Specific cellular immune responses in patients with malignant gliomas.

The leukocyte adherence inhibition assay was used to measure cell-mediated immunity in 26 patients with malignant glial neoplasms and 41 control subjects. A significant inhibition of leukocyte adherence was observed in 21 of 26 (80%) glioma patients in the presence of a 3 M KCl extract of glioma tissue, as compared to that of normal brain extract. Among the control group, no significant difference in the percentage of nonadherent leukocytes was noted in the presence of either antigen. To study the specificity of the reaction, a 3 M KCl extract of meningioma, pituitary tumor, carcinomas of breast, and lung, melanoma, brain, and heart tissues were used as nonspecific antigens. Such studies revealed significantly lower values of nonadherent leukocytes. These data indicate that patients with malignant glial neoplasms manifest a cellular immune response to glioma-associated antigens which can be measured by the tube leukocyte adherence inhibition assay and that leukocyte adherence inhibition assay may render additional useful information in diagnostic and prognostic evaluation of malignant glial neoplasms.

Staphylococcal Protein A column: correlation of mitogenicity of perfused plasma with clinical response.

Eleven patients with advanced breast cancer and four with astrocytoma were treated with plasma perfused over columns containing staphylococcal Protein A (SPA). Doses of 5 to 20 mg of SPA were bound to collodion charcoal particles, and this treatment resulted in partial remissions in one patient with astrocytoma and in two patients with breast cancer. Remission duration was 6 wk to 6 mo. Resolution of lymphadenopathy and a decrease in carcinoembryonic antigen were noted in an additional two breast cancer patients. Systemic reactions to infused plasma consisted of fever, chills, and rigors. In brain cancer patients, increased intracranial pressure was also noted. A mitogenic substance was generated in plasma of 11 patients after it was perfused over the SPA charcoal matrix. The mitogenic material induced lymphoproliferation comparable to concanavalin A and required the presence of SPA on the collodion charcoal but was not due to leakage of SPA from the column during plasma perfusion. Of considerable significance was that only patients whose column perfused plasma contained this mitogenic activity exhibited systemic reactions, and five of these patients obtained antitumor responses. This striking correlation implies that the mitogenic factor is an active component of SPA therapy. The ability to demonstrate mitogenicity in column perfused plasma might also be useful for selecting patients amenable to SPA therapy. These findings attest to the therapeutic value of this mode of treatment and provide an initial definition of a mediator of SPA antitumor activity.

Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen.

The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.

Dosimetric comparison of three photon radiosurgery techniques for an elongated ellipsoid target.

PURPOSE: To examine the dosimetric differences among three radiosurgery techniques: gamma knife, linac multiple arcs, and conformally-shaped static fields. METHODS AND MATERIALS: A simulated target was taken to be a prolate ellipsoid, 25 mm in diameter, 35 mm in length, centrally located in a three-dimensional (3D) model of a patient head taken from MR images. Single isocenter linac treatment plans were developed, 9 portals for the static shaped field technique, and a 7-arc plan for the multiple arc method. A total of 13 isocenters with 3 different collimators were used in the gamma knife plan. RESULTS: At dose levels from 25% to 50% of the reference dose, multiple arc and shaped-field plans treated a greater volume than the gamma knife plan. The linac plans, however, delivered the dose more homogeneously across the target volume as compared to the gamma knife plan. For the dose levels between 50-100%, the shaped fields and gamma knife plan have a similar dose distribution, and treated slightly less volume than the multiple arc plan. CONCLUSION: For a target of limited volume and essentially any shape, one can obtain closely conformal dosimetry with the gamma knife. For a regular-shaped target, the single isocenter multiple arc technique gives a more homogenous dose distribution within the target. Static shaped fields offer an alternative radiosurgery technique, with dosimetry similar to the multiple arc method, applicable to targets of any shape.

Treatment results of stereotactic interstitial brachytherapy for primary and metastatic brain tumors.

A total of 41 stereotactic interstitial brain implants in 39 patients were performed for recurrence after teletherapy (recurrence implant), or as part of initial treatment in conjunction with teletherapy (primary implant). Implanted tumors consisted of malignant gliomas (33), other primary brain tumors (3), and single metastatic lesions (3). All patients were temporarily implanted with Ir-192 using a coaxial catheter afterloading system; two patients were implanted twice. Survival post-implant for glioblastoma multiforme (GBM), 13 patients, was 10 months whether implanted primarily or for recurrence. Mean time to recurrence, measured from initiation of teletherapy to implantation, was 10 months. Twenty patients with anaplastic astrocytoma (AA) had a median survival post-implant of 23 months for primary implants (7 patients) and 11 months for recurrence implants (13 patients). Mean time to recurrence, measured from initiation of teletherapy to implantation, was 19 months. Three patients (9%) of the evaluable group required reoperation for symptomatic mass effect, all with initial diagnosis of AA. Survival for this subgroup was 14, 22, and 32 months post-implantation. Using stereotactic techniques, interstitial brachytherapy of brain tumors was technically feasible with negligible acute morbidity and mortality, and appeared to offer limited prolongation of control for a subset of patients with recurrent malignant gliomas. The role of this modality in primary treatment for malignant gliomas needs to be further defined by prospectively randomized trials.

