The Brain Tumor Research Center (BTRC) was conceived a little over 40 years ago at Tulane University School of Medicine. There, Charles Byron Wilson MD - a resident at Charity Hospital in New Orleans - was frustrated by the knowledge that neither surgery nor radiation could offer a survival time of more than about 5 months for patients who had a malignant brain tumor. Deeply interested in and concerned about the dismal outlook for these patients, Wilson thought that future hope might lie in chemotherapy - the use of anticancer drugs.
Chemotherapy had originated from medical observations of soldiers exposed to sulfur mustard in chemical warfare during World War I. Evidence that the agent lowered lymphocyte counts led to the use of a somewhat less toxic agent, nitrogen mustard, to treat lymphoid cancers (27). By the 1950s, intracarotid injection of nitrogen mustard was being used in some centers to treat brain malignancies (21), but by 1961 brain tumor chemotherapy in the United States (US) still involved little more than an occasional heroic effort to administer a randomly selected agent to a patient in the final stages of disability (31). In that year, Wilson began a series of laboratory experiments which, he later said, were based on assumptions that seemed amazingly naive in retrospect (31). Trained in neurosurgery and pathology, Wilson published papers on chemotherapy by continuous arterial infusion in 1962 (28) and on brain tumor tissue culture in 1963 (33).
After faculty appointments at Tulane and then Louisiana State University, Wilson established the Division of Neurosurgery at the University of Kentucky Medical School in 1963. Between 1963 and 1968, he launched an experimental program to study the behavior of brain tumors, the nature and rate of their growth, and the manner in which they cause death. Among the most promising areas of investigation was a series of experiments in which potentially effective drugs were administered to tumor-bearing rats. Wilson, with Harvard cerebrospinal fluid physiologist Edgar Bering, organized the Kentucky Conference on Brain Tumor Chemotherapy that was held in 1965. Wilson outlined the objective of the conference before an audience of senior workers in the field - to seek a cure for malignant brain tumors.
A Laboratory to Study Neoplastic Disorders of the Nervous System
In 1968, Wilson was invited to be Professor and Chairman of the Neurological Surgery Division at the University of California, San Francisco (UCSF), an institution that held a position of renown among academic neurosurgeons. The first Chairman of Neurological Surgery at UCSF had been Howard C. Naffziger, who had trained with Harvey Cushing - widely considered the father of neurosurgery in America. Naffziger was an artist surgically, a pioneer of neurosurgery, and a nationally lauded educator. Although he did not do laboratory research himself, he recognized its vital importance to the future of neurological surgery and encouraged young neurosurgeons training with him to look to basic science to resolve neurosurgical problems. Edwin B. Boldrey, who succeeded Naffziger, was a pioneer of brain tumor therapy who would work with Wilson in developing the BTRC. John E. Adams was a key figure in the evolution of modern neurosurgery who shepherded the Neurological Surgery Division from a respected clinical center to one of the most productive centers of academic neurological surgery and research in the US.
Charles Wilson was the next in this distinguished line, and he transferred his laboratories from Kentucky to the UCSF School of Medicine with the aid of his research colleague from Kentucky, Marvin Barker MS. Joining them in 1968 was Professor Takao Hoshino, a scientist already internationally recognized for his work with cell cultures of human brain tumors. Work in the laboratories followed two major lines of research, one investigating the biological nature of brain tumors and implementing treatment, in particular with chemotherapy, and the other studying the pathophysiology and neuropathology of neurosurgical disorders to improve the neurosurgical techniques used to treat them (20). The brain tumor laboratory was subspecialized for cell culture, cell proliferation kinetics, cloning, chromosome and ultrastructural analysis, biochemistry of culture media, animal models for chemotherapy, and in vitro chemotherapy.
Clinical Research on Brain Tumors
The Clinical Chemotherapy Service, which would constitute the major clinical research arm of the BTRC, was initiated in 1968 under the joint direction of Wilson and former chairman Edwin Boldrey. In his long association with the United States Public Health Service, Boldrey had chaired its Neurological Sciences Research Training Committee A from 1966 to 1970 and served on the National Advisory Council for the National Institute of Neurological Disorders and Stroke (NINDS) from 1973 to 1977.
By 1970, 90 patients were registered for treatment. Clinical screening for agents with oncolytic potential depended on the physical, neurological, and radiological follow-up evaluation of patients, which was done by a chemotherapy nurse coordinator and a chemotherapy fellow. Derek Fewer MD, a resident from the Montreal Neurological Institute, was the first Chemotherapy Fellow. The Clinical Chemotherapy Service rapidly became the Northern California regional center for referral of people with brain tumors. As such, it was among the most active services of its kind in the US. Referrals of patients were not limited to this region, however - then, as now, patients came to UCSF from throughout the world.
