A History of Neurological Surgery at the University of California, San Francisco 1912-1995


Harold Rosegay PhD, MD
Department of Neurological Surgery
School of Medicine
University of California, San Francisco, California
 
Adapted with permission from Dr. Rosegay and from Williams & Wilkins, publishers of Rosegay H: A History of Neurological Surgery at the University of California, San Francisco. Neurosurgery 38:794-805, 1996.
 
Over a span of 80 years and four chairmanships, the Department of Neurological Surgery at the University of California, San Francisco has held a position of renown among academic institutions serving neurological surgery. This history attributes this reputation to the qualities of the Chairmen, an unforgettable group including Naffziger, Boldrey, Adams, and Wilson. Some of their accomplishments are described.
 
Introduction
 
In 1912, Howard Naffziger returned to San Francisco from Baltimore, where he and Walter Dandy had spent almost a year as assistant residents under Harvey Cushing. Cushing was entering his second decade in the practice of neurological surgery. Others in that newly developing field on the East Coast at the time were Samuel Mixter and William Jason Mixter in Boston, Charles Elsberg and Alfred Taylor in New York, Charles Frazier in Philadelphia, and Claude Coleman in Virginia. In the western United States (US) at that time, there were only Allen Kanavel in Chicago and Ernest Sachs, who went to St. Louis in 1911. Carl Rand in Los Angeles and Alfred Adson at the Mayo Clinic were not to begin their neurosurgical careers for 3 or 4 more years. For all these men, neurological surgery began as a distillate of general surgery to which William McEwen, Victor Horsley, and Fedor Krause had added their genius.
 
Naffziger had much to reflect on during his trip home, for he had learned current clinical practice and refined neurosurgical technique from Cushing; but, as importantly, he could not have left without a sense of his responsibility for advancing neurosurgery. Being a "path-finder" meant as much to Cushing as did "brilliancy of operative manipulation," and he wrote at length on this theme in 1910, giving also his appraisal of the state and promise of neurosurgery (14).
 
The beginning of neurological surgery at the University of California, San Francisco
 
In researching the early years of Neurological Surgery at the University of California, San Francisco (UCSF), we had access to the charts of Naffziger's patients beginning in 1913, when he was assistant in surgery in the School of Medicine and assistant surgeon at the University of California (UC) Hospital. Working along lines established by Cushing, he performed 21 decompressions for brain tumor, seven tumor verifications, and two removals by 1920, the same proportions as were reported by Cushing in 1910 and 1920. Cushing had said that subtemporal and suboccipital decompression are "the two most useful procedures in craniocerebral surgery" as a first step for tumors that cannot be localized (15). One patient who came to Naffziger in 1920 brought with him a letter which his consultant had sent to the patient's brother (a physician) as follows: "You and I know that surgical assaults upon the brain, although spectacular, do not give much promise from the patient's standpoint. Therefore, I am suggesting that a simple decompression be done by a competent surgeon. Should a dural growth be present, it can be dealt with." In this case Naffziger verified a left frontal glioma by frontotemporal osteoplastic craniotomy, which allowed him to make a subtemporal decompression first.
 
Besides craniotomy for brain tumor, the following operations were done during this period: osteoplastic craniotomy for epilepsy related to trauma or congenital brain lesions [15 cases]; craniotomy or subtemporal decompression for trauma [15]; neurorrhaphy and neurolysis [14]; hydrocephalus procedures, mainly the Balkenstich operation [6]; laminectomy for spinal-cord tumor [6] and for acute trauma [2]; root section, neurectomy, or alcohol injection for trigeminal neuralgia [6]; drainage of brain abscess [2]; cranioplasty [4]; and orbital decompression [2 cases].
 
Naffziger's name does not appear in the surgical records from 1917 to 1919 as he was serving in the US Army Medical Corps, stateside and in France (11). During that time, only eight cases were operated by the surgical staff: trigeminal ganglionectomy [3], brain tumor surgery [2], drainage of brain abscess [1], surgery for Jacksonian epilepsy [1], and one operation for depressed fracture with epidural hematoma.
 
The Twenties: expansion and writings
 
A resurgence of patients greeted Naffziger on his return in 1919 and so he began to build his staff. Howard Fleming, a surgical resident at UCSF from 1917 to 1919, was sent to Cushing to be his assistant resident. A fine surgeon, he returned and was appointed assistant in surgery in 1921. Naffziger next brought CE Locke, Jr., into the newly designated division of neurological surgery in 1923. Locke had followed Fleming as Cushing's assistant resident, and later became a Fellow of the National Research Council. In 1923, Locke and Fleming began to operate independently with the surgical residents, relieving Naffziger of sole responsibility for the operations. In 1923, Naffziger was assisted by Locke in a transtentorial approach beneath the occipital lobe in which an exophytic glioma was partially removed from the cerebellopontine angle. This was one of the cases that led to the important paper concerning alternative ways of relieving impaction in the posterior fossa (33). They worked together for another year, during which a study of the cerebral subarachnoid pathways was published, and Locke then left to take a position at the Cleveland Clinic.
 