Malignant glioma modulation of immune function: relative contribution of different soluble factors.

We analyzed a series of human glioma cell lines with regard to establishing what variables may contribute to their overall functional immunomodulating capability. We observed that supernatants derived from the gliomas, but not those from non-malignant human astrocyte cultures, suppressed lymphocyte proliferation. The extent of suppression elicited differed between tumors and for the same tumor depending upon its growth phase. For individual gliomas, supernatants from cultures approaching or at confluency elicited maximal lymphocyte suppression. For the series of tumors, levels of production of the immunosuppressive molecules transforming growth factor beta 2 and prostanoids (prostaglandin E2) did not correlate with the levels of functional suppression observed at any of the different growth phases. In some cases, glioma cultures grown in the presence of indomethacin to abolish prostanoid synthesis resulted in supernatants with net stimulatory activity. Our results indicate that malignant transformation of astrocytes is associated with acquisition of immunosuppressive capability which is determined by the combined effect of multiple immunomodulatory soluble factors, inhibitory or enhancing, and is dependent on the growth phase of the tumor.

Flow cytometric DNA and nuclear antigen content in astrocytic neoplasms.

Simultaneous flow cytometric DNA content and proliferation-associated nuclear antigen (p105) quantitation was performed on 23 astrocytic tumors and the results correlated with histologic subtype. Three of nine anaplastic astrocytomas and one of ten glioblastomas had an identifiable aneuploid peak, while all four well differentiated astrocytomas were diploid. Cell cycle analysis of malignant gliomas revealed a higher mean percentage of S and G2M cells compared to well differentiated astrocytomas but there was considerable overlap between histologic subtypes. Nuclear antigen analysis of diploid tumors showed a higher mean p105 fluorescence of S + G2M cells than G0G1 cells from the same case but there were no apparent differences in p105 expression by histologic subtype. Aneuploid tumors showed enhanced expression of p105 relative to diploid cells. The findings suggest that the aggressive course of high grade glial tumors may be related to an abnormal DNA stemline or an increase in proliferative activity.

Intraventricular cysticercal cysts: further neuroradiologic observations and neurosurgical implications.

Intraventricular cysticercosis is potentially lethal. Six of 46 patients died from acute hydrocephalus shortly after hospital admission. The need for early computed tomographic scanning in immigrants from endemic areas complaining of headaches is emphasized by this experience. If time has elapsed since the initial diagnosis, these cysts may migrate within the ventricular system. Reconfirmation of the location of an intraventricular cysticercal cyst is advisable before surgery. Contrast enhancement of an intraventricular cysticercal cyst implies associated granular ependymitis. Surgical removal of such cysts probably should not be attempted as long as the cysts are not causing significant mass effect with neurologic signs and symptoms. Shunting alone is advocated for the treatment of hydrocephalus.

The Richard C. Schneider Lecture. New dimensions of neurosurgery in the realm of high technology: possibilities, practicalities, realities.