The Howard C. Naffziger Laboratories for Neurosurgical Research
By 1970, too, the experimental arm of the BTRC was established in UCSF's new Howard C. Naffziger Laboratories for Neurosurgical Research. Naffziger, who had died in 1961, had envisioned a neurological institute in San Francisco, but circumstances had prevented its development during his lifetime. Originally designated the Howard C. Naffziger Institute for Neurological Research by the UC Regents in 1962, the laboratories were endowed by Berthold and Belle N. Guggenhime and Charles D. Kaeding. The dedication ceremony was held on May 6, 1970, the day that would have marked Naffziger's 86th birthday. The program for the dedication bore the following commemoration:
Doctor Naffziger was a man with the surgeon's impatience for inactivity and the critic's intolerance of mediocre performance. The use of Doctor Naffziger's name implies acceptance of his high standards. We are confident that the Naffziger laboratories will function in accordance with his wishes.
As director of the new laboratories, Wilson gave the welcoming remarks. The principal address was given by W. Eugene Stern, Naffziger's student and son-in-law, who developed the neurosurgical program at the University of California, Los Angeles. John Oswald, Executive Vice President of the University of California, announced in the course of his remarks that the Regents had just approved the reestablishment of Neurological Surgery as a distinct department at UCSF. Acknowledged in the program for their cooperation and collaborative efforts were several members of the UCSF faculty: W.F. Ganong MD and Clifford Kragt PhD in Physiology; Harvey Patt MD and James Cleaver PhD in the Radiobiology Institute; Selma Kaplan MD and Charles Epstein MD in Pediatrics; Nathan Malamud MD in the Langley Porter Neuropsychiatric Institute; Elizabeth Roboz-Einstein PhD and Robert Fishman MD in Neurology; and Jack deGroot PhD in Anatomy.
The new facilities were generous. The Department of Neurological Surgery was assigned a total of 4400 square feet for research. The Howard C. Naffziger Laboratories for Neurosurgical Research occupied 2634 square feet in the West Research Tower of the Health Sciences Building at UCSF's School of Medicine. An additional space of 1770 square feet was located in the East Research Tower. The space housed several research groups and included the offices of six principal investigators (PIs). Together with Wilson, the researchers who held academic appointments were Barker, who was in charge of cell culture and animal models, and Yoshio Hosobuchi MD, who had joined the faculty in 1969 to be in charge of the electron microscope laboratory and teaching activities. Supporting associates at UCSF were neuroradiologist T. Hans Newton MD, neuropathologists Nathan Malamud MD and Surl Nielsen MD, nuclear medicine specialist Malcom Powell MD, neuro-ophthalmologist William F. Hoyt MD, and radiation oncologists Glenn Sheline MD and Theodore Phillips MD - all of them outstanding within their respective disciplines and active in the applications of their specialties to brain tumor therapy.
Multidisciplinary Translational Research
Wilson had developed a comprehensive master research plan to pursue the objectives he had set years earlier - to seek effective treatment and, ultimately, a cure for malignant brain tumors. The Naffziger Labs provided a focal point for the research projects and a multidisciplinary center that represented the first concentration of scientific effort devoted exclusively to tumors of the central nervous system. In laboratory investigations, brain tumors were studied through basic and applied approaches. As the objective was to define the biological nature of brain tumors, the investigators had to represent a spectrum of the basic sciences, including experimental therapeutics, cell biology, cell kinetics, cell culture, radiation biology, and pharmacology. The correlation of data derived from the clinical and laboratory programs provided a means of rapid exchange of information among investigators, a process that was mutually enlightening and sometimes synergistic in effect. Accordingly, there was concerted emphasis on the importance of maintaining active intercommunication with other scientists engaged in every aspect of cancer research in the US and throughout the world. The faculty member's involvement, whether direct or indirect, was the pivotal factor in the quality of the work achieved in this multidimensional approach to brain tumor research. Their expertise spanned diverse fields and specialties of UCSF's distinguished School of Medicine, and they included neurosurgeons, neurologists, oncologists, radiologists, radiation therapists and physicists, nurses, clinical pharmacologists, pharmacists, pharmaceutical chemists, biometricians, kineticists, cellular biologists, and many other specialists.
With a translational approach unique at that time, BTRC researchers were soon to establish the first drugs effective against brain tumors - but for a variety of reasons progress in brain tumor research initially was slow. Not the least of these reasons was the limited support available to interested investigators. Within the National Institutes of Health (NIH), interest in the field was expressed by the NINDS∗ and by the National Cancer Institute (NCI), but brain tumors seemed to fall into an area that was not entirely within the province of either institute. On September 17, 1970, Wilson wrote to William Hammond MD at the NCI about the evolution of a Brain Tumor Research Center at UCSF and the possibility of obtaining NCI support for its program of clinical chemotherapy, research, and training - the letter that initiated the BTRC.
By 1972, the Naffziger Labs had grown in size and personnel, and the proposed research plan listed 15 projects, including immunological and DNA studies. That year, Kenneth T. Wheeler PhD, a pioneer in experimental radiation oncology, became a BTRC PI, and Victor Levin, who had trained in clinical pharmacology at the NIH and in neurology at Massachusetts General Hospital, joined the BTRC to work on the pharmacokinetics of anticancer drugs. The clinic had grown to 239 patients, requiring the assignment of a second fellow, Justin Renaudin MD.