To augment his staff, Naffziger went into the ranks of the surgical residents, as Cushing had done in 1909 to get George Heuer, and he selected Ottiwell Jones, Jr., to be his full-time resident from 1926 to 1928. Jones then spent a year in the neuropathology laboratory at the Royal Victoria Hospital under Wilder Penfield and William Cone, contemporaneously with Dorothy Russell. They studied brain tumors, and in particular worked on the origin of the oligodendroglia and microglia using the metallic staining methods. Howard Brown followed Jones as resident from 1928 to 1930. In 1930, the neurosurgery staff consisted of Professor Naffziger, Fleming, Jones, and Brown. Notwithstanding his new responsibilities as chairman of the department of surgery in 1929, Naffziger maintained a dominant presence in the neurosurgery operating room.
 
 
Publications from the division of neurological surgery during that decade are written with clarity and conciseness, and they fit a mold of clinical instruction and surgical technique with relatively little input from laboratory work. A paper on peripheral-nerve repair is a primer on end-to-end suture, filled with technical details now taken for granted (29). The 1922 clinic on spinal-cord meningiomas puts one in the amphitheater with six cured patients and drives home the lesson that meningioma is not to be overlooked in the rush to diagnose syphilis (30). The clinic on acute head injury was ahead of its time, with its insistence on understanding both the pathophysiology and the neurology of the injury (31). It points out that the Traube-Herring reflex, with its clinical correlate of fluctuating restlessness, and Cushing reflex are grave prognostic signs calling for immediate exploration.
 
Noting that about 20% of brain tumors cannot be localized despite all clinical skills brought to bear, a paper on the shift of the pineal gland recalled Schueller's 1912 observation of its displacement and described its diagnostic value in several cases (32). Naffziger then pointed out that even a midline pineal gland can be useful, as in one patient with papilledema, by correctly focusing attention on the cerebellum.
 
Naffziger's art of surgery is nowhere better displayed than in the beautifully illustrated paper on cerebellar exposures (33). An occipital flap serves as a supratentorial approach to the cerebellopontine angle through a tentorial incision that extends to the petrous bone anteriorly, to the sinus rectus medially, and to the lateral sinus. His experience with this approach went back to 1923, when he biopsied an exophytic glioma. The subtemporal transtentorial approach is still used by some neurosurgeons for the removal of large meningiomas of the cerebellopontine angle. Also illustrated is the entirely straight midline incision without lateral offsets at the nuchal line, and the hockey-stick incision for unilateral cerebellar exposure. The tone of this magnificent paper is set at the beginning by Naffziger's disarming understatement, "the fascination of brain surgery lies in its difficulties."
 
From division to department
 
In 1927, Naffziger was asked by the president of UC to survey leading eastern US medical centers with a view toward improving surgical teaching methods (11). His detailed report committed him to leadership in medical education and led to his appointment as professor and chairman of the department of surgery in 1929. With this appointment came the responsibility for training surgical residents, and, as he believed they should spend time with the specialties (40), one may speculate that this was the reason he trained relatively few neurosurgeons while he was chairman of the Department of Surgery. This is especially noteworthy inasmuch as the American Medical Association (AMA) Council on Medical Education and Hospitals gave approval to UCSF for a 3-year training program in neurological surgery in 1934 (12, 13). Naffziger, however, pursued his commitment to the department by having surgical, rather than neurosurgical, residents work and operate with the neurosurgery attending staff.
 
In the ensuing years, Naffziger's reputation as an educator grew and, in 1939, as president of the American College of Surgeons, he again gave his views on the training of surgeons - this time neurological surgeons (36). He pointed out that some neurosurgeons being trained in nonteaching hospitals were not receiving well-rounded preparation. He proposed a course of study - well established today - that he considered necessary for adequate neurosurgical training, and he added laboratory investigation to that curriculum. Not surprisingly, he was elected to chair the preliminary planning sessions that established the American Board of Neurological Surgeons in 1940, and then served as chairman of the Board until 1949. In 1943, he reported on the advisory role of the Medical Research Council in mobilizing neurosurgeons and materiel for the war and in setting up centers for specialized treatment (37).
 
Naffziger was admired for his pioneering work in thyroid-related exophthalmos (34, 35, 38). Vogt and Torkildsen called the orbital decompression operation the Naffziger Operation (51). His name was also used in connection with the scalenus anticus syndrome described in 1937 - the Naffziger Syndrome - and with radicular pain brought on by jugular vein compression - the Naffziger Test (1935). A partial hypophysectomy for Cushing's disease, which he did in 1933, was the first such operation (26).
 
In May 1944, a Naffziger number of the Journal of Nervous and Mental Disease honored him on his 60th birthday. In the introduction, Foster Kennedy could hardly contain his admiration. Salutations to Naffziger by Robert Sproul, President of UC, and by Francis Scott Smyth, dean of the medical school, expressed the profound indebtedness of the university to "one of the most distinguished brain surgeons in the country," and assured his continued service in the wide range of his interests. Coming from these men, the words presaged the creation of the Department of Neurological Surgery in 1947, with Naffziger as Professor and Chairman.
 
After World War II, the training of residents accelerated remarkably as many surgeons interested in formal training returned from military service. John Adams was graduated in 1948, the first to complete training in the new academic department. Eugene Stern completed the residency in 1951, after military service and 2 years spent at Queen Square and Johns Hopkins. Changes occurred in the faculty as well. Edwin Boldrey had joined the staff in 1940, having trained at the Montreal Neurological Institute (MNI), and Fleming's chronic illness had forced his retirement in 1943.
 
