After studying the recent literature, the authors have summarized the latest published surgical procedures, and radio- and/or chemotherapeutic regimens for the management of malignant gliomas. Study of this data has yielded the facts listed below. The median survival time (MST) of cases treated only by surgery was 4 to 5 months, whereas the MST of cases treated by combining surgery with radiation was 10 months, and that of cases given surgery, radiation, and chemotherapy was 14 months. Further, several innovative therapeutic approaches have recently been attempted, such as interstitial irradiation, based on an after-loading method, and intra-operative radiation. Also, by using a heavily charged particle, a new radiation method with different characteristics from the γ-ray has been developed. Additionally, so as to achieve an autologous bone marrow rescue, an intra-arterial injection and high-dose chemotherapy have been employed to deliver a higher concentration of drugs into the targeted brain tissue. The results by all these recent approaches are described. Finally, based on the assumption that an ideal model providing the tumor kinetics of a malignant glioma has been developed, the authors compare the beneficial effects of radiation and chemotherapy. They emphasize that radiation has no advantage over other therapies for treating a malignant glioma, and that in finding a cure, a chemotherapy that has the capability of influencing the total nervous system is needed.

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Using interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells were induced from the lymphocytes of patients with malignant gliomas and their killing activity examined. The mean LAK activity was found to be 54.4±10.1% against K 562 cells, 60.8±l2.7% against Daudi cells, and 38.3±8.9% against glioma cells. When IL-1 was used, the LAK activity was enhanced about 1.1 times, but a corresponding decrease in the activity of the other cytokines was noted. IL-1 and interferon-y also were able to stimulate LAK proliferation. Using these LAK cells plus IL-2, a local immunotherapy was tested in 44 patients with a malignant glioma. Approximately 1×10^8 LAK cells and 400 U of IL-2 were injected into the tumor cavity in one puncture through the Ommaya reservoir. As a result, 15 out of a total of 44 patients showed a clinical improvement; 17 of the 44 patients are still alive and their condition is stable, and 9 patients, whose recurrent progressive gliomas have not responded to other forms of treatment, showed no clinical changes. Further, based on criteria established for a CT scan evaluation, 4 patients showed a partial response, 7 patients showed a minor response, and 4 patients showed no change. Patients who showed a response on CT scans also demonstrated a neurological response, and their mean Karnofsky rating was higher than that of patients in whom no response was seen. Further, 24 of the 44 patients received this local immunotherapy as a maintenance therapy for an extended period, so that a follow-up study of these patients could be done. Also, the median survival time of 5 patients who initially responded to this therapy was 38.2 months, whereas in 10 patients who did not respond the median survival time was only 24.2 months. Finally, a significant difference in the survival time was found between patients who received this therapy repeatedly and a control group (p < 0.005). Therefore, this immunotherapy seems to have a significant impact on patient survival for patients given this immunotherapy from the early stage of the disease. There also were no major side effects. In conclusion, this therapy proved to be effective for patients with a malignant glioma, and the authors believe that an even more effective immunotherapy can be developed by incorporating the latest immunological and biological findings.

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Radiation-induced damage to the brain has been reviewed etiologically and histopathologically, based on reports in the literature and our own data. Recently, instances of late delayed radiation necrosis of the normal brain and acute brain edema have become less common, since therapists are adhering to standard radiation doses and fractionation, whereas instances of radiation-induced brain atrophy (leukoencephalopathy) are becoming a common problem. This pathologic state can be induced in the normal brain by as low a dose as 30 Gy, so that cases of radiation-induced atrophy are innevitable unless therapists recognize this problem and prevent it. The etiology, histologic findings, and clinical significance of this pathologic entity are discussed.

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The role of maintenance chemotherapy for malignant glimoas has been retrospectively analyzed. To evaluate the efficacy of combination chemotherapy in Osaka Brain Tumor Study Group (OBTSG) protocol 2, following the surgical removal of their gliomas, the patients were randomly divided into two groups. Group A received Me-CCNU or ACNU alone, and Group B, received Me-CCNU or ACNU plus local or intravenous BLM. Two years after surgery, the survival rate of the Group B patients was significantly higher than that of Group A, although no significant difference was noted in the overall survival time between the groups. After induction therapy, patients of both groups received either Me-CCNU or ACNU, depending on the choice of their doctors. Of 36 patients who survived for over two years, the duration of chemotherapy was less than 6 months in 2 patients, from 6 to 12 months in 3, from 12 to 18 months in 11, from 18 to 24 months in 6, and over 24 months in 14. The survival time after the second postoperative year was significantly prolonged in patients receiving nitrosoureas for more than 18 months than in patients receiving them for less than 18 months (p< 0.05). Therefore, as patients with a glioblastoma rarely survive for more than 3 years, this prolongation was considered due to the prolonged survival time seen in patients with an anaplastic astrocytoma. The use of a single antineoplastic agent to treat a malignant glioma over a long period of time runs counter to Goldie-Coldman's theory, which is based on the theory of somatic mutation to explain the drug resistance in a tumor cell to chemotherapy. Thus, the design of a combined chemotherapeutic regimen should have a scientific basis that takes the biology of tumors into consideration. Among such designs, an alternating non-cross resistant chemotherapy and a dose-intensive chemotherapy have been described in relation to the results of an OBTSG study.