The National Institutes of Health Sponsor Brain Tumor Research
The training of postgraduate fellows for careers in brain tumor research had become an important function of the BTRC, for which it was funded separately. The combination of active research and training programs and the prime academic and clinical setting of UCSF culminated in the NIH's approving a Cancer Center research grant to UCSF on June 1, 1972. January 17, 1973, marked inaugural ceremonies for the BTRC, at the core of which were the Naffziger Laboratories. UCSF Chancellor Francis A. Sooy opened the inaugural program, which featured internationally known neurosurgeon Paul C. Bucy MD as special guest speaker. The BTRC was the first such categorical Center approved by the NCI, and its combined clinical service and laboratory program was the only such effort in the US to receive federal support. Its creation indicated a policy of major interest and investment in brain tumor research by the NCI that encouraged activity in the field at other centers.
Wilson served as Director of the BTRC and Barker as Associate Director and Academic Administrator. In rapid succession, investigators from different disciplines joined the research group, and the BTRC's multidisciplinary approach to brain tumor research became firmly established. Among them were Laurence J. Marton MD, who became a PI in 1973. Marton began his training in neurological surgery and, after turning his interests to laboratory medicine, became chairman of that department at UCSF. Myron R. Blume MD, PhD and Robert J. Weinkam PhD were also with the BTRC at this time. Mark L. Rosenblum MD - a neurosurgery resident and already prolific in his research - became a PI in 1973. Philip H. Gutin MD - also a neurosurgery resident, who had taken a 3-year NCI fellowshipÐbecame a PI in 1979. Dennis F. Deen PhD, a research biophysicist who did his postdoctoral fellowship with Kenneth Wheeler, replaced Wheeler as a PI when Wheeler left the BTRC for a position in Rochester, New York in 1976.
In the aggregate, the laboratory and clinical observations made during the first few years by BTRC investigators influenced the direction of brain tumor chemotherapy in the US, and several centers were established at other institutions for the investigation and treatment of patients afflicted with malignant brain tumors.
The BTRC 'Takes Off'
The number of patients treated on the BTRC's clinical chemotherapy service tripled between 1972 and 1976, and by then more than 200 new patients were referred each year for chemotherapy. Intramural collaborative efforts progressed vigorously. In 1974, 250 patients were enrolled in various protocols of single and combination drugs administered with and without conventional radiation therapy, and later with hydroxyurea as a radiopotentiator. Victor Levin became Assistant Director of the BTRC in that year and later, in 1977, became Chief of the Chemotherapy Service and Associate Director of the BTRC for Clinical Services. Levin, with Wilson's support, was among the BTRC investigators who organized the first International Conference on Brain Tumor Research and Therapy, which was hosted by the BTRC at the Asilomar Conference Grounds in Pacific Grove, California, in the fall of 1975. This conference continues on a biennial basis and has been hosted by the BTRC several times.
By 1976, the BTRC had a professional working force of 31 full-time staff and 26 official collaborators. BTRC researchers were able to report limited success with chemotherapy of the most common malignant brain tumors, glioblastoma and medulloblastoma. They had published the initial reports showing the efficacies of carmustine (BCNU) (2, 30) and procarbazine (13) - still the single-drug therapies most effective against malignant glioma, the most common type of brain tumor. The clinical arm of the BTRC had identified the multidrug protocol combining procarbazine, lomustine (CCNU), and vincristine (PCV) as a highly effective treatment - the first drug combination effective against brain tumors (10). With these achievements, Wilson and his colleagues believed their progress justified optimism concerning the future of brain tumor chemotherapy. In April 1979, the BTRC was awarded its first NIH Program Project Grant to investigate the biology and therapy of malignant brain tumors - an award that would be renewed consistently during the years that followed.
Two Decades of Discovery
Over the next two decades, BTRC basic science investigators and clinical trials specialists worked together in a dedicated effort to improve known effective therapies for brain tumors and develop new ones. During the 1980s, the BTRC had collaborative ties with the University of California, Berkeley (UCB), and BTRC investigators - among them biochemist William J. Bodell PhD, who joined the BTRC in 1981 - worked with UCB scientists Ron Talcott and Martyn Smith (3, 7). Radiation biologist John R. Fike PhD became a PI in 1982, at a time when BTRC investigators were refining radiation therapy and defining new applications for its use. Also during that period, work done by Michael S.B. Edwards MD, in collaboration with pediatric radiation oncologist William M. Wara MD, and the work of resident and BTRC fellow Mitchel S. Berger MD presaged later development of the BTRC as a pediatric center for brain tumor research and therapy.
BTRC investigators were the first to propose lower doses of craniospinal-axis irradiation for medulloblastoma (14) and were among the first to oppose whole-brain irradiation for malignant gliomas (15). They introduced hyperfractionated irradiation for brain stem gliomas (6) and introduced radiosurgery to the west coast of the US. They were among the first to use brachytherapy for brain tumors in the US and have treated more patients with this modality than has any other center. They were the first to use high-activity iodine-125 for brachytherapy (9) and suggested it as an optimal treatment for glioblastoma in selected patients (23). They also pioneered the use of hyperthermia and brachytherapy for recurrent malignant glioma (24) and primary glioblastoma multiforme (25).
