserves or restores bowel and bladder function and may confer a survival benefit,” Dr. Toms says.

Based on their personal experience as well as data from several small retrospective studies, Dr. Benzel, Chairman of the Cleveland Clinic Spine Institute, and Dr. Toms, a neurosurgeon in the Cleveland Clinic Brain Tumor Institute, have been promot-ing this broader treatment approach for patients with meta-static spine tumors for several years. A recent study in Lancet (2005;366(9486):643-648), in which surgery plus radiothera-py resulted in significantly better outcomes in quality of life measures and pain control compared with radiosurgery alone, has sparked wide-spread interest in surgical treatment as an adjunct to radiotherapy for these patients.

At Cleveland Clinic, surgical resection and spinal reconstruction, kyphoplasty to stabilize the spine, radiosurgery with the Novalis system, external beam radiation and chemotherapy all are potential elements of the treatment plan for spinal tumor patients.

“The key is to create an individualized plan for each patient based on tumor stage, the levels of the spine involved, the patient’s age and life expectancy, and quality of life considerations,” Dr. Benzel notes. Because of the often complex nature of these cases, the treatment decision is best made by a multidisciplinary team that includes spine surgeons, oncologists and radiation oncologists, he adds.

To implement this strategy at Cleveland Clinic, Drs. Toms and Benzel have established a Spine Tumor Board, an interdisciplin-ary committee that meets regularly to discuss these cases and plan appropriate treatment. The main candidates for consider-ation are patients with primary renal cell carcinoma, melanoma, or lung or breast cancer that has metastasized to the spine.

This multidisciplinary approach also offers advantages in the management of multiple myeloma. Cleveland Clinic orthopaedic surgeon Isador Lieberman, M.D., pioneered the use

of kyphoplasty in multiple myeloma patients to stabilize the spine prior to chemotherapy and/or tumor resection and spinal decompression. He has demonstrated that kyphoplasty can be performed at multiple levels in the spine and relieves pain, improves the ability to walk and significantly improves quality of life for these patients.

“Patients with pancoast tumors that have penetrated to the vertebral bodies are another population that may benefit from more aggressive surgical management,” Dr. Toms adds. At least one study has demonstrated that resection with negative margins and spinal reconstruction followed by radiotherapy confers a significant survival benefit in these patients.

To refer patients with spinal tumors to the Spine Tumor Board, call the Cleveland Clinic Spine Institute at 216.444.2225 or 800.223.2273, ext. 42225.

Figure 1 [L5 spine met files]: Patient presented with low back pain and leg pain with a history of renal cell carcinoma. Preoperative saggital MRI shows a collapsed vertebral body at the fifth lumbar level (L5) with tumor extending into the pedicle and causing compression of an exiting nerve root. The tumor was removed using a posterior approach and reconstructed with methylmeth-acrylate (bone cement), Steinmann pins and pedicle screws fixation. The patient’s pain resolved, and he remained ambulatory after surgery.

Figure 2: Patient presented with a persistent cough and new hand pain and numbness. Pre-operative axial MRI shows a lesion of the apex of the lung (superior sulcus) representing a primary lung cancer. The tumor, which had invaded the brachial plexus and vertebral body of the spine, was removed via thoracotomy. The brachial plexus was identified, and arm and hand motor function preserved. A partial vertebrectomy was performed to remove the tumor from the vertebral body while avoiding the need for anterior spinal column reconstruction. The extensive bony and soft tissue resection did require spine stabalization using lateral mass and pedicle screws from a posterior approach in a staged second surgery.

2005 Annual Report A team approach to individualized care ��

Mladen Golubic, M.D., Ph.D.

A Dietary and Herbal Approach to Reducing Peritumoral Brain EdemaCleveland Clinic cancer researchers have initiated a clinical study of the effect of a vegan diet combined with herbal therapy on edema caused by glioblastoma multiforme (GBM). The two-pronged approach will be used as an adjuvant to standard therapy.

Because 5-LO-derived eicosanoids stimulate tumorigenesis and inflammation that lead to development of peritumoral brain edema, inhibition of 5-LO is an attractive therapeutic target.

“Cancer results from complex interactions between a genetically susceptible host and a variety of environmental factors. Diet is an important, modifiable environmental factor. Foods contain a spectrum of compounds that may modulate carcinogenesis by several mechanisms, including pro- and antioxidant effects, regulation of enzymes that detoxify carcinogens and alterations of hormone metabolism. Modulation of inflammation by compounds found in foods and herbs has recently attracted a lot of attention because of identification of critical molecular links between the processes of inflammation and carcinogenesis,” says Principal Investigator Mladen Golubic, M.D., Ph.D., of the Cleveland Clinic’s Brain Tumor Institute and Center for Integrative Medicine.