 
Bertram Feinstein joined the staff in 1947. In 1949, Robert Aird advanced to Professor, and, in 1950, Adams to Assistant Professor. This configuration of staff was necessary to meet new teaching responsibilities, as instruction in neurological surgery for medical students had been separated from general surgery in 1948. Instruction was given as follows: Year 1, anatomy; Year 2, surgery, history-taking in neurological surgery, pathology, and neurology; Year 3, clinical neurosurgical training at the San Francisco General Hospital (SFGH), lectures, and ward work; Year 4, section work as clinical clerks at the UC Hospital
 
Experimental work by John Adams and Robert Aird began to appear in 1948 (1, 4). Aird, a neurologist with surgical leanings, had joined neurosurgery in 1936. In 1947, when the Department of Neurology was established, Aird became its chairman, but he maintained a joint appointment because of his continuing role in the training of neurosurgery residents. His research interests were the impaired blood-brain barrier and electroencephalography (EEG), but he also worked with Naffziger over the years on the regenerative capacity of nerve and muscle and on factors causing faulty recovery of the neuromuscular mechanism (39).
 
In 1951, chairmanship of the department passed from Howard Naffziger to Edwin Boldrey. The first description of a 3-year postdoctoral training program for residents in neurological surgery appeared in the announcement of the School of Medicine for 1951. It spelled out the requirements for acceptance, the details of clinical and laboratory rotations, the schedules for rounds and conferences, and the expected progression toward independence in surgical skills. In 1954, the program was extended to 4 years, with Byron Cone Pevehouse as the first beneficiary of the additional time for clinical training.
 
The Adams Years
 
John Adams' orientation to experimental work was well known when, despite his junior faculty status as an assistant professor, he became chairman of the department in 1956. He had wasted no time getting into the laboratory during his residency in 1948. At the Donner Laboratory, he studied the absorption of cerebrospinal fluid (1) and the water and electrolyte shift in experimental convulsions by using radioisotopes (4). With Louis Bakay, he was among the first investigators to use radionuclides in cerebral metabolic and blood-flow studies. He used this technique also in his later work on the metabolic changes during hypothermia.
 
A clinical interest in stereotactic surgery led Adams to spend 3 weeks with Mundinger and Leksell, architects of the technique, in 1954. On his return to UC, he assembled a team - consisting of himself, Joseph Witt, and Burt Rutkin - to start a clinical stereotactic surgery program. Witt, a Mayo-trained neurosurgeon just finishing duty at the Oakland Naval Hospital, joined the faculty in 1958. Rutkin was the electrical engineer responsible for all the equipment. Adams and Witt did examinations and follow-up evaluations at a weekly clinic. By 1960, a stereotactic surgery service was established at the Langley Porter Institute.
 
 
The Leksell frame was used in treating Parkinsonism, cerebral palsy, and intractable pain. Problems under study were the methods of producing a lesion by radiofrequency, freezing, or beta-emitting isotopes, and the methods of localizing targets and standardizing parameters for stimulation and recording so that results could be evaluated. Other members of the department also active in the laboratory were Burton Wise on electrolyte and water metabolism and the effect of hypertonic mannitol on intracranial pressure (58-61), and Adams and Pevehouse on profound hypothermia (6).
 
The annual case load did not change remarkably from 1956 to 1962. Admissions ranged from 700 to 800 annually, with about 500 operations: brain tumor [75 to 90 cases] and herniated lumbar disc procedures [60], anterior cervical discectomy and fusion [30], carotid ligation [20], carotid thrombectomy [20], chemopallidotomy [16 to 30], aneurysm procedures [15 to 25], stereotactic procedures [15, but 38 in 1963], procedures under hypothermia [13 to 22], spinal tumor procedures [11 to 23], hypophysectomy [2 to 15], trigeminal root section [8], angioma [4], and Selverstone clamp procedures [4].
 
Adams became an Associate Professor in 1957 and Boldrey a Professor in 1960; others on the faculty were Jones, Brown, Wise (vice chairman), Witt, Pevehouse, Webb, and Dunbar, with Siefert, Arnstein, and other graduates as clinical instructors. William Hoyt held a joint appointment in neuro-ophthalmology and neurological surgery. A landmark in the history of the UC Medical School occurred in 1960, when it held its first commencement in San Francisco, apart from Berkeley. Many senior surgeons were invited to visit during these years. The first, in 1960, was Lyle French, followed by such eminent names as Oscar Hirsch, Wilder Penfield, Richard Schneider, Eben Alexander, and William Sweet. Dr. Naffziger died on March 21, 1961.
 
Looking back on the first half of the Adams chairmanship, one can see the extent to which he directed the division of neurosurgery toward experimentation and its clinical applications. This was typified by the work he did with his residents on profound hypothermia, which he considered to be a valuable ancillary technique for increasing proximal occlusion time in aneurysm surgery (2, 3, 5, 6, 9, 10, 47, 48). He used hypothermia with vascular surgery in 18 cases in 1966. Almost as a sideline, in 1964, at a meeting of the Neurosurgical Society of America, he and Witt described the use of the microscope in operating on intracranial aneurysms, a first according to Robert Rand (42). At the 1967 meeting of the American Association of Neurological Surgeons, Adams spoke on 16 patients treated with cryohypophysectomy for acromegaly, an operation first performed by Rand. The patients for whom that procedure failed, who had persistent excessive secretion of growth hormone, provided Charles Wilson with his first opportunities to use the transsphenoidal procedure (56).
 
