Nobuyuki Shitara

Clinical Course and Surgical Prognosis of 33 Cases of Intracranial Epidermoid Tumors

Thirty-three cases of intracranial epidermoid tumors treated during the past 25 years were analyzed with regard to clinical manifestations, recurrence rates related to the extent of surgery, and long-term survival rates. Epidermoid tumors caused various symptoms, especially in the cerebellopontine angle (15 cases), of which a transient remission of symptoms was observed in 4 cases (23.5%). The average time from initial symptoms to surgery was much shorter in suprasellar region and third ventricular locations (average of 11 months) than in other locations (average of 7 years). In 28 patients (84.9%), the tumor was removed totally or subtotally. Most of the patients could lead an independent and useful life after operation (93.1%). Among the 29 patients in a long-term follow-up survey, seven tumors recurred after an average interval of 8 years and 10 months (from the first to second operation) and 12 years and 6 months (from the second to third operation). Patients with recurrent tumors were successfully treated, and excellent functional prognosis was observed even after the second or third operation. The 20-year survival rate was 92.8% (Kaplan-Meier method).

Prognosis of intracranial germ cell tumours: effectiveness of chemotherapy with cisplatin and etoposide (CDDP and VP-16).

SummaryA co-operative study for patients with intracranial germ cell tumours was performed to analyze their prognosis and the effectiveness of Cisplatin/Etoposide (CDDP/VP-16) chemotherapy.A total of 46 patients; 30 primary and 16 recurrent cases were registered from 15 participating neurosurgical institutions in Japan. Based on histological criteria and tumour markers, they were classified into three groups; germinoma, germinoma with syncytiotro-phoblastic giant cell (STGC), and non-germinomatous malignant tumour.Sixteen patients were treated with CDDP/VP-16 chemotherapy alone and the other 30 patients were treated by a combination of surgery and/or radiation in addition to chemotherapy. Eleven out of 13 patients (85%) with germinoma showed a complete (n=10) or partial (n=1) response to CDDP/VP-16 chemotherapy even if their tumours were recurrent and there was evidence of CSF dissemination. For the germinoma with STGC and non-germinomatous malignant tumour, a high response rate; 100% for the former and 78% for the latter, could also be achieved in both the primary and the recurrent cases except in those cases of immature teratoma. Their survival times were still different between them. Two-year survival was 50% in germinoma with STGC and 48% in non-germinoma, while it was 88% in germinoma cases.

Factors possibly influencing the prognosis of oligodendroglioma.

&NA; Fifty‐seven cases of oligodendroglioma (including eight cases of malignant oligodendroglioma) treated at the University of Tokyo Hospital between 1961 and 1985 were analyzed for factors influencing the survival rate. Factors related to a poor outcome were findings of malignancy and symptoms of dementia. Survival rate and postoperative survival period were not influenced significantly by radiation therapy, extent of resection, tumor characteristics, or ABO blood groups.

Local Recurrence of Metastatic Brain Tumor after Stereotactic Radiosurgery or Surgery Plus Radiation

In this study, we compared the recurrence of metastatic brain tumors after radiosurgery versus after surgery plus radiation, and analyzed the factors associated with the recurrence of brain metastases. Twenty-eight and 35 patients with metastatic brain tumors underwent radiosurgery (52 lesions) and surgery plus radiation (46 lesions), respectively, between 1995 and 2001. The median tumor volume was 1.55 ml (range: 0.02–10.4 ml) in radiosurgery patients and 17.9 ml (range: 0.26–195 ml) in surgery plus radiation patients. The median radiosurgical tumor central and margin doses were 28.9 and 23.8 Gy (range: 20–35 and 25–15 Gy), respectively. The median total dose was 46.7 Gy (range: 30–63 Gy) in the surgery plus radiation group.The recurrence time from surgery plus radiation group (25 months) was significantly longer than that from the radiosurgery group (7.2 months) (p=0.0199). The factors affecting the recurrence of brain metastases after radiosurgery were size, central dose of radiation and histology (colon vs. others). No factors affected the recurrence of brain metastases after surgery plus radiation. To avoid early recurrences of metastatic brain tumors, surgery plus radiation is the preferable therapeutic modality. The size and histology of brain metastases, and the dose of radiation should be considered for the effective treatment of tumors by radiosurgery.