Fueled by a buoyant economy, popular attitudes and demands, and parallel progress in transferable technical and biological areas, neurosurgery has enjoyed a remarkable quarter of a century of progress. Developmental trends in the discipline have included the following: 1) a refinement of preoperative definition of the structural substrate, 2) miniaturization of operative corridors, 3) reduction of operative trauma, 4) increased effectiveness at the target site, and 5) incorporation of improved technical adjuvants and physical operative tools into treatment protocols. In particular, the computer has become a formidable ally in diagnostic and surgical events. Trends in technical development indicate that we are entering an exciting era of advanced surgery of the human cerebrum, which is heralded by the following: 1) current developments in areas of imaging, sensors, and visualization; 2) new devices for localization and navigation; 3) new capabilities for action at the target point; and 4) innovative concepts related to advanced operative venues. Imaging has provided structurally based surgical maps, which now are being given the new dimension of function in complex and integrated formats for preoperative planning and intraoperative tactical direction. Cerebral localization and navigation based on these advances promise to provide further refinement to the field of stereotactic neurosurgery, as linked systems are superseded by more flexible nonlinked methodologies in functionally defined volume-oriented navigational databases. Target point action now includes not only ablative capabilities through micro-operative methods and the use of stereotactically directed high-energy forms but also the emergence of restorative capabilities through applications of principles of genetic engineering in the areas of molecular and cellular neurosurgery. Complex, dedicated, and self-contained operative venues will be required to optimize the emergence and development of these computer-oriented micro/stereotactic capabilities, which appear to be unavoidably required as locales for the practice and development of virtual reality-based stations for operative rehearsal, simulation, training, and, ultimately, enhancement of operative events through robotic interfaces. Primary impetus for progress has relied upon new combinations of technologies, disciplines, and industries. Philosophical and practical problems include the spectrum of availability of these methods to the population at large, the training of individuals to properly administer these methods, defining the acceptable envelope of expertise, and maintaining suitable delivery and progress while containing spiraling costs. Advanced neurological surgery and the use and development of high-technology adjuvants require a robust economy that has a populace willing to invest in the luxury of such developments. The current socioeconomic situation is fragile from the standpoint of both economics and attitudes of the patients and health care providers, with diversion of economic resources, redistribution of funding bases, modification of patient referrals, practice styles, and service attitudes undermining progress. Economic pressures have brought high-technology methods under great scrutiny regarding their effectiveness and cost-effectiveness. Reform proposals have specifically targeted technology-oriented services, and the Office of Technology Assessment has recommended increasing the use of managed care providers who look to information on cost-effectiveness and clinical practice guidelines to establish efficient management strategies and issue "report cards." Although the premise is laudable and "gimmickry" needs to be identified, it might be argued that such scrutiny and control might be overbearing and overused, impeding appropriate delivery and progress.

Architecture and functional design of advanced neurosurgical operating environments.

Although modern operative neurosurgery is a complex technical undertaking requiring an amalgam of technologies and instrumentations, few reported efforts have dealt with the definition and development of suitable and optimal dedicated operating environments. This report presents the first detailed description of a dedicated, self-contained neurosurgical operating suite incorporating major surgical instrumentation and visualization technologies to provide an "idealized" environment for stereotactic, microscopic, and microstereotactic procedures. Advanced computer technology for visualization to augment, simulate, document, and facilitate all aspects of neurosurgery is described. The architectural and functional design of the operating suite is itself an integral surgical instrument as well as a laboratory for development of new dimensions of neurosurgery.

Computed tomographic guidance stereotaxis in the management of intracranial mass lesions.

A prototype Brown-Roberts-Welles stereotactic instrument has been used as both a diagnostic and a therapeutic surgical adjunct in cases of intracranial mass lesions. Eighty-three procedures (142 point placements) required computerized guidance stereotaxy. The unit accomplished point intracranial access with an accuracy of greater than 1 mm. Pathological processes included a variety of neoplasms (56 cases), strokes (7 cases), and infections (20 cases) affecting deep regions of the cerebral hemispheres, the ventricular system, the cerebellum, and the rostral brain stem. Procedures were undertaken with the patient under local anesthesia for biopsy (300 point specimens), culture, evacuation, aspiration, endoscopic excision, and implantation of radioisotopes. The techniques and instrumentation for each of these procedures are described. Procedural objectives were satisfactorily accomplished with no mortality and an overall complication rate of 4%. Recovery of tissue specific to establish a histological diagnosis or the etiological factors related to each disease process was realized in 94% of the cases. These results were obtained with scanner utilization times averaging 15 minutes and procedurally related patient recovery periods of less than 4 hours. The value and adaptability of the instrumentation and techniques are illustrated, and potential future applications are discussed.

The metamorphosis of communication, the knowledge revolution, and the maintenance of a contemporary perspective during the 21st century.

OBJECTIVE: To define and discuss elements of the escalation in scientific data availability and their importance to neurosurgery. METHODS: This multifactorial essay describes the evolution of communication methodologies, the information revolution, and the advent and effect of Internet communication with its potential effect on the practice of neurosurgery, professional assemblies, journals, and the infrastructure of the discipline. Practical and philosophical viewpoints are rendered to assess the existing and developing availability of information to the neurosurgical community. CONCLUSION: Knowledge must be discerned from information. The individual does not have the luxury of detachment and must remain consistently, intellectually, and actively involved in the adaptations required to stay truly informed and current.

Sine qua non: the formulation of a theory of neurosurgery.