In chemotherapy research, BTRC investigators showed that single-dose BCNU is as effective as multidose therapy and showed the superiority of PCV over single-dose therapy for anaplastic astrocytoma and oligodendroglioma. They published the first reports regarding steroid dose dependency (19) and on the use and efficacy of polyamine biosynthesis inhibitors (16). They designed and implemented the first protocol to overcome BCNU resistance by using thioguanine, and were among the first centers to use multiagent nitrosourea-based chemotherapy as primary treatment for childhood glioma (18). BTRC investigators were also leaders in brain tumor clinical trials. They established the response criteria for phase 2 studies (13), the importance of controlling for steroids, irradiation, and intercurrent illness in judging progression or regression of treated tumors, and the critical importance of obtaining scans within 72 hours of surgery. BTRC laboratory studies defined the kinetic parameters of gliomas and other primary brain tumors (11) and established the prognostic value of the bromodeoxyuridine (BUdR) labeling index (12).
BTRC investigators developed the first clonogenic assay for human gliomas (22) and an assay for measuring urinary polyamines in patients with medulloblastoma (17), and they developed numerous BCNU-resistant glial animal and human cell lines. They developed and characterized the 9L rat brain tumor, which had been introduced by the Massachusetts General Hospital and has become the most widely used animal model for brain tumor research (26). They also developed a canine model for noninvasively studying radiation damage to normal tissue (8). The BTRC's large and completely characterized Tissue Bank currently holds frozen samples from more than 4500 cases collected since 1978.
Transsphenoidal Surgery for Pituitary Tumors
While dedicated to improving treatment for brain malignancies, Charles Wilson had clinical interest in another form of brain tumor and in a surgical approach that had intrigued chairmen who preceded him at UCSF. Naffziger had done a successful transsphenoidal operation for acromegaly in February 1922 (20). Just as Wilson arrived at UCSF in 1968, Adams' report on transsphenoidal cryohypophysectomy as treatment for acromegaly was published (1). The patients undergoing that procedure who continued to have persistent excessive secretion of growth hormone - 25% of those operated - were the first patients Wilson treated with the transsphenoidal microsurgical procedure (32). His success with this approach led to its use as initial therapy for acromegaly with preservation of normal pituitary function (20), and he used the transsphenoidal operation for prolactinoma, and later for corticotrophin-secreting adenomas. He had operated on 40 patients through the transsphenoidal route by 1970, 95 by 1974, and, by the time he retired from surgical practice on January 2, 2002, more than 3300. Acknowledged for his preeminence as a pituitary neurosurgeon, he was asked to deliver the Herbert Olivecrona Lecture on the treatment of pituitary adenomas at the Karolinska Institute in Stockholm in 1984 (29).
When Victor Levin left the BTRC in 1988 to join the University of Texas M. D. Anderson Cancer Center, Michael D. Prados MD became Chief of the Neuro-Oncology Service (NOS), as the Clinical Chemotherapy Service had come to be known. Dennis Deen became Associate Director for Scientific Research. That year, too, Griffith R. Harsh IV became a BTRC PI after taking his neurological surgery residency training and a neuro-oncology fellowship at UCSF.
On June 6, 1988, Edwin Boldrey died. His lifelong interests had encompassed brain tumor therapy, epilepsy, aneurysms, and AVMs. Revered by a generation of neurosurgeons for his grace and integrity, his memory is honored with the Boldrey Lectureship in Neurological Surgery, which was established at UCSF in 1983.
The BTRC's Preuss Laboratory for Molecular Neuro-Oncology opened in 1990 under the direction of Mark A. Israel MD. He investigated the molecular basis for the regulation of differentiation and growth in the nervous system, and worked to establish a molecular classification for neoplastic disorders of the nervous system and to identify targets for the development of novel therapeutic strategies. Israel became Director of the Norris Cotton Cancer Center at Dartmouth College in New Hampshire in 2001, and a search began to recruit a new investigator to the laboraotory.
The year 1992 marked the beginning of real transition for the BTRC. Laurence Marton, a pioneer in the use of polyamines to treat human diseases related to cell growth, accepted the position of Dean of the University of Wisconsin-Madison Medical School. Mark Rosenblum left UCSF to chair the Department of Neurosurgery and become Co-director of the Hermelin Brain Tumor Center at Henry Ford Hospital in Detroit, Michigan. Griffith Harsh accepted a position at Harvard Medical School in Boston, and then in 1998 returned to California to join the Neurosurgery faculty at Stanford.
In 1993, Marvin Barker, whose understated leadership, research skill, and administrative wisdom had helped build the BTRC and steer its course since its inception, stepped down as Associate Director and Academic Administrator and retired to Northern California. Dennis Deen assumed the responsibilities of Academic Administrator of the BTRC together with his Associate Directorship.
