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A 57-year-old male presented with a rare case of spontaneous vertebral arteriovenous fistula manifesting as radiculopathy of the right arm, subsequently associated with pulsating tinnitus and vascular bruit in the nape. He had a past history of chiropractic-induced vertebrobasilar infarction. Angiography showed a simple and direct fistula between the third segment of the right vertebral artery and the epidural veins at the C-1 level, where the artery runs backward above the arch of the C-1 just proximal to the penetration of the dura. The fistula was successfully obliterated by coil embolization, resulting in rapid improvement of the signs and symptoms. Mechanical compression to the nerve roots by the engorged epidural veins with arterial pressure was considered to be the major cause of radiculopathy. Vertebral artery dissection induced by chiropractic manipulation is most likely responsible for the development of the fistula.

A 68-year-old male presented an unusual dural arteriovenous fistula (AVF) located at the craniocervical junction. Magnetic resonance imaging revealed dilated perimedullary veins around the spinal cord at C-1 and C-2 levels, as well as high intensity signals in the spinal cord on T2-weighted images. Vertebral angiography identified an AVF at the point where the right vertebral artery penetrates the dura. The fistula was a single and direct communication between the vertebral artery and the spinal vein. Surgical interruption of the fistula at its venous side resulted in prompt improvement of both motor and sensory signs and symptoms.

To plan the optimal BNCT using BSH for glioblastoma patients, the 10B concentration in tumor and blood was investigated in 11 newly diagnosed glioblastoma patients. All patients received 20 mg BSH/kg body weight 2.5-16 hrs prior to tumor removal. The quantitative distribution of 10B was determined by prompt gamma ray spectrometry and/or alpha-track autoradiography. 10B distribution in tumors was heterogeneous, +/- 25% of scattering at the microscopic level, and the distribution was also heterogeneous at the tissue level. 10B concentration in blood decreased in bi-exponential decay as a function of the time after the end of the administration. The T/B ratio showed non-exponential increase with large variation. The maximum T/B ratio would be around 1. The tumor/normal brain (T/N) ratio of 10B concentration was 11.0 +/- 3.2. The 10B content in normal brain is originated in vascular 10B in parenchyma, since the 10B content in normal brain to blood (N/B ratio) being compatible with the blood content in parenchyma. These values allow for BNCT, using thermal neutrons, on brain tumors located less than approximately 3.3 cm in depth from the brain surface of neutron incidence, providing that the dose on the normal endothelium is controlled to less than the tolerance limit. In our preliminary study of BNCT, a 31% 3-year survival was achieved over all for 16 glioblastoma patients and a 50% 2-year survival was achieved on 8 glioblastoma patients in our recent dose escalation study based on these data.

Bioactive bone cement (BABC) is a novel artificial bone cement. It has some noteworthy characteristics that are applicable to neurological surgery. The toxicity of BABC to the nervous system was tested by implanting BABC and polymethylmethacrylate (PMMA) cement as a control at the parietal and the suboccipital regions of the skull in beagles. The auditory brainstem response (ABR) was tested before and after implantation. Sections of the cerebral cortex and the acoustic nerve were examined at 3 and 6 months after implantation. No abnormal ABR was found in any animals. Histological examination of the cerebral cortex and acoustic nerve demonstrated slight gliosis in both the BABC and PMMA cement groups, but no other abnormalities.

A 45-year-old male presented with sudden onset of severe headache, mild disorientation, and gait disturbance due to intracystic hemorrhage from a cerebellar hemangioblastoma. He was successfully treated with ventricular drainage followed by total removal of the tumor. Reported cases of intracranial hemangioblastoma with massive hemorrhage show male predominance, tend to be solid rather than cystic, and occur in supratentorial more than infratentorial locations. Thin-walled and dilated vessels in the present and other cases were a possible cause of hemorrhage. Massive hemorrhage from hemangioblastoma is rare but needs prompt treatment because of the relatively high mortality.

A 60-year-old male and a 36-year-old female suffered shunt migration after lumboperitoneal shunt procedures, upward into the spinal subarachnoid space and downward into the abdominal cavity, respectively. Defects of the fixation devices in the shunt system are considered the main cause in both cases. Upward migration of the lumbar tube in the subarachnoid space is extremely rare. We suppose that raised abdominal pressure is related to this unusual complication.