The legacy of John Adams is his introduction of the neurological surgery department to the experimental method. He was trained by a supreme clinician and surgeon who, while he himself did not engage in laboratory research, recognized its importance to neurological surgery. In this regard, Adams is Naffziger's finest product. Over a period of 15 years, Adams fostered a research environment in which residents flourished and earned principal authorships. Burton Wise, too, made many significant independent research contributions. The vitality of their "laboratory" prompted the Regents, in 1962, to honor the memory of Dr. Naffziger by proposing an institute for neurological research in his name. The director of the institute was to occupy the Guggenhime Chair of Experimental Neurological Surgery. The "institute" materialized as a laboratory on the seventh floor of the UCSF Health Sciences west tower in 1966. It was officially opened, though not yet dedicated, in 1968, and Adams was named Guggenhime Professor of Neurological Surgery.
 
The Wilson Years
 
On June 1, 1968, Charles Wilson became professor and chairman. Edwin Boldrey was named vice chairman. In the Naffziger Laboratories, few projects were underway before January 1969, as time was needed to make the laboratory ready for work. The dedication ceremony for the Howard C. Naffziger Laboratories for Neurosurgical Research took place on May 6, 1970, with welcoming remarks by Wilson as director of the laboratories. The principal address was given by Eugene Stern. John Oswald, executive vice president of UCSF, announced in the course of his remarks that the Regents had just approved the re-establishment of neurological surgery as a separate department. In the course of its existence, neurological surgery had been a division of surgery from about 1922 to 1946, a department from 1947 to 1958, a division as of 1959, and a department again in 1970.
 
 
Brain Tumor Research Center
 
Research during 1969 proceeded along two lines, one involving brain tumor biology and chemotherapy and the other elucidating the pathophysiology and neuropathology of certain disorders directed toward improving the neurosurgical technique used to treat them. Examples of the latter efforts are experiments on graded cryohypophysectomy to determine the temperature that inactivates each pituitary cell type (45), and the experimental production of myelopathy by using compression and vascular insufficiency (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. Trained in neurosurgery and pathology, Wilson had published papers on chemotherapy by continuous arterial infusion in 1962 (53) and on brain tumor tissue culture in 1963 (57). He, Edgar Bering, and Horace Norrell had organized the Kentucky Conference on Brain Tumor Chemotherapy, held in 1965, at which he had outlined the conference objectives before an audience of senior workers in the field. His appointment at UC Hospital in 1968 was only 3 short years away.
 
By 1972, the laboratory had grown in size and personnel, and the proposed research plan listed 15 projects, now including immunologic and DNA studies. The training of postgraduate fellows for careers in brain tumor research also became an important function of the laboratory, for which it was funded separately. This combination of active research and training programs, and the prime academic and clinical setting of UCSF, culminated in the National Institutes of Health (NIH) approving a Cancer Center research grant on June 1, 1972. On January 17, 1973, inaugural ceremonies were held for the Brain Tumor Research Center (BTRC), at the core of which were the Naffziger laboratories.
 
The BTRC provides a multidisciplinary approach to clinical research and laboratory investigation of malignant brain tumors. The principal clinical arm is the Neuro-Oncology Service, which now enrolls about 400 new patients annually. The principal investigators still with the BTRC in 1995 were Wilson (director) , Dennis Deen (associate director), William Bodell, Pak Chan, Michael Edwards, Burt Feuerstein, John Fike, Philip Gutin, Mark Israel, David Larson, and Michael Prados
 
BTRC and UC radiation oncology investigators were among the first to oppose whole-brain irradiation for malignant gliomas (25) and were the first to propose lower doses of craniospinal-axis irradiation for medulloblastoma (24). They introduced hyperfractionated irradiation for brain stem gliomas (17) and introduced radiosurgery to the West Coast. 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 (125I) for brachytherapy (18) and have suggested it as the optimal treatment for glioblastoma in selected patients (46). They also pioneered the use of hyperthermia and brachytherapy for recurrent malignant glioma (49) and primary glioblastoma multiforme (50). In chemotherapy research, BTRC investigators published the initial reports showing the efficacies of carmustine (BCNU) (8, 55) and procarbazine (23), and later showed that single-dose BCNU is as effective as multidose therapy. They published the first report of the multidrug protocol combining procarbazine, lomustine (CCNU), and vincristine (PCV) (19), and showed the superiority of PCV over single-dose therapy for anaplastic astrocytoma and oligodendroglioma. They also published the first reports on steroid dose dependency (43) and on the use and efficacy of polyamine biosynthesis inhibitors (27). 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 (41).
 
BTRC investigators have also been leaders in brain tumor clinical trials. They established the response criteria for phase II studies (23), 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. Laboratory studies in the BTRC defined the kinetic parameters of gliomas and other primary brain tumors (21) and established the prognostic value of the bromodeoxyuridine (BUdR) labeling index (22).
 
BTRC investigators also 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 (52). They developed the first clonogenic assay for human gliomas (44) and an assay for measuring urinary polyamines in patients with medulloblastoma (28), and they developed numerous BCNU-resistant glial animal and human cell lines. They have developed a canine model for noninvasively studying radiation damage to normal tissue. The BTRC has also established a large and completely characterized tissue bank, currently with more than 2500 frozen specimens. Altogether, the BTRC has trained more clinical neuro-oncologists and basic scientists in brain tumor research than any other center - more than 130 postdoctoral fellows, many of whom have gone on to successful careers in the field. Aspects of the research guidelines (16) developed for BTRC trainees have been incorporated into the ethical guidelines adopted by UCSF and other biomedical institutions.
 