Professor Takao Hoshino died on January 23, 1993, having made important contributions with his work on cell kinetics, the proliferative potential of astrocytomas and glioblastomas, and the prognostic value of the BUdR labeling index. Internationally respected as a research neuro-oncologist and revered as an educator, Hoshino fostered a bridge between brain tumor research communities in the US and Japan. During his career, he supported and trained more than 20 physician-researchers at UCSF, many of whom returned to Japan to create their own laboratories and brain tumor treatment centers. He left as his legacy a grant awarded annually to a young neurosurgeon with a bright future. His memory is honored with The Takao Hoshino Lectureship in Basic Brain Tumor Biology at UCSF.
The Baton is Passed
In 1994, amid unprecedented changes in the health care system in the US, Charles Wilson was appointed Director of Tertiary Care Services at UCSF. Concurrently, he resigned as Chairman of the Department of Neurological Surgery to undertake graduate study and commit a major part of his time to his new role, believing that he could serve the best interests of UCSF by acting as an intermediary between the Medical Center and outside entities ranging from health care delivery systems to health plans. After earning his Master of Science in Health Administration degree from the University of Colorado, he became Senior Associate on Medical Affairs to the President of the University of California in 1996. At the 11th International Conference on Brain Tumor Research and Therapy, held at Silverado in California's Napa Valley during October 1996, Wilson announced that he would step down as Director of the BTRC. At the time, the basic science principal investigators in the BTRC were Associate Director and Academic Administrator Dennis F. Deen PhD; William J. Bodell PhD; Burt G. Feuerstein MD, PhD; John R. Fike PhD; Philip H. Gutin MD; and Mark A. Israel MD. The principal clinical investigators were Director of the Neuro-Oncology Program Michael D. Prados MD; Assistant Director Susan M. Chang MD; M. Kelly Nicholas MD, PhD; and radiation oncologist David Larson MD, PhD and neurosurgeon Michael W. McDermott MD, both specialists in Gamma Knife® radiosurgery.
After a search for a new chairman, Philip Gutin was named to chair the Department of Neurological Surgery. Shortly afterward, offered the position of Chief of the Neurosurgical Service at Memorial Sloan Kettering-Cancer Center in New York, Gutin left UCSF in 1996. Wilson resumed the chair while another search was undertaken and in April 1997, Mitchel S. Berger was recruited from the University of Washington, Seattle, to return to UCSF to succeed Wilson as Department Chair and the BTRC's Director. Founding Director of the BTRC, Chairman of Neurological Surgery at UCSF for 28 years, and the first professor to hold the Tong-Po Kan Chair of Neurological Surgery at UCSF, Wilson began a new career that enabled him pursue his interests in issues regarding academic medical centers, emerging medical technologies, the health care workforce, and the impact of genomic medicine on health and health care. He became UCSF Professor Emeritus of Neurological Surgery on January 2, 2002.
During this period, the BTRC's principal investigators continued their productivity unabated. In the laboratory of Dennis Deen, ongoing work continued to develop methodologies to identify tumors sensitive to radiation or to quantify tumors' sensitivity to radiation, and to see if combinations of drugs and radiation might have efficacy in brain tumor therapy. William Bodell investigated molecular mechanisms for cellular resistance of gliomas to chemotherapy and the development of regimens that can overcome drug resistance. Molecular biologist Burt Feuerstein continued his groundbreaking work investigating and developing genetic markers of brain tumor outcome and elucidating mechanisms that underlie marker performance. John Fike's work to improve and develop radiation therapies further described how damage to normal tissues develops from the irradiation of malignant brain tumors - work that has markedly improved clinical applications of radiation therapy for patients with brain tumors. Kelly Nicholas focused on basic research developing transgenic brain-tumor model systems. Biostatistician Kathleen Lamborn PhD formally joined the BTRC faculty to work with BTRC investigators in the design and analysis of their studies.
The clinical aspect of the BTRC became even more robust during this time. Michael Prados was named the leader of the NCI's North American Brain Tumor Consortium (NABTC), which sponsors trials of treatment regimens for brain tumors and is based at UCSF. Working with him, Susan Chang - who had joined the BTRC in 1994 - became Assistant Director of the Clinical Neuro-Oncology Program and Director of Clinical Services with the BTRC Neuro-Oncology Program. Prados was also named a principal investigator of the Pediatric Brain Tumor Consortium (PBTC) and leader of the PBTC site at UCSF, which is one of nine institutions in the US selected to participate in this NIH-funded cooperative effort to develop effective new strategies for treating children with malignant brain tumors. Together with Prados and Mitchel Berger, key members of the PBTC at UCSF are pediatric specialists including neurosurgeon Nalin Gupta MD, PhD; neuro-oncologist Anuradha Banerjee MD, MPH; neuroradiologist James Barkovich MD; research neuroradiologist Sarah J. Nelson PhD; Burt G. Feuerstein MD, PhD; radiation oncologists Daphne Haas-Kogan MD and William M. Wara MD; and neuropathologist Andrew W. Bollen DVM, MD.
