Yukitaka Ushio

Chemotherapy of brain metastases from lung carcinoma: a controlled randomized study.

A controlled randomized study was carried out to evaluate the effects of chemotherapy in patients with brain metastases from lung carcinoma. One hundred patients were randomly divided into three groups at the time of diagnosis or after surgery for metastases. Group A received radiotherapy alone; Group B received radiotherapy and chloroethylnitrosoureas (methyl-CCNU, 100-120 mg/m2, or ACNU 80-100 mg/m2, every 6-8 weeks), and Group C received radiotherapy and a combination of chloroethylnitrosoureas and tegafur (300 mg/m2, daily). Of the 100 patients, 88 could be evaluated. The reduction rates of the tumors of the patients in whom tumor was not surgically removed or not totally removed were compared. Complete resolution of the tumor was noted in 29, 69, and 63% of the patients in Groups A, B, and C, respectively. Tumor regression of greater than or equal to 50% was seen in 36, 69, and 74% of the patients in Groups A, B, and C, respectively. The difference in the response rates of Groups A and C was statistically significant (P less than 0.05). Median survival after the start of treatment for brain metastasis was 27, 30.5, and 29 weeks in Groups A, B and C, respectively. There was 1 long-term survivor (more than 5 years) in Group A, 3 in Group B, and 1 in Group C. The main cause of death was deterioration attributable to the primary lesion or systemic metastasis, and no statistical difference was noted in survival time among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical localization of apolipoprotein E in human glial neoplasms.

Immunocytochemical analyses revealed the presence and distribution of apolipoprotein E (apo E) in normal human brain tissue as well as in 77 human intracranial neoplasms. In normal brain tissues, the perikarya of astrocytes exhibited a strong positive reaction, whereas the Bergmann glia were stained to a moderate degree. However, no immunoreactivity was observed with neurons, oligodendrocytes, ependymal cells, and choroidal epithelium. Among the intracranial neoplasms, oligodendroglioma, choroid plexus papilloma, hemangioblastoma, primary malignant lymphoma, neurinoma, meningioma, pituitary adenoma, and craniopharyngioma were all negative. Immunoreactivity in the peripheral neuroblastoma was nil. However, the perikarya of astrocytomas and glioblastomas showed a positive reaction. Analyses on the degree of anaplasia and the amount of apo-E as an intensity of immunostaining showed a negative correlation. The astrocytic elements were stained in mixed oligoastrocytomas and medulloblastomas with glial differentiation. A few cases of ependymomas showed weak perikaryal immunostaining. Western blot analyses with anti-apo E antibody of a freshly prepared surgical specimen with astrocytomas revealed a single band with a molecular weight of approximately 37,000. The well differentiated cultured human astrocytoma cells secreted apo E into the medium. These lines of evidence suggest that apo E may serve as a potential marker specific for astrocytomas and glioblastomas, as well as an indicator of astrocytic tumor cell differentiation. The apo E localization in human brain tumors could be clinically relevant and diagnostically useful.

Characterization of polyclonal antibodies to brain protein phosphatase 2A and immunohistochemical localization of the enzyme in rat brain

Polyclonal antibodies to the catalytic subunit of protein phosphatase 2A (PrP-2A) from bovine brain were prepared by immunizing rabbits and then purified by antigen-affinity column chromatography. The purified antibodies recognized only PrP-2A among proteins examined, including calcineurin and PrP-1. The antibodies cross-reacted only with a protein in the crude homogenate from rat brain, which comigrated with the catalytic subunit of PrP-2A on SDS-PAGE. The antibodies completely inhibited the activity of PrP-2A, and immunoprecipitated the purified enzyme. Immunoblot analysis demonstrates that, among the subcellular fractions from rat brain, the cytosol fraction and the synaptosomal cytosol fraction show high immunoreactivities, and that any of examined regions of rat brain shows immunoreactivity more or less, in which the caudatoputamen was highest. Immunohistochemical studies demonstrate that the enzyme is distributed widely in various regions of rat brain and that the immunoreactivity is localized mainly in neurons. In general, immunostaining of neurons was strong in neurites as well as somata. It was noted that intracerebellar nuclei were strongly stained in both neuronal somata and dendrites. Amygdaloid complex, thalamus, neocortex, hippocampal formation, and caudatoputamen were moderately stained.

Ventriculolumbar Perfusion of 3-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea Hydrochloride

We report on the toxicity, intrathecal pharmacokinetics, and therapeutic effect of the ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea hydrochloride (ACNU) against the subarachnoid dissemination of primary central nervous system tumors. Fifteen patients received ventriculolumbar perfusion of ACNU. One was treated with ventriculolumbar perfusion of ACNU alone, and the others underwent concomitant systemic chemotherapy; three of these patients received irradiation as well. ACNU was administered at an initial dose of 0.5 and was increased to 1.5 to 10.0 mg in six patients. Because of a lack of Level 2 or greater toxicity, the subsequent seven patients received 8.7 to 10.0 mg of ACNU dissolved in artificial cerebrospinal fluid (CSF) at a concentration of 0.1 mg/ml, from the start of the treatment. During ACNU administration, the lumbar CSF was drained at approximately the same rate as that of the infusion. Twelve patients received from 3 to 42 courses (average, 14 courses). The cumulative dose of ACNU ranged from 5 to 330.4 mg (average, 82.9 mg). One patient had a convulsion; two patients experienced transient headache, nausea, and vomiting; two others reported transient headache, nausea, vomiting, and fecal incontinence; and one experienced transient nausea, vomiting, and fecal incontinence. No side effects were noted in the other nine patients. When 9.0 to 9.5 mg of ACNU, dissolved in 90 to 95 ml of artificial CSF, was administered for 37 to 52 min, the maximum concentration of ACNU in the lumbar CSF was 9.86 to 12.79 micrograms/ml and the area under the drug concentration-time curve was 260.8 to 502.5 micrograms.min/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunocytochemical detection of calcineurin and microtubule-associated protein 2 in central neurocytoma