The BTRC's Preuss Laboratory for Molecular Neuro-Oncology opened in 1990 under the direction of Mark Israel to investigate the molecular basis for the regulation of differentiation and growth in the nervous system, to establish a molecular classification for neoplastic disorders of the nervous system, and to identify targets for the development of novel therapeutic strategies. A grant from the NIH also supports a Pediatric Brain Tumor Research Center program that includes a pediatric neuro-oncologist and an investigator from the departments of neurology and genetics. The mission of the BTRC is the development of effective therapies by experimental and clinical studies, and, in the long-term, to define the basic nature of human brain tumors through developments in molecular and cell biology.
 
In 1981, a group of patients, their families, and others created the National Brain Tumor Foundation to raise funds for brain tumor research and to provide support services. Members of the department have been active in this valuable group, contributing to its support-group program and educational conferences, and developing an expanded edition of its informational publication, Brain Tumors - A Guide.
 
One cannot end this section on the BTRC without remembering Professor Takao Hoshino, who joined the BTRC in 1968, already internationally recognized for his work with cell cultures of human brain tumors. As a BTRC principal investigator, he 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. Admired as a scientist and colleague, he died on January 23, 1993.
 
Residency training
 
UC residents in the early years trained on rotation at UC Hospital and three affiliated sites, Franklin Hospital, later renamed the RK Davies Medical Center, the Fort Miley Veterans Administration (VA) Hospital, and SFGH. There was unevenness among these sites with respect to the amount and variability of clinical material, but the patients at each hospital were attended, and the residents trained, by UC medical school faculty. Training by preceptorship was largely the norm before the early 1930s. Jones and Brown had trained for 2 years. Lawrence, a resident from 1932 to 1935, was the first beneficiary of the AMA's stipulation of a 3-year program, but no other residents were trained under this policy until 1944. The 3-year program consisted of 1 clinical year each at the UC and Franklin Hospitals, and a third year of laboratory work in neuropathology, EEG, neurophysiology, neuroanatomy, or clinical research. Around 1954, the residency was increased to 4 years. In 1960, all four hospitals were used. The resident (R) rotation schedule in 1960 was as follows: internship constituted the first, R1, year; the R2 year entailed 6 months each at Franklin Hospital and UC Hospital; R3, 6 months each at UC Hospital and SFGH; R4, laboratory, neuropathology, neurology and EEG, and neuro-ophthalmology rounds; R5, 6 months each at UC Hospital and the VA. The chief resident arranged teaching rounds and the operating schedule. In 1969, the residency was increased to 5 years to include 1 full year of research as R4.
 
The rotation at Franklin Hospital was discontinued in 1973 in favor of increasing time at UC Hospital. The schedule that emerged and was in effect until 1986 had the pattern of clinical rotations in R2, R4, R6, and basic sciences and laboratory in R3, R5. The R4 year was the key to its stability, as it provided the Wilson service with an R4 resident who had gained major operative and patient-management experience at SFGH
 
Changes since then have been required to accommodate requests for focused training in the subspecialties, mainly pediatric, stereotactic, epilepsy, and spinal surgery. In 1992 when the number of operations peaked at 2,383 (Table 1), three residents were accepted and the program was temporarily extended to 6 years beyond internship. California has now restricted specialty training, and so the department will select only two residents each year. The imposed attrition does not alter the department's standard for training academic neurosurgeons. Charles Wilson attracted 50 applicants in 1968 and saw this number grow to 100 applicants in 1994. During those 26 years, 41 residents were trained. Twenty-five now hold academic positions, five as a department chairman (Mitchel Berger, Philip Gutin, Stephen Powers, Mark Rosenblum, Robert Spetzler) and two as an acting chairman (James Boggan, Robert Levy). The training of academic surgeons remains the cornerstone of the department.
 
The clinical service
 
Many clinical services contributed to the growth of the department. Each year during the 1960s at UCSF, the average number of index cases - craniotomies for tumor, aneurysm, arteriovenous malformation (AVM), and laminectomies for spinal cord tumor and AVMs - was 125; it was 150 in 1969, 226 in 1974, and 170 in 1978. Table 1 shows the incremental increase from 285 in 1981 to 739 in 1992. The decline in the next 2 years reflects changing patterns in medical care and referral of patients. The remarkable increase in brain tumor operations is certainly related to the professional and public confidence in the BTRC and the clinicians identified with it. The appointment of Grant Hieshima in 1986 made UCSF a major center of diagnostic and therapeutic interventional neuroradiology for cerebral and spinal AVMs, attracting more patients for these procedures.
 
Stereotactic and functional surgery
 
After the beginning of this service under John Adams in 1960, starting with a nucleus of 16 chemopallidotomy cases, the service in 1965 had grown to 117 cases, including surgery for movement disorders and epilepsy. From 1968 to 1970, the following operations were performed: dentate nucleus lesions for choreoathetosis [116 cases]; depth electrode implantation and thalamotomy for movement disorder [103]; amygdalectomy [32]; thalamotomy for pain [10]; radiofrequency electrode implantation for choreoathetosis [5], and for pain [4]; medullary tractotomy [4]; drainage of craniopharyngioma [2]; and biopsy of thalamic tumor [1 case].
 
