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Object: The current prognosis for patients with malignant brain tumors remains poor, and new therapeutic options are urgently needed. We previously have shown that prolongation of survival can be achieved in C57BL/6 mice (H-2b) with a syngeneic intracerebral or subcutaneous glioma when treated with allogeneic mouse fibroblasts (H-2k) genetically engineered to secrete interleukin-2 (IL-2). Like other antigens, tumor-associated antigens are recognized by cytotoxic T lymphocytes in the context of determinants specified by the major histocompatibility complex class I locus. Because the rejection of allogeneic major histocompatibility complex determinants has the property of an immune adjuvant, immunotherapy of glioma with a cellular immunogen that combines the expression of both syngeneic class I determinants and allogeneic antigens could have advantages over an immunogen that expresses syngeneic or allogeneic determinants alone., Methods: To investigate this question in a mouse glioma model, we further modified allogeneic mouse fibroblasts (H-2k), not only for IL-2 secretion, but also for the expression of H-2Kb class I determinants. We tested the immunotherapeutic properties of these semiallogeneic cells (LM-IL-2/H-2Kb) in C57BL/6 mice with Gl261 glioma in both subcutaneous and intracerebral glioma models., Results: C57BL/6 mice with either a subcutaneous or intracerebral glioma treated solely by injection of these IL-2-secreting semiallogeneic cells had significantly prolonged survival rates compared with untreated mice or mice treated with cells secreting only IL-2 or cells lacking the H-2Kb determinants. In some instances, the mice treated with the semiallogeneic cells survived indefinitely, suggesting total eradication of the glioma. When a 51Cr release assay was used, the specific immunocytotoxicity measured by release of isotopes from labeled Gl261 glioma cells coincubated with spleen cells from mice immunized with the semiallogeneic IL-2-secreting cells was significantly higher than that of spleen cells from nonimmunized mice or mice immunized with allogeneic cells lacking syngeneic major histocompatibility complex determinants. In addition, antibody depletion studies using monoclonal antibodies against CD8+ and natural killer/lymphokine-activated killer cells demonstrated a specific CD8+ immunocytotoxic response in animals immunized with the semiallogeneic IL-2-secreting cells compared with only a natural killer/lymphokine-activated killer response in mice immunized with the allogeneic IL-2-secreting cells., Conclusion: The augmented immune response against glioma in mice treated with the semiallogeneic IL-2-secreting cells points toward a new form of immunotherapy, "immuno-gene therapy," for patients with malignant intracerebral glioma.

Objective: Ependymomas arise from different areas in the neuraxis and have variable outcomes that depend on tumor location and patient age at the time of presentation. The predictive value of histology for these tumors is unresolved. We report a series of adult patients with supratentorial ependymomas to characterize the roles of surgery, histology, ploidy, and proliferation index in tumor control., Methods: Fourteen of the 23 supratentorial ependymomas were in the region of the third ventricle and the remainder were located in the hemispheres. Resections were gross total in 12 patients, subtotal in 8, and biopsy in 3. A single pathologist reviewed all slides and quantitated the deoxyribonucleic acid. The mean follow-up duration was 95 months (+/-75 mo)., Results: All of the malignant ependymomas were hemispheric (n = 4). Mortality occurred only in patients with third ventricular tumors; two patients died as a result of surgical complications and three as a result of tumor progression. Kaplan-Meier estimates of 5- and 10-year survival rates were 100% for hemispheric and 72.5% for third ventricular tumors (62.5% including the two perioperative deaths). The median time to recurrence was 53 months, with a 10-year progression-free survival rate of 27%. Univariate analysis revealed that recurrence was associated with malignant histology, including mitoses, cellularity, and aneuploidy. For nonmalignant ependymomas, recurrence was associated with subtotal resection and metastases. S-phase fraction did not correlate with recurrence. Only malignant histology correlated with recurrence on multivariate analysis., Conclusion: Although the numbers are too small to draw any definite conclusions, treatment of ependymomas that arise in the supratentorial compartment in adult patients results in excellent outcomes despite frequent recurrences. Association with the third ventricle and metastases seem to have a negative impact on survival, whereas malignant histology, subtotal resection, and metastases may be predictors of recurrence.