Immunohistochemical demonstration of protein kinase C isozymes in human brain tumors.

Immunohistochemical studies of the expression of protein kinase C isozymes were done in 38 human brain tumors using monoclonal antibodies to three major isozymes: Type I, Type II, and Type III. The brain tumors, with the exception of 3 medulloblastomas and 2 of 6 pituitary adenomas, showed strong immunoreactivity for the Type III isozyme. Astrocytomas, anaplastic astrocytomas, and glioblastomas also showed weak immunostaining for Type II, whereas other tumors lacked this staining. Immunoreactivity for Type I was present, although weak, in some astrocytic gliomas. There was no correlation between the presence of immunoreactivity for protein kinase C isozymes or the intensity of staining for the Type III isozyme and the pathological grade of malignancy. In normal human brain tissue, Type I is localized mainly in neuronal cells, Type II in the neuropil of the cerebral cortex and the molecular and granular layers of the cerebellum, and Type III almost exclusively in astrocytes. The presence of immunoreactivity for the Type III isozyme in varying tumor cells, including those of non-astrocytic tumors and the presence of the Type II and/or Type I isozymes in astrocytic gliomas demonstrate that the expression of protein kinase C isozymes differs between normal and transformed cells.

Prediction of survival in patients with suspected recurrent cerebral tumors by quantitative thallium-201 single photon emission computed tomography

PURPOSE To assess whether quantitative 201Tl single photon emission computed tomography (SPECT) can be used as a prognostic test in patients with suspected recurrent cerebral tumor, regardless of various combined therapies given. METHODS AND MATERIALS The study population consisted of 22 patients with grade 4, 3, or 2 glioma and 7 patients with solitary cerebral metastasis. All patients had undergone combined radiotherapy and chemotherapy after or during surgical debulking. Each patient underwent 201Tl brain SPECT to differentiate recurrent tumor from cerebral radiation necrosis, because the prior computed tomography and/or magnetic resonance imaging showed a mass lesion with an irregularly enhanced rim in the irradiation field. RESULTS Higher values of 201Tl index (L/N ratio) showed a tendency for shorter survival (r = -0.502, p < 0.05). In patients with grade 3 glioma or solitary cerebral metastasis, survival time was definitely dependent upon 201Tl index values, that is, above or below the baseline index of 2.5. Grade 4 glioma patients, however, had a very short-term survival independent of 201Tl index values. CONCLUSION Quantitative 201Tl SPECT may be a useful tool for predicting survival of patients with suspected recurrent cerebral tumor and may be used in place of fluorine-18-2-deoxy-2-fluoro-D-glucose (18F-FDG) scan.

Astrocytic localization of the immunoreactivity for protein kinase C isozyme (type III) in human brain

The localization of 3 major types of protein kinase C (PKC) was immunohistochemically studied in human brain using monoclonal antibodies raised against each of the types. Immunoreactivity for type I was observed in neuronal cells in cerebrum and Purkinje cells in cerebellum. Immunoreactivity for type II was mainly observed in neuropil of cerebral cortex and in the molecular and granular layers of cerebellum. Occasional neurons in cerebrum were also stained. Immunoreactivity for type III was almost exclusively localized in astrocytes in gray and white matter, subpial astrocytes, and cerebellar Bergmanns glia. The present study suggests that the type III of PKC is preferentially expressed in astrocytes in human brain.