Fundamental postulates underlying the fabric of biomedicine are rarely discussed, much less seen in print. Scientific surgery and its subspecialties are relatively new fields, and their philosophical basis has received little attention since Halsted's day. During the last quarter century, we have "reinvented" neurosurgery, and a concatenation of forces is escalating that is further accelerated by technological change. Social, economic, political, and scientific climates concurrently exert unusually stressful influences on all practitioners, irrespective of the individual setting. This provides a reason to reexamine what neurosurgeons do and why, and to attempt to define the guidelines of theoretical basis for the specialty of neurosurgery and its procedures. This article examines the accomplishments of past generations in an effort to establish surgical substrata and proceeds to attempt to readdress elements of a theoretical basis of our current practice.

2001: Things to come.

THIS ARTICLE DISCUSSES elements in the definition of modernity and emerging futurism in neurological surgery. In particular, it describes evolution, discovery, and paradigm shifts in the field and forces responsible for their realization. It analyzes the cyclical reinvention of the discipline experienced during the past generation and attempts to identify apertures to the near and more remote future. Subsequently, it focuses on forces and discovery in computational science, imaging, molecular science, biomedical engineering, and information processing as they relate to the theme of minimalism that is evident in the field. These areas are explained in the light of future possibilities offered by the emerging field of nanotechnology with molecular engineering.

Cellular and molecular neurosurgery: pathways from concept to reality--part I: target disorders and concept approaches to gene therapy of the central nervous system.

Recent advances in cellular and molecular biology and better understanding of genetic and biochemical bases of different central nervous system (CNS) disorders have made gene therapy of the CNS a realistic goal. Concept approaches for gene therapy of CNS disorders are reviewed and include the following: 1) gene replacement with a single normal allele to correct the inherited global neurodegenerative disorders, such as enzyme deficiencies; 2) brain repair to restore the function of a particular subset of cells that were lost because of a neurodegenerative process; 3) gene therapy of brain tumors; and 4) gene therapy of stroke. Techniques of viral vector-mediated CNS transfer of a therapeutic gene, transplantation of genetically modified cells, fetal embryonic implantation and/or implantation of genetically engineered neural progenitor cells, and production of a specific enzyme, neurotransmitter, and/or growth factor are discussed with respect to the therapeutic potential for global and localized CNS neurodegenerative disorders and stroke. Transfection of the CNS tumor cells with the drug susceptibility ("suicide") gene and/or "toxic" gene and antisense strategies and a concept of adoptive immunotherapy of brain tumors are also discussed. Other approaches, such as transfer of drug-resistant genes and monoclonal antibody gene transfer, are briefly discussed. In addition to summarizing current principles of gene therapy for several groups of CNS disorders, the issues that remain to be resolved in clinical reality, such as delivery of the genetic material and regulation of the cellular expression of the transgene, and the negatives associated with the concepts of gene therapy, such as transient gene expression, toxicity of viral proteins, drawbacks of antisense therapy, and the problem of immune response to the transfected protein, have been also identified.

Cellular and molecular neurosurgery: pathways from concept to reality--part II: vector systems and delivery methodologies for gene therapy of the central nervous system.

Different vector systems that have been used and/or specifically developed for central nervous system (CNS) gene transfer studies are briefly discussed along with their advantages and disadvantages with respect to potential clinical application. These include retroviruses, recombinant herpes simplex virus, adenoviruses, adenoassociated viruses, encapsulation of plasmid deoxyribonucleic acid into cationic liposomes, and neural and oliogodendroglial stem cells. Particular attention has been paid to relate the modality of a specific CNS gene therapy to the strategy for adequate delivery of genetic material to the brain for either global or localized CNS neurodegenerative chronic disorder, as well as for CNS tumors and stroke. Techniques to circumvent the "impermeable" blood-brain barrier and how to breach the more versatile blood-brain-tumor barrier to deliver the genetic material to the target CNS cells are reviewed and include the following: 1) local stereotactic CNS injection/infusion of viral vectors, administration of vector producer cells, or cell replacement; 2) local administration of genetic material into the cerebrospinal fluid ventriculocisternal system; 3) osmotic opening of the blood-brain barrier; 4) local intra-arterial infusion; and 5) administration of blood-brain-tumor barrier permeabilizers, such as a bradykinin B2 agonist RMP-7. It is concluded that gene therapy for several brain disorders holds great potential, as suggested mainly by in vitro experiments and, to some extent, by a limited number of animal experiments. However, several drawbacks currently hamper the application of gene therapy under the clinical setting. The problems associated with gene therapy that still present major obstacles are as follows: 1) inefficient transfection of host cells by viral vectors; 2) restricted delivery of genetic material across vascular barriers of the CNS and brain tumors; 3) nonselective expression of the transgene; and 4) in situ CNS regulation of the transgene expression in a therapeutically controlled manner, as imposed by the course and phenotype of the CNS disease.