In July 1969, Yoshio Hosobuchi from the University of Chicago joined the faculty, starting a program for the treatment of chronic pain that included percutaneous cordotomy, medullary tractotomy, dorsal-column stimulation, and thalamic and internal-capsule stimulation for thalamic and paraplegia pain. By 1978, percutaneous dorsal-column stimulation was largely abandoned as ineffective in 70% of cases, and deep-brain stimulation was used for relieving thalamic pain, anesthesia dolorosa, and intractable low back pain. In 1991, 305 stereotactic and functional cases were done. Hosobuchi also introduced Mullan's procedure of electrothrombosis of carotid-cavernous fistula by the stereotactic insertion of copper needles or the direct intracavernous insertion of thrombogenic wire, which he also used to treat otherwise inoperable giant aneurysms. He had treated about 50 patients with electrothrombosis by the late 1970s, but this technique has now been superseded by intravascular catheter techniques.
 
Pituitary surgery
 
Adams, in 1958, used hypophysectomy to treat the pain of metastatic breast cancer and prostate cancer. Adams and Seymour then moved to the use of cryohypophysectomy (7), doing 19 cases in 1966, after Robert Rand had described its use for acromegaly in 1965. By 1970, 70 operations had been done for acromegaly and 15 for diabetic retinopathy and metastatic disease. In 25% of the patients with acromegaly, serum growth hormone values did not return to normal after surgery. This is more than a passing detail because the first acromegaly cases operated transsphenoidally by Wilson in 1970 were those in which irradiation, alone or with hypophysectomy, had failed (56). His success led to the use of the transsphenoidal approach as initial therapy for acromegaly, with preservation of normal pituitary function. The transsphenoidal operation for prolactinoma followed, and then for corticotrophin-secreting adenomas. Naffziger had done a successful transsphenoidal operation for acromegaly in February 1922, and had done a craniotomy and subtotal hypophysectomy for Cushing disease in 1933. Wilson had operated 40 patients through the transsphenoidal route by 1970, 95 by 1974, and, at this writing, over 2500. He delivered the Herbert Olivecrona Lecture on this subject at the Karolinska Institute in Stockholm in 1984 (54).
 
Neuro-Oncology
 
The Chemotherapy Service affiliated with the BTRC was established in 1968, under the joint direction of Wilson and Boldrey, who was a member of the National Institute of Neurological Disorders. By 1970, 90 patients were registered for treatment. Clinical screening for agents with oncolytic potential depended on the physical, neurologic, and radiologic follow-up evaluation of patients, which was done by a chemotherapy nurse coordinator and a chemotherapy fellow. Derek Fewer, a resident from the MNI, was the first fellow. By 1972, the clinic had grown to 239 patients, requiring the assignment of a second fellow, Justin Renaudin. In 1973, Philip Gutin, then in his R2 year, spent 6 months in the clinic before going to the Baltimore Cancer Research Center on a 3-year fellowship from the NIH. 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, trained in clinical pharmacology at the NIH and in neurology at Massachusetts General Hospital, joined the department in 1972 to work on the pharmacokinetics of anticancer drugs. He became assistant director in 1974 and chief of the chemotherapy service in 1977. In 1988, he left to join the staff of the MD Anderson Cancer Center, and Michael Prados became chief of the Neuro-Oncology Service, as it had come to be known. Its contributions to the management of malignant brain tumors over the years in terms of best postoperative treatment may be summarized as follows: PCV and BUdR are used for anaplastic astrocytoma and anaplastic oligodendroglioma, and stereotactic implantation of 125I sources (brachytherapy) for selected cases of glioblastoma multiforme.
 
On June 6, 1988, Edwin Boldrey died. His lifelong interests had encompassed epilepsy, aneurysms, AVMs, and brain tumor therapy. Revered by a generation of neurosurgeons for his grace and integrity, his memory is honored with the Boldrey Lectureship in Neurological Surgery, established in 1983 at UCSF.
 
Pediatric neurosurgery
 
The pediatric neurosurgery service began about 1971, with Pevehouse as the chief. A spina bifida-hydrocephalus clinic was already in place, begun by Wilson in 1969. It was an interdisciplinary clinic, using resources of the Birth Defects Center in the department of pediatrics for genetic analysis and counseling. Renaudin joined Pevehouse, assisting with the clinic and pediatric neurosurgery cases. When Julian Hoff moved to the UC Hospital from SFGH in 1976, he resumed his interest in pediatric neurosurgery and was supported in this by Pevehouse. When Hoff left to head the section of neurosurgery at the University of Michigan in 1981, Pevehouse encouraged Michael Edwards to pursue his long-standing interest in pediatric neurosurgery. Edwards became chief of the service in 1982. In 1984, Roger Hudgins became the first pediatric neurosurgery fellow. He was followed by four UC residents, Mitchel Berger, Corey Raffel, James Baumgartner, and Samuel Ciricillo, all of whom are now established academic clinicians. Philip Cogen, assistant chief from 1990 to 1993, did productive work in the laboratory on the molecular biology of medulloblastoma and meningioma. He left UC to become chief of pediatric neurosurgery at the University of Chicago. In 1993, the staff consisted of Edwards, Ciricillo, a fellow, and a resident, and 444 operations were performed.
 