Objective: In previous studies, we determined that C57BL/6 mice (H-2b) with intracerebral (i.c.) malignant glioma or melanoma treated with allogeneic fibroblasts genetically engineered to secrete interleukin (IL)-2 results in prolonged survival and a cellular antitumor response when the treatment is administered intratumorally (via i.c. injection). For this study, we evaluated the survival and toxicity of the cytokine-secreting cellular vaccine administered directly into the central nervous system in both syngeneic (C3H H-2k) and allogeneic (C57BL/6 H-2b) mice using bioassay and polymerase chain reaction techniques., Methods: First, brain sections were prepared at varying time intervals (2-60 d) after i.c. injection of the IL-2-secreting fibroblasts (H-2k) into allogeneic and syngeneic mice, and the presence of the cells was detected by polymerase chain reaction for the neomycin gene, which was used as a selection marker for the gene transfer. As a second means of assessing survival of the IL-2-secreting cells, an in vitro bioassay technique was used. Brain sections were prepared at varying time intervals (2-60 d) after i.c. injection of the IL-2-secreting cells into allogeneic and syngeneic mice. Cells were disassociated and grown in media containing neomycin., Results: A positive signal by polymerase chain reaction was no longer detectable 14 days after injection into allogeneic C57BL/6 (H-2b) mice. In contrast, under similar circumstances, the IL-2-secreting cellular vaccine could be detected for more than 55 days in histocompatible (C3H) syngeneic mice (H-2k). Allogeneic cells could be recovered from tissue culture for only 2 to 5 days after i.c. injection of the modified cells. In contrast, syngeneic cells were recovered for up to 28 days after i.c. injection. At no time did the mice exhibit signs of neurological deficit or adverse affects on their survival (>60 d)., Conclusion: An allogeneic cytokine-secreting cellular vaccine has a limited lifespan in the central nervous system, surviving only 14 days or less, and has no apparent adverse effects. These results indicate the advantage of using a modified allogeneic cell line as the delivery vehicle for gene therapy in the treatment of an i.c. neoplasm.

Objective: The purpose of this study was to determine the optimal route of delivery of gene therapy for an intracerebral (IC) tumor. In previous studies, treatment of an IC tumor with the IC administration of a cellular vaccine consisting of allogeneic fibroblasts genetically engineered to secrete cytokines prolonged survival. Systemic delivery of gene therapy is of significant clinical interest., Methods: In this study, allogeneic fibroblasts engineered to secrete interleukin (IL)-2 (LM-IL-2 cells) were administered either subcutaneously or intracerebrally to C57BL/6 mice with IC glioma. In addition, fibroblasts genetically engineered to express (antibody-defined) melanoma-associated antigens and to secrete IL-2 (RLBA-IL-2) were injected either intracerebrally or subcutaneously into mice bearing IC melanoma., Results: The results indicate a significant prolongation of survival in mice with IC glioma treated intracerebrally with LM-IL-2 cells, relative to the survival of mice with IC glioma treated subcutaneously with LM-IL-2 cells or untreated mice with glioma. The specific release of isotope from 51Cr-labeled glioma cells coincubated with spleen cells from animals treated either subcutaneously or intracerebrally with LM-IL-2 cells was significantly greater than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. In a similar fashion, the survival of mice with IC B16 melanoma immunized intracerebrally with RLBA-IL-2 cells was significantly longer than nonimmunized mice injected with B16 cells alone. In contrast, the survival of mice with IC melanoma treated by subcutaneous injection with RLBA-IL-2 cells was not significantly different than that of untreated mice. Using a 51Cr-release assay, the specific release of isotope from labeled B16 cells coincubated with spleen cells from mice immunized either intracerebrally or subcutaneously with RLBA-IL-2 cells was significantly higher than that of B16 cells coincubated with cells from nonimmunized mice., Conclusions: Direct IC administration of fibroblasts genetically engineered to secrete IL-2 was more effective in prolonging survival than peripheral subcutaneous administration in the treatment of mice with IC glioma or melanoma.

Tumor cells are characterized by abnormalities in growth and metabolism, including the autocrine secretion of certain growth factors. On the basis of our previous demonstration of the production of insulin-like growth factors (IGFs) and their binding proteins by central nervous system (CNS) tumors, we asked whether the levels of IGFs in the CSF may be altered in patients with pituitary and other CNS tumors and may reflect autocrine secretion. We used specific radioimmuoassays for IGF-I and -II and measured these growth factors in the cerebrospinal fluid (CSF) from 26 patients with tumors located adjacent to the ventricular system. The tumors included were eight pituitary tumors (five nonsecreting, three growth hormone secreting), five gliomas, two meningiomas, five medulloblastomas, three metastases, and three other tumors. CSF from patients without tumors served as controls. For radioimmunoassay, CSF was treated with acetic acid overnight and IGF-binding proteins were separated from IGFs by C-2 solid phase cartridge extraction. The pituitary tumors were characterized by significantly elevated levels of IGFs in the CSF. In nonseceting pituitary tumors, the levels of IGF-I in the CSF were similar to normal levels, whereas IGF-II levels were significantly elevated. In acromegalic patients, levels of both IGF-I and -II in the CSF were significantly elevated compared with normal levels and compared with levels in patients with nonsecreting tumors. In contrast, the levels of IGFs in the CSF from most of the primary and metastatic CNS CNS tumors did not significantly differ from normal values. In summary, although IGFs may contribute to the regulation of cell growth in primary CNS tumors, CSF levels are not elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