Outcome prediction after penetrating craniocerebral injury in a civilian population: aggressive surgical management in patients with admission Glasgow Coma Scale scores of 3, 4, or 5.

In an attempt to evaluate the response of patients who have low admission Glasgow Coma Scale scores (GCS) after a penetrating craniocerebral injury to aggressive management, we evaluated a series of 190 patients with penetrating injuries who presented with a GCS score of 3, 4, or 5 during a 6-year period. Entrance criteria required replicable neurological examinations that were not altered by the presence of hypotension, drugs/toxins, or systemic injury. The surgical patients included 21 patients with an admission GCS score of 3, 24 with an admission GCS score of 4, and 15 with an admission GCS score of 5. All patients underwent surgical intervention and aggressive perioperative management in the neurosurgical intensive care, including resuscitative protocols. Five of the patients with a GCS score of 3 survived, all with poor outcomes. Seven of the patients with a GCS score of 4 survived, although only one had a good outcome. Eleven of the patients with a GCS score of 5 survived. Five had a Glasgow Outcome Score of 2, five had a Glasgow Outcome Score of 3, and one had a Glasgow Outcome Score of 4. We have devised a prospective model of outcome based on our series in an attempt to predict nonsurvivors at admission (while overpredicting for survivors). The variables most predictive of mortality include admission GCS score and subarachnoid hemorrhage in one model and admission GCS score and pupillary changes in a second, when pupillary response was definitive at admission (P < or = 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Definition of the role of contemporary surgical management in cisternal and parenchymatous cysticercosis cerebri.

With increasing immigration from endemic regions, the incidence of neurocysticercosis in North America is rising. This retrospective study was undertaken to examine the role of surgery in those cases presenting with large cystic parenchymal and cisternal lesions in the current era of anthelminthic agents administered orally. A total of 237 patients presented with newly diagnosed neurocysticercosis to our institution over a recent 5-year period (mean age, 31.2 years). Among those who presented with cystic mass lesions predominantly affecting the brain parenchyma and cisternal spaces, 20 (8.4%; mean age, 40.2 years) with large cystic lesions subsequently underwent surgical intervention, either because of an emergent presentation or because they were refractory to medical management. Clinical presentation included increased intracranial pressure, focal neurological deficit, and seizure. Radiographic imaging (computed tomography and/or magnetic resonance imaging) demonstrated 12 cases with cisternal lesions, 7 with parenchymal lesions, and 1 involving both compartments. Based on imaging guidelines, 30 operative procedures (excluding shunt revisions) were performed (14 craniotomies, 8 cerebrospinal fluid diversions, 7 stereotactic procedures, and 1 burr hole drainage). Fifteen (75%) showed neurological or symptomatic improvement over a median follow-up period of 36.4 months. There were three surgery-related complications and no deaths.

Stereotactic biopsy in the diagnosis of brain masses: comparison of results of biopsy and resected surgical specimen.

We report the pathological accuracy of image-directed stereotactic brain biopsy in 30 patients who had mass lesions of the brain and subsequently underwent resection of the mass. The histological diagnosis at stereotactic biopsy was appropriate for direction of clinical management in 28 of 30 patients. Correlation between the stereotactic and resection diagnoses was exact in 19 of 30 cases. These included 11 of 12 nonastrocytic neoplasms and 8 of 13 astrocytic neoplasms. Correlation was imperfect in 9 of 30 cases, but not to the extent of having significant clinical impact. These included 2 cases of anaplastic astrocytoma that were upgraded to glioblastoma multiforme, 2 cases of astrocytoma that had a significant oligodendroglial component, and 5 non-neoplastic lesions that were reported on biopsy as showing nonspecific reactive changes. In 2 of 30 patients, the stereotactic biopsy was not accurate. This included one patient who had glioblastoma multiforme whose stereotactic biopsy showed only necrotic tissue. Serious diagnostic error that resulted in clinical mismanagement occurred in one patient who had a pineal germinoma that had large areas of granulomatous inflammation at which the stereotactic biopsy was directed. This study provides evidence that, with careful target placement, stereotactic biopsy can provide biopsy material that represents the entire lesion with an accuracy that is sufficient for clinical management.

Third ventricular cysticercal cyst mimicking a colloid cyst: case report.

We describe a case of a 28-year-old Latino man who presented with signs and symptoms of raised intracranial pressure and radiographic evidence of a third ventricular cystic lesion. The cyst was removed via a transcallosal approach; the histology was noted to be a cysticercal lesion. The radiographic and histological features of this interesting case are discussed.