We studied the effect that treating two types of glioblastoma cell lines, U-87 MG and U-251 MG, with interferon (IFN)-gamma had on their susceptibility to lysis by lymphokine-activated killer (LAK) cells. We also examined the participation of cell-adhesion molecules and major histocompatibility complex (MHC) class I and II antigens present on the target cells in lysis by LAK cells. Treatment with IFN-gamma (1000 U/ml) for 48 hours resulted in the increased expression of both intercellular-adhesion molecule 1 and MHC class I antigens on tumor cells. In addition, untreated tumor cells expressed neural-cell-adhesion molecules and MHC class II antigens highly, but their expression was not affected by IFN-gamma treatment. These changes in expression were accompanied by a decreased susceptibility to lysis by LAK cells. Treatment with antisense-intercellular-adhesion molecule-1 oligonucleotide further inhibited LAK lysis of target cells, following treatment with IFN-gamma. In contrast, acid treatment of tumor cells after treatment with IFN-gamma increased their susceptibility to lysis by LAK cells. These findings suggest that treatment of glioblastoma cells with IFN-gamma decreased their susceptibility to lysis by LAK cells, and that this decrease in susceptibility is attributable principally to the increased expression of MHC class I antigen on target cells.

In order to investigate the clinical significance of glucose consumption (GC) in recurrent gliomas, positron emission tomography with 18F-labeled fluorodeoxyglucose was measured in 18 cases of histologically verified recurrent gliomas. The GC of the tumors were categorized into four groups. Five tumors were in Group IV, the highest GC, four were in Group III, eight were in Group II, and one was in Group I. Masses in Groups III and IV were clearly defined as a hot spot higher than or similar to the GC of the contralateral cortex. Half of the recurrent gliomas showed the lower GC of Group I or II, but two thirds of these were histologically high-grade gliomas. Although GC in the recurrent gliomas did not always increase as expected, a focal increase of GC, even mild and small, in the area of previous surgery is diagnostically important. Tumors with high GC showed high histological malignancy, irrespective of tissue damage. Patients with tumors of low GC had longer survival rates than those with high GC, although statistical significance was not obtained. Thus, positron emission tomography with 18F-labeled fluorodeoxyglucose was useful for detecting the recurrence of gliomas and suggesting their histological malignancy and prognosis. Care should be taken because viable tumor cells could be present in areas of low GC and small recurrent masses could be missed because of the poor spatial resolution of positron emission tomography.

A case of treatment-related leukoencephalopathy is presented. A patient with medulloblastoma was postoperatively treated with craniospinal axis irradiation. One month after irradiation, weekly intrathecal administration of methotrexate was performed 4 times to treat cerebrospinal fluid dissemination of the tumor. Two months after the initiation of intrathecal chemotherapy, the patient became somnolent and developed decerebrate posturing. Magnetic resonance imaging showed diffuse leukoencephalopathy. Positron emission tomography revealed a diffuse decrease in glucose uptake in the deep white matter. Auditory evoked potential also showed diffuse abnormalities, not only in the cerebrum, but also in the brain stem. High dose intravenous leucovorin rescue was attempted without any neurologic improvement.

The mechanism by which interferon gamma (IFN-gamma) decreases the susceptibility of the established cultured gliosarcoma line Gl-1 to lymphokine-activated killer (LAK) lysis was analyzed. The results of monolayer depletion and lectin-dependent cellular cytotoxicity assays by LAK cells revealed that the resistance to LAK lysis of IFN-gamma-treated Gl-1 cells is manifested at the stage of LAK cell target recognition alone. We have also divided LAK cells into populations of phenotypically natural killer (NK)- and T-like cells with monoclonal antibodies and complement, respectively. We have used these cells to examine the mechanism of IFN-gamma-induced protection of Gl-1 cells from LAK lysis in cold target inhibition, monolayer depletion, and direct binding assays. The results revealed that NK-like cells do not recognize IFN-gamma-treated Gl-1 cells as efficiently as they do untreated targets, whereas T-like cells show the opposite tendency. In conclusion, we have demonstrated that the IFN-gamma induced protection of tumor cells from LAK lysis is predominantly regulated by the target recognition of NK-like cells. On the other hand, IFN-gamma-treated tumor cells may bind to T-like cells but fail to trigger them to initiate further stages for lysis as effectively as NK-like cells.