The genes for interleukin (IL)-2, interferon (IFN)-gamma, or both IL-2 and IFN-gamma were introduced into a mouse fibroblast cell line (LM) expressing defined major histocompatibility complex determinants (H-2k). The cytokine-secreting cells were then co-transplanted with the Gl261 murine glioma cell line (H-2b) into syngeneic C57BL/6 mice that differed at the major histocompatibility complex from the cytokine-secreting cells. The period of survival of mice with glioma treated with IL-2- or IL-2/IFN-gamma-secreting allogeneic cells was significantly prolonged (P < 0.025) relative to the survival of mice receiving equivalent numbers of tumor cells alone or mice with glioma treated with nonsecreting fibroblast (LM) cells. Gliomas in the treated mice had an extensive lymphocytic cell infiltrate. Using a 51Cr release assay, the specific release of isotope from labeled Gl261 cells co-incubated with spleen from mice injected with the glioma cells and IL-2-secreting fibroblasts was higher (P < 0.001) than the release from glioma cells co-incubated with spleen cells from nonimmunized mice. Significantly higher levels of release (P < 0.005) were found in the group immunized with fibroblasts secreting both IL-2 and IFN-gamma. Based upon the effect of monoclonal antibodies for T-cell subsets on the antiglioma response, the immunity was mediated predominantly by natural killer/lymphokine-activated killer cells.

Between 1987 and 1988, we utilized magnetic resonance imaging (MRI) in the diagnosis of seven cases of "subacute" pituitary apoplexy, that is, intra-adenomatous pituitary hemorrhage associated with clinical symptoms atypical of acute pituitary apoplexy. These symptoms lasted longer than 24 hours and included visual changes in four patients, headache in five, and seizures, endocrine dysfunction, and oculomotor palsy in one each. Estimates of the ages of the hemorrhages were also possible based on characteristics on the MRI scan and ranged from 48 hours to more than 14 days. Four of our seven patients underwent transsphenoidal decompression at which time the presence of intratumoral hemorrhage was confirmed. The remaining three patients have been followed as outpatients with serial MRI examinations and have shown improvement in clinical symptoms and stabilization of the radiological picture. From our series of patients, it is now apparent that the MRI scan is an invaluable tool in identifying this subacute form of intra-adenomatous pituitary hemorrhage and has proven especially useful as a means of therapeutic planning and follow-up care in patients presenting with symptoms not typical of classic pituitary apoplexy.

epsilon-Aminocaproic acid (EACA) has been used to prevent rebleeding in patients with intracranial aneurysms because it crosses the blood-brain barrier and is an inhibitor of fibrinolysis. Recommended doses have ranged from 24 to 48 g/day. We now describe an inhibitory effect on platelet function at the higher dose range. In vitro, a dose-dependent inhibition of adenosine diphosphate- and collagen-induced platelet aggregation was observed with concentrations of EACA beginning at 7.6 mM. In vivo, prolongation of the template bleeding time was observed in all eight patients receiving 48 g/day (greater than 20 minutes in four), in all five on 36 g/day (greater than 20 minutes in three), and in none of seven on smaller doses. More importantly, rebleeding and excessive intraoperative bleeding (requiring more than 1 litre of blood replacement) occurred predominantly in patients receiving the larger doses of EACA. Within 48 hours of the discontinuation of EACA, the bleeding times returned to normal values in all but one patient. We conclude that EACA exerts a dose-dependent inhibitory effect on platelet function and that patients receiving doses in excess of 24 g/day may be at risk of serious bleeding. Patients receiving EACA should be monitored with serial bleeding time tests.

Phenylpropanolamine (PPA) is the major ingredient in more than 70 over-the-counter preparations including diet pills, nasal decongestants, and the legal "look-alike" stimulants. Structurally and functionally similar to amphetamine and ephedrine, PPA has recently been associated with several neurological manifestations including psychosis, stroke, severe headache, seizures, and intracerebral hematoma. We report a case of intracerebral hematoma and subarachnoid hemorrhage in a young woman with angiographic and biopsy-proven vasculitis of the central nervous system (CNS) induced by PPA in her diet pills. From review of the literature, we distinguish drug-induced vasculitis as a separate entity from primary CNS vasculitis, both clinically and pathologically. This report should alert physicians, in general, to this potentially fatal side effect of PPA, a commonly used over-the-counter drug. Also, neurosurgeons in particular should consider the possibility of drug-induced vasculitis when faced with cases of intracerebral or subarachnoid hemorrhage without apparent cause.