Dr. Golubic’s team recently demonstrated that a pro-inflamma-tory 5-lipoxygenase (5-LO) enzyme is aberrantly upregulated in GBM. 5-LO oxidizes nutritionally relevant fatty acids present in abnormally high concentrations in GBM, turning them into biologically active eicosanoids. Because 5-LO-derived eico-sanoids stimulate tumorigenesis and inflammation that lead to development of peritumoral brain edema, inhibition of 5-LO is an attractive therapeutic target. The research team is hoping their twopronged approach will inhibit 5-LO eicosanoid production and decrease peritumoral brain edema with fewer side effects than glucocorticoids.

In this study, funded by the national cancer institute, patients are randomized to a low-fat vegan diet plus boswellia serrata (frankincense) or to a diet recommended for cancer survivors by the american cancer society. B. serrata resin contains boswellic acids that inhibit 5-LO in a direct, non-redox, and non-competi-tive way distinct from that of other inhibitors. In two small german studies, crude herbal preparation of B. serrata was found to be beneficial in reducing brain edema in some patients with GBM. However, patients were not asked to reduce intake of dietary fats, which 5-LO uses to produce pro-inflammatory and pro-tumorigenic eicosanoids.

In the Cleveland Clinic study, B. serrata is combined with a low-fat vegan diet. Arachidonic acid, the key fatty acid from which eicosanoids are produced, is derived almost exclusively from animal sources. Thus, the intervention diet will consist exclusively of plant foods such as vegetables, legumes, unrefined whole grains, spices and fruits. A novel standardized preparation of B. serrata is used in place of crude extract. Because the preparation is solubilized in lipids, boswellic acids are expected to be more bioavailable.

GBM tumor growth, peritumoral brain edema and use of glucocorticoids are monitored every two months. Plasma measurements of 5-LO eicosanoids and boswellic acids are taken to evaluate adherence to therapy. “Incorporation of a combina-tion of dietary and herbal approaches as an adjuvant to standard

care allows patients to take charge of their lives, which is a major reason why patients with GBM are attracted to nutritional and herbal therapies,” says Dr. Golubic. To reach Dr. Mladen Golubic, call 216.445.7641 or e-mail golubim@ccf.org.

Frankincense, Key Medicinal Herb of the Ancient WorldTWO THOUSAND YEARS AGO, the “bestselling drug” was frankincense. The herb, with medicinal properties, is the product of a medium-to-large tree, Boswellia serrata, found in the dry hills of North Africa, the Middle East and India. The resin, exuded by the tree during winter months and deposited on the bark, contains oils, terpenoids and gum.

Historically, crude preparations of oleoresin exudate from the frankincense tree were widely used to treat wounds and various types of skin lesions. Hippocrates used frankincense to treat persistent ulcers. Avicenna, the foremost Arab physician of the 11th century, recommended it for inflammation, infections of the urinary tract, tumors, fevers, vomiting and dysentery. In Indian Ayurvedic medicine, frankincense is used as a remedy for rheumatism as well as inflammatory conditions of the eye and respiratory system. Modern clinical studies concur with ancient medical wisdom regarding its effectiveness in patients with bronchial asthma, ulcerative colitis, Crohn’s disease and osteoarthritis.

NeurosurgeryGene H. Barnett, M.D., F.A.C.S. Chairman, Brain Tumor Institute

Lilyana Angelov, M.D.

William Bingaman, M.D.*

Nicholas Boulis, M.D. *

Joseph F. Hahn, M.D.*

Damir Janigro, M.D.*

Joung Lee, M.D. Director, Section of Neurofibromatosis and Benign Tumors Head, Section of Skull Base Surgery

Mark Luciano, M.D., Ph.D.*

Peter Rasmussen, M.D.*

Samuel Tobias, M.D.*

Steven Toms, M.D., M.P.H. Head, Section of Metastatic Disease

Michael A. Vogelbaum, M.D., Ph.D. Director, Center for Translational Therapeutics

Robert Weil, M.D. Section Head, Pituitary and Neuroendocrine Surgery and Associate Director of Basic Laboratory Research

Henry Woo, M.D.*

NeurologyBruce H. Cohen, M.D.* Co-Director, Pediatric & Adolescent Brain Tumor Program

Glen H. Stevens, D.O., Ph.D. Head, Section of Adult Neuro-Oncology

Radiation OncologyAleck Hercbergs, M.D.*

Roger M. Macklis, M.D.*

John H. Suh, M.D. Director, Gamma Knife Center

Radiation Physics Christopher Deibel, Ph.D.