Three murine monoclonal antibodies, designated GA-17, GB-4, and GC-3, were prepared by the hybridization of murine myeloma cells (NS-1) and spleen cells of BALB/c mice immunized with the crude membrane fraction of cultured human gliosarcoma cells (GI-1). Two of them (GA-17 and GB-4) reacted exclusively with the membrane of glioma cells, and the other (GC-3) reacted with the membrane of glioma cells and a T cell line (MOLT-4). Although these antibodies reacted with almost all of the gliomas, the reactions differed. GA-17 reacted equally well with all glioblastoma (17 cases) and low-grade astrocytoma (10 cases), whereas GB-4 reacted poorly with 7 cases of glioblastoma and GC-3 did not react with 7 cases of low-grade astrocytoma. The antigens, exclusively expressed on the cell surface, were analyzed by surface labeling with 125I followed by a cell lysis and immunoprecipitation with these antibodies. The findings obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that GA-17, GB-4, and GC-3 reacted with Mr 140,000-145,000, Mr 160,000, and Mr 145,000-150,000 proteins, respectively. Some evidence has been obtained indicating that these antigens are composed of the same polypeptide chain (Mr 120,000) with the carbohydrate chains being different.

A permanent cell line, GI-1, was established from a human gliosarcoma, and its characteristics were investigated. The original tumor was a mixture of two different neoplasms which had components of both glioma and sarcoma. The established cell line expressed various mesenchymal antigens, but not neuroepithelial antigens. It was noted, however, that the cell line produced tumors with the morphological features of human glioma after inoculation in athymic mice. The contrast of the pathological characteristics in tissue culture and in xenograft was unique, and this finding suggests that the GI-1 cell line may have the features of both glioma and sarcoma.

We examined the expression of fibroblast growth factor receptor-1 (FGFR-1), namely FLG, in tissues of 18 human gliomas, 10 human meningiomas, 3 human metastatic brain tumors, and 2 normal human brains by means of immunohistochemistry. All tissues were positively stained for FGFR-1. Primary brain tumors were more abundantly immunoreactive than normal brain tissues (Mann-Whitney U test, P < 0.05). There was significant correlation between the expression level of basic fibroblast growth factor (basic FGF) and that of FGFR-1 in tissues of human glioma (Spearman's test, P < 0.05). The expression level of FGFR-1 of tumor cells increased in correlation with that of endothelial cells in glioma tissues (Spearman's test, P < 0.001). We previously reported that basic FGF is produced in more than 90% of human glioma and meningioma tissues. Together with these data, it is suggested that basic FGF is involved in autonomous cell growth and tumorigenesis of gliomas and meningiomas as an autocrine growth factor in vivo.

Fluosol-DA, 20%, was intravenously infused in 28 patients suffering from cerebrovascular disease, and, was found to be effective in 60% of the cases with vasospasm and in 80% of the cases with stenosis and/or occlusion of the artery. Administration of the solution increases r-CBF by 10.1 to 37.9% when measured by either intra-arterial injection or inhalation of 133Xe. However, an increase of arterial oxygen tension appears to have little effect on r-CBF after administration of the solution. The increase of r-CBF caused by Fluosol-DA, 20%, may be due not only to the lowering viscosity of the mixed blood but also to its direct effect on dilating cerebral vessels.

Alumina ceramic (Bioceram®) is an excellent material that is stable in and compatible with biological tissues, though harder and more fragile than antogenous bone. Recently, new ceramics have been developed for the purpose of overcoming the disadvantages of alumina ceramics. For example, zirconia ceramics have almost the same flexural strength as iron and hydroxy apatite consists of the same molecular elements as autogenous bone. Tissue compatibilities and radiological properties of three ceramics were investigated. First, tissue culture dishes (30 mm in diameter and 5 mm in depth) were made of the three ceramics and the adherence of cultured tumor cells to these dishes at 37°C for 90 minutes were compared with glass dishes and plastic culture dishes (Nunclon®). There was no difference in adherence between alumina ceramics and zirconia ceramics, both of which are superior to hydroxy apatite. Next, the growth rate for 1 week of cultured tumor cells on the ceramic dishes were examined. There were no differences between the three ceramics with regard to doubling time, while the growth rate on alumina ceramics exceeded that of the other ceramics. Thirdly, ceramic pieces were implanted in the parietal bone of mongrel dogs and histological changes, especially new bone formation, were investigated. Tongue-like exostosis of new bone along the ceramic piece was observed 2 months after implantation of alumina ceramic and 3 months for zirconia ceramic. Tissue reaction was slight. Finally, the artifacts of each ceramic on computerized tomography (CT) scan image were investigated. In the application of ceramics to neurosurgical field, artifacts on CT scan are an obstacle. Alumina ceramic showed minimum artifact on CT scan. Alumina ceramic is considered to be the most suitable material among the three ceramics in the neurosurgical field at present.