SummaryAn immunohistochemical study was carried out on four cases of central neurocytoma, which had characteristic clinicopathological features including ultrastructural findings. Specific antibodies to calcineurin (CaN), microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) were used. All tumor tissues examined showed specific immunoreactivity for CaN and MAP2. Immunolabelling of both molecules revealed that they were mainly localized in the perikarya and proximal processes of the tumor cells. SYP immunoreactivity was found in three of the four cases. SYP immunoreaction products were predominantly seen in the tumor cell processes, while the perikarya were weakly or moderately positive for SYP. The data suggest that CaN and MAP2, together with SYP, can be useful tools for identifying and characterizing of the central neurocytoma.

Treatment of gliomas in adults.

Gliomas are the most common tumors in the brain and are almost always malignant in adults. The most malignant and most common glioma is glioblastoma multiforme. Median survival of patients with glioblastoma is less than 20 months following treatment. This poor prognosis reflects the limited efficacy of the currently available treatment modalities. Therefore, many attempts have been made to improve the treatment of this lethal disease. This paper reviews the progress that has been made recently in the treatment of malignant glioma with a focus on studies reported during the last year.

Monoclonal antibody against ependymoma-derived cell line

SummaryMouse myeloma cells were fused with spleen cells from mice that had been immunized with a human ependymoma derived cell line, KMS II. Hybridomas producing monoclonal antibodies (MAbs) were screened and cloned. Specificity of the antibody was determined by enzyme-linked immunosorbent assay (ELISA) and/or indirect immunofluorescence assay. One of the MAbs, designated Ep-C4 (subclass = IgGl), reacted with two cell lines derived from ependymoma but did not react with 17 cell lines derived from other types of brain tumor nor with 4 neuroblastoma cell lines or 19 cell lines derived from carcinoma, hematopoietic tumors and amnion. Indirect immunofluorescence and immuno-electron microscopy studies revealed that the antigen recognized by MAb Ep-C4 was located on cell surface membrane. The membrane antigen of KMS II cells, immunoprecipitated by MAb Ep-C4, was a protein of 81,000 dalton. The reactivity of MAb Ep-C4 was further examined using immunofluorescence and/or immunoperoxidase methods and frozen sections and short-term cultures of various types of brain tumors. No cross-reactivity with normal adult or fetal brain tissues was detected by absorption assay and immunoperoxidase staining. Our results suggest that the antigen defined by MAb Ep-C4 is specific for ependymoma cells, and different from the antigens of glioma cells or other neuroectodermal-derived cells previously described.

Accessory function of human glioma cells for the induction of CD3-mediated T cell proliferation: a potential role of glial cells in T cell activation in the central nervous system

Accessory function of human glial cells for the induction of anti-CD3 antibody-mediated proliferation of T cells was investigated by using seven glioma cell lines. Three of them were found to function as accessory cells and one of them, U118, was used for further analysis. U118 cells showed the cell-contact-mediated accessory function for T cell proliferation. It was found that protein synthesis was required to reveal this function, suggesting that some surface molecules are synthesized and expressed on U118 cells during interaction with T cells to mediate effective signals in T cells. Intercellular adhesion molecule-1 seemed to be one of such inducible molecules and was shown to contribute to effective accessory cell-T cell interaction, but necessity of other molecule(s) was also suggested.

Distribution of mouse interferon-β in normal and brain tumour-bearing mice

SummaryThe distribution of125I-labelled recombinant mouse interferon-β (rMuIFN-β) in normal and glioma (203 glioma) bearing mice was studied by radioassay and macro-autoradiography at 15 and 30 min after a single intravenous injection. The level of rMuIFN-β in the spleen was about 20-fold higher than in serum. Concentrations higher than the serum level was detected in the lung, liver and kidney. The concentration of rMuIFN-β in the brain was 8% of the serum level and the concentration in the glioma 30 min after administration was about 10-fold higher than in normal mouse brain. Macro-autoradiographic study demonstrated a wide distribution range and selective uptake in glioma tissue. Furthermore, we found that mouse gliomas were sensitive to mouse IFN-β. Our findings demonstrate that in the mouse glioma model, intravenously administered interferon reaches the tumour.

Histochemical Study of Alkaline Phosphatase in Primary Human Brain Tumors

Histochemical analysis of frozen, thin sections revealed the distribution of alkaline phosphatase (ALPase) in 47 primary intracranial neoplasms in humans. The cytoplasm of meningioma cells exhibited the strongest ALPase reactivity. Pretreatment of these materials by levamisol indicated that the isozymes of ALPase had the characteristic liver-bone-kidney form. In meningiomas and astrocytomas, there was no particular relationship between ALPase activity and malignancy. In neurinomas, there was weak ALPase reactivity in a few neoplastic cells. These findings are suggestive of diagnostic implications for fibroblastic meningiomas and neurinomas at the light microscopic level.