Looking to the Future
Since 1997, Berger's tenure as Director of the BTRC has been marked by dynamic growth and expansion of the BTRC's programs and potential. To the strong research faculty of the BTRC have been added outstanding new investigators in complementary fields. They include Anuradha Banerjee MD, MPH; Krys Bankiewicz MD PhD; Gabriele Bergers PhD; Arturo Alvarez-Buylla PhD; Soonmee Cha MD; Joseph F. Costello PhD; Nalin Gupta MD, PhD; Daphne Haas-Kogan MD; Sandeep Kunwar MD; Andrew T. Parsa MD, PhD; Russell O. Pieper PhD; William A. Weiss MD, PhD; and Margaret R. Wrensch PhD. Institution of the Michael Douglas Pediatric Brain Tumor Research Center in 1999 made the BTRC the largest brain tumor treatment program in the nation and one of the few centers in the world offering state-of-the-art research and treatment for brain tumors afflicting both children and adults. In September 2001, funding of the NIH Program Project Grant supporting the Program for the Treatment of Malignant Brain Tumors was once again renewed for a 4-year period ending in 2005 - in all, a period of nearly 27 years since the BTRC was first awarded a Program Project Grant. Funding of an NIH Specialized Programs of Research Excellence (SPORE) Grant for brain tumor research beginning in 2002, with Mitchel Berger as Program Director, Michael Prados as Director of Clinical Science, and Russ Pieper as Director of Basic Science, opened collaborative work between BTRC investigators and three BTRC Associates and PIs, Sarah J. Nelson PhD, John Park MD, and David Stokoe PhD, as well as between investigators in the BTRC and those in the other SPORE programs in the UCSF Comprehensive Cancer Center. Through Berger's vigorous efforts, the BTRC's financial base has expanded, its work is secure, and the Department of Neurological Surgery is gratified to have eleven endowed professorial chairs, of which six are held by BTRC principal investigators.
Since its inception, the BTRC has trained new clinicians and researchers to carry on its mission. Medical students, graduate students, residents, chemotherapy or neuro-oncology fellows, and postdoctoral fellows and researchers from throughout the US and much of the world have studied or worked in collaboration with BTRC faculty members and contributed to the BTRC's work. Aspects of research guidelines developed for BTRC trainees have been incorporated into guidelines adopted by departments at UCSF and other biomedical institutions (5). Altogether, the BTRC has trained more clinical neuro-oncologists and basic scientists in brain tumor research than any other center - more than 170 young researchers, many of whom have gone on to successful careers in the field.
Missing from this history have been the many staff members who have contributed their knowledge, skill, and dedicated efforts to the BTRC. Staff Research Associates are the backbone of a laboratory. Among those who worked with the BTRC for many years and were important to its success during its development are Enav Bar-Shira, Anne Byrd, Judit Csejtey, Laleh Daneshvar, Mary Freeman-Dove, Jane Giblin, Shirley Hervatin, Mary Helen Barcellos-Hoff, Madeline Huey, David Hung, Carol Julin, Laura Kendall, Kathy Knebel, James Linn, Jane Liu, Warren Lubich, Sandra Miranda, Stephanie Pentecost, Tana Pischer, Jytte Rassmussen, Connie Reese, Jerome Seidenfeld, Theresa Seilhan, David Shiba, Donna Spencer, Pamela Vestneys, Mary Williams, and Cindy Wang. Lab assistants Charles Nelson and Benjamin Usog were geniuses at finding anything needed to furnish a lab.
Dolores V. Dougherty worked with Mark Rosenblum to create a tissue bank beginning in 1978 and developed this valuable research resource as Manager of the BTRC Tissue Bank since it was formally established in 1992 (4). Peter Coopersmith was the first Tissue Bank assistant.
Essential to the clinical branch of the BTRC are the nurses of the Clinical Neuro-Oncology Program, which was known for many years as the Chemotherapy Service. K. Jean Enot RN was the nurse for the Chemotherapy Service at its inception in 1968. In 1971, she was joined by Margaret Seager RN, who was with the BTRC until she retired in 1987. Working with Peggy Seager over the years were Marguerite Neely RN, Martha Roberts RN, Janice Scott RN, Elinor Silverstein RN, and Carol Maroten RN. During that time, their branch of nursing evolved to become a nursing subspecialty - Neuro-Oncology Nursing. Jane E. Rabbitt RN, BSN joined the Neuro-Oncology Program in 1988. She and Margaretta Page RN, MS, the current Clinical Nurse Specialists, were recently joined by a third nurse, Anne Fedoroff RN.
As the BTRC's first Research Administrator and later Management Services Officer of the Department of Neurological Surgery, Kathleen Smith was a vital contributor to the BTRC's success from the beginning. Among other administrative staff who have kept the BTRC on course have been Ruth Burke, Francoise Case, Dorothy Mark, Marilyn Minnaar, Lydia Moskwin, Ann Schlee, Frances Schroeder, Corinne Tofilon, and Leslie Williams. Heading the Neurological Surgery Editorial Office, established by John Adams in 1962, Judith T. MacMillan was succeeded by Marty Sucec and then, in 1977, by Susan Eastwood. Many PIs, fellows, and postdocs met grant deadlines and lengthened their publication lists with the help of editors Neil Buckley, Pamela Derish, Stephen Ordway, and Barbara Riddle, and editorial assistants Cindy Huff, Beverly McGehee, Tania Retivov, Cheryl Christensen, Renee Drouet, Mary Ellen Kuhlmann, and Deborah Morgan.