In 24 patients suffering from cerebrovascular diseases, alteration of the cerebral blood flow was investigated by means of the 133Xe clearance technique before and after the intravenous infusion of perfluorochemical suspension (Fluosol-DA, 20%, 10 ml/kg). Since perfluorochemicals exhibit high solubilities for not only oxygen but other kinds of gases, the partition coefficient of Xe (lambda tb) is considered to change depending on the amount of perfluorochemicals contained in the blood (Fct). The solubilities of Xe in the perfluorochemicals contained in the solution were then measured by gas chromatography to obtain an equation for lambda tb: lambda tb = 1.50/(Hct/100 + 12.48Fct/100 + 0.95). The cerebral blood flow was found to increase significantly by 10.1% in the lesional hemisphere and by 10.8% in the healthy one. The cortical small artery with a diameter between 0.1 and 0.2 mm appeared to dilate by 13% after its administration. From these results, the decrease of blood viscosity and some vasodilating effect of the solution might be responsible for the increase of the cerebral blood flow.

Immunological cross-reactivities between rat spontaneous mammary carcinoma or ethylnitrosourea (ENU)-induced neurogenic tumors and various fetal and adult tissues were tested in vitro by the migration inhibition test (MIT). Wistar/Fib rats were immunized with either live cells or radiation-killed tumor cells of over 37 transplant generations. ENU-induced neurinomas of the peripheral nerve (T1, T3) lost some of their antigenicities in the later transplantation generations, and failed to react with fetal or brain tissues. On the other hand, ENU-induced oligodendroglioma (T5) retained strong antigenicities at least up to the 10th passage. In addition, T5 and syngeneic spontaneous mammary carcinoma (T9) showed similar responses to fetal extracts. Among the tissues examined, two-week fetal tissues showed the highest expression of fetal antigens detected by cross-reaction with these tumor cells. MIT with 3M KG extracts of fetal tissues demonstrated that sensitization with live tumor cells elicited stronger immunological responses than that with radiationkilled cells.

The radiosensitizing effect of misonidazole was studied in an experimental system of intracranially transplanted 203-glioma in C57BL mice. When 5 × 105 tumor cells were transplanted into the right frontal area of 4-week-old male mice, all the control mice died within 3 weeks after transplantation. The experimental mice were treated with 1, 000 rads of irradiation using 60Co, with or without misonidazole administration, given after various lengths of time after transplantation. When used, misonidazole was given intraperitoneally in a dose of 20 mg, 30 to 60 minutes prior to irradiation. Misonidazole had no remarkable effect when the mice were treated 6 days after transplantation. However, when they were treated with misonidazole 10 days after transplantation and irradiated, the mean survival time of the mice was longer (about 6.5 weeks) than that of the mice treated by irradiation alone (about 4.5 weeks). In order to evaluate the radiosensitizing effect of misonidazole in the terminal stage to contain a large number of hypoxic tumor cells, the following in vivo assay was designed. Intracranial tumors, with or without misonidazole treatment, were removed immediately after irradiation. Then, 5×105 viable tumor cells were retransplanted into other groups of mice, and their survival rates were observed. While all the mice retransplanted with tumor cells treated by irradiation alone died of tumor growth within 5 weeks, those retransplanted with tumor cells treated by irradiation and misonidazole became free of tumor and survived for the observation period of 8 weeks. These results suggest the radiosensitizing effect of misonidazole. As regards the side effects, there was no notable decrease in body weight after the administration of misonidazole. On histological examination there was no specific change ascribable to misonidazole, while there were many necrotic regions after irradiation with or without misonidazole. As a clinical trial, misonidazole was given to 21 patients with brain tumors in an oral dose of 1.0 g/m2, 4 to 6 hours prior to irradiation twice weekly. The total dose was limited to 10 g/m2. Because the series of patients was not large enough and because most of them were also given chemotherapy, it was difficult to distinguish the effect of misonidazole from that of conventional radiotherapy and chemotherapy. There was no remarkable side effects due to misonidazole except for nausea and vomiting in some patients. It is clear, however, that the limiting factor in the clinical dose of misonidazole is its various toxicities, such as peripheral neuropathy and gastrointestinal symptoms, which have occasionally been reported, and so the local application of misonidazole may be the next step.