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In using radiotherapy to treat a malignacy, such as a malignant glioma, the amount of the radiation dose, the radiation volume, the area to be irradiated, and the vulnerability of the tissue to radiation are important considerations so as to avoid adversely affecting the central nervous system (CNS). Yet, based on in vitro studies and clinical data, a radiation dose of from 70 to 209 Gy may be needed to treat a human glioblastoma. Therefore, how to provide the proper radiation dosage to effectively treat the glioblastoma and still not damage the CNS is a problem that must be solved by perfecting radiation techniques based on neuro-radiobiologic and clinicopathologic studies. Further, adiuvant chemo- and immunotherapy applied either generally or selectively during and/or after irradiation must become more effective to stabilize a tumor.

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As the brain is encased within the skull, the space available for a tumor to grow is severely limited, before it reaches a size fatal to the patient. Thus, a quantitation of the proliferative potential of individual gliomas is extremely important. The development of monoclonal antibodies against bromodeoxyuridine (BUdR), a thymidine analogue, was a breakthrough for cell kinetic studies of human tumors in situ, since it has enabled the rapid measurement of cells in the DNA synthesis phase (S-phase). The BUdR LIs (the percentage of S-phase cells) obtained from over 500 gliomas have revealed: 1) that the S-phase fraction (or BUdR LI) of individual brain tumors reflects the proliferative activity or biological malignancy as a whole; 2) that histologically similar tumors may have different proliferative potentials, demonstrated by differences in the LIs: and, 3) that a higher LI indicates a higher rate, as well as a shorter interval of tumor recurrence, that correlates well with the survival of individual patients. The development of new antibody allowed us to use two probes, BUdR and IUdR (iododeoxyuridine), for cell cycle progression analyses. On choosing an appropriate timing for the BUdR and IUdR administration, one can measure the LI, the duration of the S-phase (Ts), the potential doubling time (Tp), and the growth fraction of each tumor from a single biopsy specimen. The Ts' measured in 29 gliomas was fairly uniform (mean 8.9±2.0 (SD) hr) regardless of the differences in their LIs. The Tps calculated varied from two days to over a month, which Is very short for high LI tumors, and closely correlated with the BUdR LIs (Tp= 17.8/LI 0.77: r=0.95). The cell cycle time calculated for gliomas with LIs of I to 20% ranged within I to 2 days. The information thus obtained elucidates not only the growth characteristics of individual gliomas, but also benefits patients by predicting the precise prognosis and in selecting appropriate treatment modalities and evaluating the effects of such treatments.

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The strategies of two new therapies being developed to treat an intracranial malignant glioma are discussed, and the current immunotherapies based on LAK, CTL, TIL, and STT modalities evaluated for their anti-glioma efficacy, TIL and STT, in this regard, being considered particularly effective because of their known high specificity for targeted glioma cells. To harness the human immune response to combat tumors of the brain, the propagation of killer cells with an anti-tumoral reactivity is critical. Keeping this in mind, the diversity of the RNA transcripts of the TIL T-cell receptors (TCRs) have been examined within malignant glial tumor specimens obtained at surgery. Using the polymerase chain reaction (PCR) method, detection of limited TCR-variable regions, V_α, and, to a lessor degree, TIL V_β mRNA transcripts was possible. This finding has led to the speculation that some specific T cell populations may be directed to antigenic determinants in the malignant glial cells and thereby provide a more beneficial and effective immunotherapy. Further, a molecular analysis of growth regulation in gliomas may provide an opportunity for the development of an improved therapy. Two approaches have been considered: one, a tumor cell- or effector cell-targeted lymphokine gene therapy, and the other, an antisense gene-mediated therapy. The use of genes as means of treating malignant gliomas, however, is still under experimental study, since the safety of both the procedural steps and the gene delivery system have yet to be established. However, gene therapy also may become a new method to combat cancers.