This retrospective can relate only highlights of the past 30 years. The work of the people named here has been supported and catalyzed by a great many others - by fellows and residents; by collaborating faculty in Neurological Surgery and other departments, laboratories, and institutions; and by other staff who have contributed to the success of the BTRC. Today, the BTRC's mission is still to develop effective therapies and define the basic nature of human brain tumors - and, in the long term, to find a cure through a translational approach to clinical research that is based on a foundation of experimental laboratory investigation. The BTRC's Clinical Neuro-Oncology Program now sees approximately 2400 patients each year, of whom approximately 500 are new patients with primary malignant brain tumors. With the contributions of everyone who has participated in the journey, the multidisciplinary effort that began with a vision has matured into the creative and dedicated scientific community that now functions as the BTRC - a center focused on its goal and the only such center designated by the NCI and continuously funded by the NIH since 1972.
This history was reproduced or adapted in part with permission from Harold Rosegay PhD, MD and Williams & Wilkins, publishers of Rosegay H: A History of Neurological Surgery at the University of California, San Francisco (Neurosurgery 38:794-805, 1996); from BTRC. Brain Tumor Research Center (Sucec M. San Francisco: University of California San Francisco Publications Office, 1976.); and from the program for the dedication of the Howard C. Naffziger Laboratories for Neurosurgical Research. Contributions were provided by Charles B. Wilson MD, MSHA, DSc; Dennis Deen PhD; Harold Rosegay PhD, MD; John Adams MD; Cone Pevehouse MD; Robert Fishman MD; Marvin Barker MS; Nicholas Barbaro MD; Michael Prados MD; Grant Gauger MD; Paul Matz MD; Kathleen Smith; and Susan Eastwood ELS(D).
∗The National Institute of Neurological Disorders and Stroke (NINDS) is referred to consistently by that name to avoid confusion. Actually, in 1975, the NINDS became the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS). In 1988, the communicative disorders program became the nucleus of the National Institute of Deafness and Other Communication Disorders, and the NINCDS was renamed the NINDS.
1. Adams JE, Seymour RJ, Earll JM, Tuck M, Sparks LL, Forsham PH: Transsphenoidal cryohypophysectomy in acromegaly: Clinical and endocrinological evaluation. J Neurosurg 28:100-104, 1968.
2. Barker M, Hoshino T, Gurcay O, Wilson CB, Nielsen SL, Downie R, Eliason J: Development of an animal brain tumor model and its response to therapy with 1,3-bis(2-chloroethyl)-a-nitrosourea. Cancer Res 33:976-986, 1973.
3. Berger MS, Talcott RE, Rosenblum ML, Silva M, Ali-Osman F, Smith MT: The use of quinones in brain tumor chemotherapy: preliminary results from preclinical investigations. J Tox Environ Health 16:713-719, 1985.
4. Dougherty DV, Chiu K, Lamborn K, Deen DF : Organization and Maintenance of a Tissue Bank and Its Related Database. Eleventh International Conference on Brain Tumor Research and Therapy; October 31-November 3, 1995.
5. Eastwood S, Cogen PH, Fike JR, Rosegay H, Berens M: BTRC Guidelines on Research Data and Manuscripts. San Francisco, Brain Tumor Research Center, Department of Neurological Surgery, School of Medicine, University of California, San Francisco, 1989. Reprinted in: Responsible Science: Ensuring the Integrity of the Research Process. Washington, DC: National Academy Press, vol II, 1993, pp 206-222; and in Bulger RE, Heitman E, Reiser SJ (eds.): The Ethical Dimensions of the Biological and Health Sciences (2nd edition). Cambridge: Cambridge University Press, 2002.
6. Edwards MSB, Wara WM, Urtasun RC, Prados M, Levin VA, Fulton D, Wilson CB, Hannigan J, Silver P: Hyperfractionated radiation therapy for brain-stem glioma: A phase I-II trial. J Neurosurg 70:691-700, 1989.
7. Evans CG, Bodell WJ, Tokuda K, Doane-Setzer P, Smith MT: Glutathione and related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1 -nitrosourea and nitrogen mustard. Cancer Research 47: 2525-2530, 1987.
8. Fike JR, Cann CE, Davis RL, Phillips TL: Radiation effects in the canine brain evaluated by quantitative computed tomography. Radiology 144:603-608, 1982.
9. Gutin PH, Phillips TL, Hosobuchi Y, Wara WM, MacKay AR, Weaver KA, Lamb S, Hurst S: Permanent and removable implants for the brachytherapy of brain tumors. Int J Radiat Oncol Biol Phys 7:1371-1381, 1981.