Cross-reactivities between chemically induced rat tumors and fetal tissues were examined by the migration inhibition test. Wistar/Fib adult rats were immunized by intracutaneous injection of Freund incomplete adjuvant with or without the extracts of various fetal tissues (one-week whole fetal tissue, two-week fetus without brain and spinal cord, and two-week fetal brain). A mixture of thymic and lymph-node cells was used as migration cells. Peripheral neurinomas (T1 and T3) and oligodendroglioma (T2) were induced by ethylnitrosourea with single intraperitoneal injection in pregnant rats in the third week of gestation; 3M KCl extracts of these tumors served as antigens. The animals sensitized by two-week fetus reacted with all neurogenic tumors although in half of them (4/8) no significant differences from the reaction of the lymphoid cells sensitized by Freund incomplete adjuvant alone were demonstrated. The lymphoid cells sensitized by one-week fetus showed the weakest responses (especially in the reaction with T3 tumor) among all fetal extracts. The T1 tumor was also suggested to have brain specific antigens. When the lymphnode cells served independently as the migration cells, it was very difficult to obtain positive results which were easily obtained by a mixture of lymph-node cells and thymic cells. However, the lymph-node cells sensitized by one-week fetus reacted much more strongly than the mixture of thymic and lymph-node cells. In vivo tumor rejection studies on the embryonic tissue of immunized rats are now in progress.

Local cerebral blood flow (lCBF) and electroencephalogram were monitored in six monkeys after a transfusion using a perfluorochemical suspension (Fluosol-DA, 20%) that has been manufactured as a blood substitute and is known to be synthetic, biologically inert, and nontoxic and to have a high capacity for carrying oxygen. The animals were mechanically ventilated, and blood gases were maintained at physiological levels. Fluosol-DA, 20% was administered either by an exchange transfusion of 20 ml/kg or by an infusion of 8 ml/kg followed by an exchange transfusion of 12 ml/kg. lCBF was measured using the hydrogen clearance technique. An equation was proposed to estimate the tissue-blood partition coefficient of hydrogen; this coefficient is considered to be dependent upon the amount of perfluorochemicals in the blood and was used to calculate lCBF. Systemic blood pressure, pulse rate, central venous pressure, electroencephalogram, and gas analysis of the blood from the femoral artery, the femoral vein, and the superior sagittal sinus showed little change throughout the experiment. lCBF was increased by 12% (p less than 0.005) after the infusion of Fluosol-DA, 20% of 8 ml/kg and by 31% (p less than 0.02) after the exchange transfusion. Hyperventilation reduced lCBF significantly (p less than 0.005), which implies that the reactivity of the cerebral blood vessels to hypocarbia was not impaired by the administration of FLuosol-DA, 20%. Both the results of this study and the physical properties of Fluosol-DA, 20% suggest that this blood substitute can safely be used for normal human brains and that it might also be effective for ischemic brains.

The authors report 3 cases of epidural hematoma of the posterior fossa in children. The clinical signs and symptoms are discussed. Onset of symptoms is not necessarily acute. The radiological findings are discussed. Epidural hematoms of the posterior fossa in children have a tendency to liquefy earlier than supratentorial hematomas. We emphasize the value of computed tomography for the diagonosis of epidural hematoma of the posterior fossa. One should keep in mind the possibility of the presence of an epidural hematoma of the posterior fossa in the treatement of head injury in children, even in the case of a minor head injury.

The authors previously reported a new, in vitro technique for determining the invasiveness of four rat neurogenic tumor cell lines. Now this method has been modified and applied to the analysis of the invasiveness of human brain tumors. Eighty-seven tumors, including 61 gliomas, six metastatic brain tumors, 10 meningiomas, four neurinomas, one melanoma, one hemangioblastoma, two craniopharyngiomas, one chemodectoma, and one pituitary adenoma, were studied. Since gliomas were of primary interest, their invasiveness was studied more extensively. Fresh tumor specimens obtained during craniotomy were immediately minced in Dulbecco's modified Eagles's minimum essential medium containing 20% fetal calf serum to obtain fragments of 300-500 μm in size. These tumor fragments and precultured embryonic chick heart fragments were placed together on semisolid agar (0.35%) for 2 hours at 37°C. These fused tissues were then cultured in a gyratory shaker at 100 rpm for 7 days. From hematoxylin-eosin stained and immunostained serial sections, the degree of invasiveness was determined according to the “classification of invasiveness.” Although there were discrepancies between the histologic findings and the degree of invasiveness in 22.5% of high-grade astrocytomas, conventional histological diagnosis was well correlated with invasiveness in almost all low-grade astrocytomas. This in vitro technique appears to be a simple and useful means of evaluating the invasive potential of brain tumors.