The pediatric neurosurgery service received a Program Project grant from the NIH for a pediatric BTRC in 1992. Carolyn Russo, a pediatric neuro-oncologist, was recruited in 1994. The service supports a number of clinics. The expanded spina bifida clinic is part of the Northern California Spina Bifida Association. The Hydrocephalus Foundation, an organization for the education and support of patients and their families, was started at UC Hospital and is now a national organization. Other specialty clinics are: 1) craniofacial anomaly, 2) neurocutaneous syndrome, 3) brain tumor, and 4) selective posterior rhizotomy. The service receives valuable clinical and teaching support from radiologist James Barkovich.
 
Epilepsy surgery
 
This service was begun in 1960 by John Adams. His epilepsy program was funded by a grant from the US Vocational Rehabilitation Administration and was established to treat patients with intractable seizures, who were selected by an interdisciplinary committee. Multilead electrodes were implanted stereotactically in strategic regions of the brain. The recordings made during seizures were processed by computer to determine the coordinates for stereotactic lesions. Behavioral aspects of this protocol were overseen by colleagues in psychiatry. Later, Adams extended epilepsy surgery to include cortical resection and temporal lobectomy. In 1986, the Northern California Comprehensive Epilepsy Center was established together with the UCSF neurology department to evaluate and treat patients who have medically refractory epilepsy. A video-telemetry unit was opened, and the first operation was done in 1986. Functional mapping of the cortex was added to the surgery of tumors and AVMs, The center's administrative director is neurologist Michael Aminoff. Kenneth Laxer, also a neurologist, is the clinical director. Nicholas Barbaro is the neurosurgeon for adults and adolescents, Edwards and Ciricillo the neurosurgeons for children, and John Walker the neuropsychologist. About 50 operations are done each year, including temporal lobectomy, suprasylvian cortical resection, subdural grid implant, hemispherectomy, and section of the corpus callosum. The center has close ties to the Epilepsy Research Laboratory of neurologist and anatomist Dan Lowenstein.
 
 
Affiliated hospitals
 
San Francisco General Hospital
 
This hospital is an immensely valuable teaching resource. Unfailingly, it provides residents at the R4 level with about 300 trauma and elective cases per year in about equal proportion. The rotation is eagerly anticipated by the residents for the opportunity it affords them to advance their clinical and surgical skills. Several distinguished faculty careers began at the "General," namely Cone Pevehouse, 1961; Julian Hoff, 1971; and Lawrence Pitts, 1976. Pitts introduced intracranial pressure monitoring and physiologically directed intensive management, and supervised a neurotrauma laboratory in which research on the blood-brain barrier and spinal cord trauma is currently being done under the direction of Linda Noble PhD. Randall Chesnut was appointed chief of service at SFGH in 1994.
 
San Francisco Veterans Administration Medical Center
 
The 6-month VA rotation has played an enduring role in the senior residents' transition to independent neurosurgical practice, whether academic or private. Training in spinal surgery has been augmented to include spinal instrumentation by the addition of Bruce McCormack to the staff in 1994. In addition, about 25 index cases, mainly brain and spinal cord tumors, are done annually. Microvascular suturing technique is taught in the Neurovascular Research Laboratory by Philip Weinstein. Robert Spetzler received the Annual Resident Award in 1977 from the Congress of Neurological Surgeons for the work on experimental arteriovenous fistula done in that laboratory.
 
UCSF - Mount Zion Medical Center
 
A neuro-spine service, begun in 1992 with Russ Nockels as chief, grew sufficiently to support the training of a junior resident. In 1994, 384 patients were operated, 323 for spinal degenerative disease, trauma, and tumor, and 61 for cranial and other procedures. Clinical practices at Mount Zion returned to the Parnassus Heights campus, but the UCSF Cancer Center remains there.
 
Acknowledgments
 
For input and time spent talking, thanks go to John Adams MD, Cone Pevehouse MD, Robert Fishman MD, Dennis Deen PhD, Marvin Barker MS, Nicholas Barbaro MD, Michael Prados MD, Grant Gauger MD, Paul Matz MD, Kathleen Smith, and Susan Eastwood ELS(D).
 
References
 
1. Adams JE: Tracer studies with radioactive phosphorus (P32) on the absorption of cerebrospinal fluid and the problem of hydrocephalus. J Neurosurg 8:279-288, 1951.
 
2. Adams JE: Cerebral metabolic studies on the human during total cerebral arterial occlusion and hypothermia. The effect on cerebral respiratory quotient. J Neurosurg 18:168-174, 1961.
 
3. Adams JE: Clinical experiences with hypothermia, in Fields WS, Sahs AL (eds): Extracranial Aneurysms and Subarachnoid Hemorrhage. Springfield IL, Thomas, 1965, pp 275-294.
 
4. Adams JE, Aird RM, Garoutte W: Fluid and electrolyte exchange in brain in experimental convulsions. Trans Am Neurol Assoc 77:34-38, 1952.
 
5. Adams JE, Elliot H, Sutherland VC, Wylie EJ, Dunbar RD: Cerebral metabolic studies of hypothermia in the human. Surg Forum 7:535-539, 1957.
 
6. Adams JE, Pevehouse BC: Regional hypothermia of the brain. Clin Neurosurg 6:104-118, 1958.
 
7. 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.
 
8. 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.
 
9. Buster CD, Pevehouse BC, McCorkle HJ: Cardiovascular changes associated with selective brain cooling in the dog. Surg Forum 9:212-215, 1958.
 
10. Chater N, Adams JE, Leake TB, Halliday B: Cardiovascular effects of local brain stem cooling. Surg Forum 11:408-410, 1960.
 