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Using helical strips of the basilar artery of the dog, changes in the cytosolic Ca^<2+> level ( [Ca^<2+>]_i) and the muscle contraction, caused by vasoactive agents, were simultaneously measured. The 500 nm fluorescence of the Ca^<2+> indicator fura-2 caused by alternative excitation at 340 nm (F_<340>) and at 380 nm (F_<380>) was obtained, and the ratio of F_<340>to F_<380> (R_<340/380>) was used as an indicator of the relative [Ca^<2+>]_i. Changes in the fluorescence always preceded changes in the muscle tension. It was noted that the receptor agonist, PGF_<2α> (3×10^<-6>M), 5-HT (3×10^<-6>M) and U-46619 (a TxA_2 analogue, 10^<-7>M) induced almost the same magnitude of contraction, as that induced by 40 mM KCl, and that the elevation in the [Ca^<2+>]_i was less than that caused by high-K^+ stimulation. Further, a phorbol ester that stimulates protein kinase C, 12-deoxyphorbol 13-isobutyrate (3×10^<-6>M) , induced a contraction that was about half that induced by high-K^+, and brought about a decrease in the [Ca^<2+>]_i below the resting level. These results suggest that receptor agonists and phorbol ester bring about an "apparent" increment in the sensitivity of the contractile system to Ca^<2+>, and that the amount of this increment caused by phorbol ester, is greater than that due to receptor agonists. What remains unclear, however, is whether this "apparent" increment is attributable to the change in myosin phosphorylation triggered by the [Ca^<2+>]_i elevation. Another finding was that glyceryl trinitrate (GTN, 10^<-5>M) relaxed the high-K^+-induced contraction by about half, without change in the [Ca^<2+>]_i. In contrast, diltiazem (10^<-5>M) decreased both the muscle tension and the [Ca^<2+>]_i to their respective resting levels. This indicates that GTN relaxes muscle contraction without affecting the intracellular Ca^<2+> level. Based on these findings, it is felt this study of the correlation between muscle tension and the [Ca^<2+>]_i Value is important in determining the smooth muscle regulatory mechanisms under both physiological and pathological conditions, such as during a vasospasm following a subarachnoid hemorrhage.

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Three cases of an anterior communcating artery (ACoA) aneurysm with the presence of a third artery (A_2) are reported. In two cases, the aneurysm was clipped successfully without occluding the third A_2 and in the remaining case, the aneurysmal clipping included the occ.1usion of the third A_2, this latter patient having also manifested neurological deficits that included a personality change and unresponsiveness. In order to perform a successful clipping of an ACoA aneurysm, it is very important to understand the anatomical variants of anterior cerebral artery and ACoA. In this regard, a third A_2 is one of the most important variants. According to some reports, the incidence of such an A_2 varies between 2 and 22 per cent of cadaver dissections and operative cases. A third A_2 usually arises from the postero-inferior surface of the ACOA and courses around the genu of the corpus callosum with the main A_2. Further, a third A_2 is found behind the fundus or the main A_2 when the fundus of the aneurysm is sited directly superiorly or posteriorly. For the successful treatment of an ACoA aneurysm, the surgeon should carefully interpret the findings of the preoperative angiography, and then dissect the circumference of aneurysm vigilantly, keeping the visualization of the ACoA complex uppermost in mind.

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The authors report the case of a 24-year-old female with congenital hepatic fibrosis who developed a subarachnoid hemorrhage due to ruptured aneurysm of right middle cerebral artery. The aneurysm was clipped and the patient recovered without delayed ischemic neurological deficit. This patient also had an unruptured aneurysm of left middle cerebral artery that was clipped three months after the first operation. At age 19, she had been diagnosed as having congenital hepatic fibrosis, when she had undergone a cesarean section at 39 weeks and one day of gestation, due to rupture of a splenic artery aneurysm. At the time of this cesarean section, her liver was found to be hard, and a histological examination of a liver specimen showed evidence of marked portal and interlobular fibrosis with a proliferation of bile ducts. The patient had no history of hypertension, and her liver function was normal, with mild renal disorder. Diagnostic imaging highly suggested bilateral autosomal recessive polycystic kidneys. This leads us to speculate that congenital hepatic fibrosis may be closely associated with cerebral berry aneurysms, although further study is needed.

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The authors describe and present a schematic drawing of a safe, simple, and reliable technique for monitoring the intracranial temperature. A thermosensor is combined with a ventricular catheter by means of a Y-shaped connector. This devised catheter has been used successfully in 8 postoperative patients who required therapeutic ventricular and/or cisternal drainage.

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The quantification of the O^6-methylguanine-DNA methyltransferase (MGMT) activity has been used to estimate the cellular resistance to chloroethylnitrosourea (CENU). Briefly, the evaluation of the MGMT expression by Northern blot analysis was correlated with the cellular resistance to BCNU, which was estimated by a colony formation assay in human glioma cell lines. A significant correlation was found between the level of the MGMT expression and the cellular resistance to BCNU. The results suggest that a Northern blot analysis for the MGMT expression appears to be a good assaying tool for screening the cellular resistance to chloroethylnitrosourea.

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