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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.

Two types of “spontaneous” malignant alteration in vitro of ST/a mouse lung fibroblasts (ST-L) have been observed. In contrast to cells which retained their fibroblastic appearance (R−ST-L cells), cells showing morphological signs of transformation (R+ST-L cells) developed strong isoimmunizing properties. Both types of cells expressed MuLV antigens which were found to be responsible for serum as well as cell-mediated immune reactions in vitro. The higher concentration of gp70 in R+ cells as compared to R− cells and possibly also the morphological differences in surface structure between the two cell types may account for the differences in immunogenicity. Preimmunization with R+ST-L cells protected ST/a mice against secondary challenge with two ascites tumors (STABAL leukemia and Ehrlich). R−ST-L cells did not have a similar protective effect. However, the two ascites tumors only showed weak or no cross-reactions in vitro with sera and lymphoid cells from ST/a mice sensitized to R+ST-L cells, and the in vitro reaction between the latter cells and sera or lymphoid cells from mice immunized against the two ascites tumors was moderate. This discrepancy between in vivo and in vitro observations is discussed.

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.

Neurogenic tumors were induced in inbred Wistar rats by the transplacental administration of ethylnitrosourea (ENU). The tumors were transplantable in syngeneic rats and they could easily be grown in vitro. Migration inhibition tests (MIT) were carried out with KCl extracts of several neurogenic tumors, a spontaneous mammary carcinoma and of various normal adult and fetal tissues. Thymocytes and lymph node cells for these tests were obtained from primary tumor hosts, recipients of transplanted tumors and from rats hyperimmunized with Mitomycin C treated tumor cells. An indirect 51Cr-release test as well as an indirect DNA inhibition test were carried out with culture supernatants derived from mixed cultures of neurogenic tumor cells and sensitized or non-sensitized lymphoid cells. All three assays revealed tumor associated antigens with cross-reactions between various neurogenic tumors. Cross-reactions were also demonstrated by MIT between neurogenic tumors and fetal tissues. A peripheral neurinoma showed cross-reaction with adult brain and a trigeminal nerve neurinoma cross-reacted with the spontaneous mammary carcinoma. None of the neurogenic tumors cross-reacted with adult liver. Thus, ENU induced neurogenic tumors share one or several common antigens which, however, are not tumor specific. The reactivity of lymphoid cells derived from tumor bearing rats was considerably smaller than that of lymphoid cells from hyperimmunized rats. It was also found that the reactivity of lymphoid cells from thymus and lymph nodes was considerably stronger than that of splenocytes.

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.

IL-5 expresses various biologic effects on several types of lymphocytes, including B cells, eosinophils, and T cells. We demonstrated that the incubation of resting splenocytes from C57BL/6 mice in murine rIL-5 enhances IL-2-mediated lymphokine-activated killer (LAK) activity against various tumor cells. IL-5 alone, however, does not induce killer activity. IL-2-mediated LAK activity increases in proportion to the dose of IL-5. During the late phase of the culture period, IL-5 seems to have some effect on the induction of IL-2-mediated LAK activity. We expect that IL-5 will prove useful for adoptive immunotherapy.

This paper presents an application of parallel processing and pipeline processing to power system analysis. The system matrix is transformed to a bordered block diagonal form (BBDF) matrix for effective utilization of the processors. After LU factorization, subnetworks organize sparse matrices and the boundary network organizes a full matrix. First, a parallel processing technique is used to calculate subnetworks. Then, as pipeline processing is applied, inverse matrix of the boundary network is multiplied. The proposed method is made operational on a parallel computing system including a pipeline processor. A consideration on the transient stability analysis using the proposed method also is presented at the end of this paper.