10. Gutin PH, Wilson CB, Kumar ARV, Boldrey EB, Levin V, Powell M, Enot KJ: Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors. Cancer 35:1398-1404, 1975.
11. Hoshino T, Barker M, Wilson CB, Boldrey EB, Fewer D: Cell kinetics of human gliomas. J Neurosurg 37:15-26, 1972.
12. Hoshino T, Prados M, Wilson CB, Cho KG, Lee K-S, Davis RL: Prognostic implications of the bromodeoxyuridine labeling index of human gliomas. J Neurosurg 71:335-341, 1989.
13. Kumar ARV, Renaudin J, Wilson CB, Boldrey EB, Enot KJ, Levin V: Procarbazine hydrochloride in the treatment of brain tumors. Phase 2 study. J Neurosurg 40:365-371, 1974.
14. Levin VA, Rodriguez LA, Edwards MSB, Wara WM, Liu H-C, Fulton D, Davis RL, Wilson CB, Silver P: Treatment of medulloblastoma with procarbazine, hydroxyurea, and reduced radiation doses to whole brain and spine. J Neurosurg 68:383-387, 1988.
15. Levin VA, Wara WM, Davis RL, Vestnys P, Resser KJ, Yatsko K, Nutik S, Gutin PH, Wilson CB: Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea to patients with malignant glioma. J Neurosurg 63:218-223, 1985.
16. Marton LJ: An approach to the use of polyamine biosynthesis inhibitors for cancer therapy. Med Biol 59:458-461, 1981.
17. Marton LJ, Edwards MS, Levin VA, Lubich WP, Wilson CB: CSF polyamines: A new and important means of monitoring patients with medulloblastoma. Cancer 47:757-760, 1981.
18. Phuphanich S, Edwards MSB, Levin VA, Vestnys PS, Wara WM, Davis RL, Wilson CB: Supratentorial malignant gliomas of childhood. Results of treatment with radiation therapy and chemotherapy. J Neurosurg 60:495-499, 1984.
19. Renaudin J, Fewer D, Wilson CB, Boldrey EB, Calogero J, Enot KJ: Dose dependency of Decadron in patients with partially excised brain tumors. J Neurosurg 39:302-305, 1973.
20. Rosegay H: A History of Neurological Surgery at the University of California, San Francisco. Neurosurgery 38:794-805, 1996.
21. Rosegay H: personal communication, August 2002.
22. Rosenblum ML, Vasquez DA, Hoshino T, Wilson CB: Development of a clonogenic cell assay for human brain tumors. Cancer 41:2305-2314, 1978.
23. Scharfen CO, Sneed PK, Wara WM, Larson DA, Phillips TL, Prados MD, Weaver KA, Malec M, Acord P, Lamborn KR, Lamb SA, Ham B, Gutin PH: High activity iodine-125 interstitial implant for gliomas. Int J Radiat Oncol Biol Phys 24:583-591, 1992.
24. Sneed PK, Gutin PH, Stauffer PR, Phillips TL, Prados MD, Weaver KA, Suen S, Lamb SA, Ham B, Ahn, DK, Lamborn K, Larson DA, Wara WM: Thermoradiography of recurrent malignant brain tumors. Int J Radiat Oncol Biol Phys 23:853-861, 1992.
25. Sneed PK, Larson DA, Gutin PH: Brachytherapy and hyperthermia for malignant astrocytoma. Semin Oncol 21:186-197, 1994.
26. Weizsaecker M, Deen DF, Rosenblum ML, Hoshino T, Gutin PH, Barker M: The 9L rat brain tumor: Description and application of an animal model. J Neurol 224:183-192, 1981.
27. Tirgan MH: Internet Web site of Tirgan Oncology Associates
28. Wilson CB: Chemotherapy of brain tumors by continuous arterial infusion. Surg Forum 13:423-425, 1962.
29. Wilson CB: A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 61:814-833, 1984.
30. Wilson CB, Gutin P, Boldrey EB, Crafts D, Levin VA, Enot KJ: Single-agent chemotherapy of brain tumors. A five-year review. Arch Neurol 33:739-744, 1976.
31. Wilson CB: Message from the Director. IN : Sucec M: BTRC. Brain Tumor Research Center. San Francisco: University of California San Francisco Publications Office, 1976.
32. Wilson CB, Rand RW, Grollmus JM, Heuser G, Levin S, Goldfield E, Schneider V, Linfoot J, Hosobuchi Y: Surgical experience with a microscopic transsphenoidal approach to pituitary tumors and non-neoplastic parasellar conditions. Calif Med 117:1-9, 1972.
33. Wilson CB, Weilbaecher R, McGarry P: Characteristics of human brain tumors in tissue cultures and animal host. Surg Forum 14:430-431, 1963.
To contact the UCSF Department of Neurological Surgery with questions about medical matters, call 415-353-7500 or fax 415-353-2889.
For information about the UCSF Neurological Surgery Residency Program, call 415-353-3904 or fax 415-353-3907.
Copyright ©2003 UCSF Neurosurgery. All rights reserved.