Gennady Neyman, Ph.D.

Martin S. Weinhous, Ph.D.

NeuropathologyRichard Prayson, M.D.*

Susan Staugaitis, M.D., Ph.D.*

Hematology & Medical OncologyBrian Bolwell, M.D.*

Medical OncologyDavid Peereboom, M.D. Head, Section of Medical Oncology

Pediatric OncologyKate Gowans, M.D.*

Joanne Hilden, M.D.* Chair, Pediatric Hematology & Oncology Co-Director, Pediatric & Adolescent Brain Tumor Program

Michael Levien, M.D.*

Gregory Plautz, M.D.*

Jawhar Rawwas, M.D.*

NeuroradiologyThomas Masaryk, M.D.*

Jeffrey S. Ross, M.D.*

Paul Ruggieri, M.D.*

Andrew Tievsky, M.D.*

Rehabilitative MedicineVinod Sahgal, M.D.*

ResearchGene H. Barnett, M.D. Chairman, Brain Tumor Institute

Nabila Bennani-Baiti, Ph.D.

Olga Chernova, Ph.D.

Peter Cohen, M.D.*

Mladen Golubic, M.D., Ph.D.

Andrei Gudkov, Ph.D.*

Jaharul Haque, M.D.*

Damir Janigro, Ph.D.*

Robert Miller, Ph.D. Senior Consultant

Gregory Plautz, M.D., Ph.D.*

Suyu Shu, Ph.D.*

Susan Staugaitis, M.D., Ph.D.*

Steven Toms, M.D., M.P.H. Head, Section of Metastatic Disease

Bruce Trapp, Ph.D.*

Raymond Tubbs, D.O.*

Michael A. Vogelbaum, M.D., Ph.D. Director, Center for Translational Therapeutics

Ilka Warshawsky, M.D.*

Robert Weil, M.D. Associate Director, Basic Laboratory Research Section Head, Pituitary and Neuro-Endocrine Surgery

Bryan Williams, Ph.D.*

Nursing/Physician AssistantsCathy Brewer, R.N.

Gail Ditz, R.N., B.S.N.

Sandra Ference, M.S.N., C.N.P.

Michele Gavin, M.P.A.S., P.A.-C.

Betty Jamison, R.N., B.S.N.

Debra Kangisser, P.A.-C.

Kathy Lupica, M.S.N., C.N.P.

Mary Miller, R.N., B.S.N.

Carol Patton, R.N.

Rachel Perez, R.N., B.S.N.

Sherry Soeder, M.S.N., C.N.P.

Lisa Sorenson, M.S.N., A.C.N.P.

Laural Turo, R.N., B.S.N.

Carla Yoder, M.S.N., C.N.P.

AdministrationKim Blevins Medical Secretary Work Leader

Michael Lawson, MBA Taussig Cancer Center Division Administrator

George Lawrence IV, MBA BTI Administrator

Henrietta-English West Patient Access Coordinator

Wendi Evanoff, B.A.

Noreen Flowers*

Charlotte Horner Patient Access Coordinator

Eric LaPresto

Systems Engineer

Sally McCartney

James Saporito Executive Director of Development

Kristin Swenson, MBA* Marketing Associate

Martha Tobin* Continuing Medical Education

Sherri Wilson

Tanya Wray, MBA* Marketing Manager

Cancer Center Research SupportJoanne Civic

Robert Gerlach

John Pellecchia

Kathy Robinson

Patricia Weiss, R.N.

Brain Tumor Institute Faculty*Denotes joint appointment

2005 Annual Report A team approach to individualized care �5

Members of the Brain Tumor Institute are available for consultation 24 hours a day, seven days a week. Their goal is to see patients with diagnosed or suspected brain tumors within 24 to 48 hours.

216.445.8971 or 800.553.5056, ext. 58971 (weekdays 8 a.m. to 5 p.m.) for consultations and/or hospital admission.

216.444.2200 (nights and weekends). Ask for neuro-oncology staff or the chief neurosurgical or neurological resident on call. For pediatric patients, ask for the chief pediatric neurological resident on call.

How to Refer a Patient to the Cleveland Clinic Brain Tumor Institute

Patient appointment line: 216.445.8971 or 800.223.2273, ext. 58971

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