11. Chatton MJ: Howard Christian Naffziger. Alumni Faculty Association Bulletin, School of Medicine, University of California, San Francisco 29:8-13, 1985.
 
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15. Cushing H: The special field of neurological surgery after another interval. Arch Neurol Psychiatry 4:603-637, 1920.
 
16. 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.
 
17. 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.
 
18. 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.
 
19. 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.
 
20. Hakuda S, Wilson CB: Experimental cervical myelopathy: Effects of compression and ischemia on the canine cervical cord. J Neurosurg 37:631-652, 1972.
 
21. Hoshino T, Barker M, Wilson CB, Boldrey EB, Fewer D: Cell kinetics of human gliomas. J Neurosurg 37:15-26, 1972.
 
22. 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.
 
23. 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.
 
24. 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.
 
25. 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.
 
26. Lisser H: Hypophysectomy in Cushing's disease. J Nerv Ment Dis 99:727-733, 1944.
 
27. Marton LJ: An approach to the use of polyamine biosynthesis inhibitors for cancer therapy. Med Biol 59:458-461, 1981.
 
28. 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.
 
29. Naffziger HC: Methods to secure end-to-end suture of peripheral nerves. Surg Gynecol Obstet 32:193-204, 1921.
 
30. Naffziger HC: Spinal cord tumors (arachnoid fibroblastomata). Surg Clin North Am 2:363-400, 1922.
 
31. Naffziger HC: Head injuries: Indications for surgical treatment. Surg Clin North Am 3:699-710, 1923.
 
32. Naffziger HC: A method for the localization of brain tumors: The pineal shift. Surg Gynecol Obstet 40:481-484, 1925.
 
33. Naffziger HC: Brain surgery with special reference to exposures of the brain stem and posterior fossa: The principle of intracranial decompression and the relief of impactions in the posterior fossa. Surg Gynecol Obstet 46:241-248, 1928.
 
34. Naffziger HC: Progressive exophthalmos following thyroidectomy: Its pathology and treatment. Ann Surg 94:582-586, 1931.
 
35. Naffziger HC: Progressive exophthalmos following thyroidectomy: Its pathology and treatment. Report of 8 cases. Surg Gynecol Obstet 54:81-87, 1932.
 
36. Naffziger HC: Content of courses for adequate training in neurological surgery. Bull Am Coll Surg 24:46-48, 1939.
 
37. Naffziger HC: Report of the activities of the Subcommittee on Neurological Surgery of the Medical Research Council. Trans Am Neurol Assoc 69:28-31, 1943.
 
38. Naffziger HC: Progressive exophthalmos. Hunterian Lecture. Ann R Coll Surg Engl 15:1-24, 1954.
 
39. Naffziger HC, Aird RB: Regenerative capacities of nerves and muscle. Experimental study of factors causing faulty recovery of the neurovascular mechanism. J Mt Sinai Hosp 9:679-685, 1942.
 
40. Naffziger HC, Bell HG: The postgraduate training of students in surgery at the University of California. West J Surg 40:384-389, 1932.
 
41. 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.
 
42. Rand RW: Microneurosurgery. St. Louis, Mosby, 1969, p 2.
 
43. 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.
 
44. Rosenblum ML, Vasquez DA, Hoshino T, Wilson CB: Development of a clonogenic cell assay for human brain tumors. Cancer 41:2305-2314, 1978.
 
45. Saglam S, Kragt CL, Wilson CB, Kaplan SL, Barker M: Graded cryohypophysectomy in the rhesus monkey. Histopathology and endocrine function. J Neurosurg 36:169-177, 1972.
 
46. 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.
 
47. Smith MC, Adams JE, Leake TB, Halliday B: Occlusion of the blood supply to the brain of the goat. Protective effect of deep hypothermia. J Neurosurg 20:46-59, 1963.  
48. Smith MC, Adams JE, Pearson KD: Profound hypothermia without extracorporeal circulation. The effects of cooling rate and hemodilution on the incidence of ventricular fibrillation in dogs. J Neurosurg 24:86-90, 1966.
 
49. 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.
 
50. Sneed PK, Larson DA, Gutin PH: Brachytherapy and hyperthermia for malignant astrocytoma. Semin Oncol 21:186-197, 1994.
 
51. Vogt JH, Torkildsen A: Primary malignant exophthalmos cured by Naffziger operation (orbital decompression). Nord Med 34:1303-1304, 1947.
 
52. 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.
 
53. Wilson CB: Chemotherapy of brain tumors by continuous arterial infusion. Surg Forum 13:423-425, 1962.
 
54. Wilson CB: A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 61:814-833, 1984.
 
55. 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.
 
56 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.
 
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58. Wise BL, Chater N: Effect of mannitol on cerebrospinal fluid pressure: The actions of hypertonic mannitol solutions and of urea compared. Arch Neurol 4:200-202, 1961.
 
59. Wise BL, Chater N: The value of hypertonic mannitol solution in decreasing brain mass and lowering cerebrospinal fluid pressure. J Neurosurg 19:1038-1043, 1962.
 
60. Wise BL, Ganong WF: The effect of ablation of the area postrema on water and electrolyte metabolism in dogs. Acta Neuroveg (Wien) 22:14-32, 1960.
 
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The Brain Tumor Research Center: Development of the Center from Vision to Reality
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 Rsearch 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).