Adenovirus-mediated transfer of P53 augments hyperthermia-induced apoptosis in U251 glioma cells

PURPOSE Hyperthermia kills glioma cells by inducing apoptosis and is thereby an effective therapeutic modality for the treatment of malignant gliomas. However, cells harboring mutated p53 are refractory to hyperthermia-induced apoptosis. In this study, we assessed whether or not adenovirus (Adv)-mediated transduction of p53 overrides this resistant mechanism. METHODS AND MATERIALS We transduced the p53 wild-type tumor suppressor gene into U251 glioma cells harboring mutated p53 using Adv vectors in combination with hyperthermia (43, 44.5 degrees C), and evaluated the degree of cell death and apoptosis. RESULTS The percentage of cells that had died, as measured by trypan blue staining, among U251 cells infected with the Adv for p53 (Adv-p53) and treated with hyperthermia, was significantly higher than the percentage of cells that had died among U251 cells infected with Adv-p53 and not treated with hyperthermia, or those infected with the control Adv for dE (Adv-dE) and treated with hyperthermia. The degree of apoptosis, measured at 24 h after treatment, in hyperthermia-treated U251 cells infected with Adv-p53 (43 degrees C, 73%; 44.5 degrees C, 92%) was much higher than that infected with Adv-p53 (41%), or that infected with control Adv-dE and treated with hyperthermia (43 degrees C, 1.3%; 44.5 degrees C, 19%). Treatment with combined hyperthermia and Adv-p53 infection induced cleavage of caspase-3 in U251 cells. CONCLUSION These results indicate that Adv-mediated transduction of p53 would render glioma cells highly sensitive to hyperthermia.

Effect of interferon- on the cell cycle of human glioma cell line U-251 MG: flow cytometric two-dimensional (BrdU/DNA) analysis

SummaryThis paper describes the determination of the effect of IFN-ß on U-251 MG cells using the bromodeoxyuridine (BrdU/DNA) analysis technique. The cell cycle perturbation of exponentially growing cells was estimated by a newly developed two-dimensional analysis of sequential BrdU/DNA distributions measured at 4-hr intervals after IFN-ß administration. The U-251 MG cell line was sensitive to IFN-ß, and cell proliferation was inhibited by 50.0% at 48 hr. Analysis of DNA histograms indicated that IFN-ß, accumulated the cells in the S-phase, from 16 to 48 hr after treatment. In the two-dimensional analysis, labeled cells treated with IFN-ß moved from the S-phase through the G2M-phase and then entered the G1-phase within 12 hr after the initial treatment, in a pattern similar to labeled cells untreated with IFN-ß. After 16 hr, labeled cells treated with IFN-ß, began to accumulate in the S-phase and remained there even after 48 hr. These results imply that IFN-ß may have an effect on the G1-phase, thereby inducing S-phase accumulation of human glioma cell line U-251 MG.

Insulin binds to specific receptors and stimulates macromolecular synthesis in C 6 glioma cells

SummaryThe existence of insulin receptors and biological responces to insulin on macromolecular synthesis have been studied in C6 glioma cells. Binding of125I-insulin to C6 glioma cells was specific, time-and PH-dependent. Porcine insulin competed for1125I-insulin binding in a dose-dependent manner. Unlabeled polypeptides, including glucagon, bovine growth hormone, bovine prolactin did not compete for125I-insulin binding. Scatchard analysis of the binding data gave a curvilinear plot which may indicate negative co-operativity or the existence of both high and low affinity (Ka=7.55 × 1010 −4.25 × 109) sites.Incubation of cultures with insulin caused a time and dose-dependent stimulation of DNA, RNA and protein synthesis in C 6 glioma cells (measured by3H-thymidine,3H-uridine or3H-leucine incorporation into DNA, RNA, or protein respectively). The increase of macromolecular synthesis was admitted at more than 2 nM concentration of insulin. Maximal stimulation of DNA synthesis (142% of control) occurred 6 hours after incubation with 167 nM insulin. The same concentration of insulin caused a 45% increase in 1 hour on RNA synthesis, a 37% increase in 2 hour on protein synthesis.These results indicate that C 6 glioma cells have specific insulin receptors capable of mediating effects of insulin on macromolecular synthesis. Insulin in the brain and even blood may be an important growth factor in the glioma cells of the patients with disrupted bloodbrain-barrier.