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Background: Patients with brain metastases of non-small cell lung cancer (NSCLC) have a poor prognosis, so chemotherapy and best-supportive care are typically pursued as initial treatments., Case Report: A 52-year-old man presented with symptoms of disorientation and disturbed consciousness as a result of multiple brain metastases. A histopathological examination revealed that the primary tumor was a large cell carcinoma located in the left upper lung. Whole brain irradiation (WBI) with a total dose of 50 Gy was immediately started. Since the brain tumors were successfully controlled, irradiation of the primary lung lesion with a total dose of 60 Gy was initiated 6 months after the WBI. Afterward, the patient was clinically free from lung cancer, but other cancers developed in the cecum and appendix and were surgically removed. He survived for more than 8 years after the WBI but eventually died of respiratory insufficiency caused by multiple lung metastases. The autopsy findings indicated that the lung lesions were metastatic adenocarcinomas from the appendiceal cancer, and the patient had remained disease-free from lung cancer., Conclusion: In view of the possibility of long-term survival in patients with stage IV NSCLC and brain metastasis, especially those with only intracranial metastases, careful consideration is be needed in the selection of treatment options.

We report a case of small cell lung cancer whose initial presentation was a solitary brain metastasis. On chest radiography the primary tumor was unclear and only detected by bronchofiberscopy. A small single pulmonary metastasis was noted in the right lower lobe. Subtotal resection and external irradiation were applied to the brain tumor and external irradiation was applied to the lung. Concurrently one course of systemic chemotherapy was administered. The tumors in the brain and lung had disappeared by the end of the treatment. The patient has been alive and well for 5 years without recurrence.

The effects of docetaxel alone and in combination with irradiation were experimentally investigated in terms of induction of apoptosis. A human ependymoblastoma was transplanted into nude mice, and they were intravenously injected with docetaxel, followed or preceded by irradiation with a single dose of 2 Gy. Apoptosis was less common in the docetaxel-alone group than in the irradiation-alone group. When administration of docetaxel was followed by irradiation, apoptosis was equal to or less common than in the irradiation-alone group. Apoptosis was most common in the irradiation-followed-by-docetaxel group. The incidence of mitosis was lower in the irradiation-alone group and the irradiation-followed-by-docetaxel group than in the docetaxel-alone group and the docetaxel-followed-by-irradiation group. The combined effect of irradiation and docetaxel appears to be useful in inducing apoptosis, but the sequence of irradiation and docetaxel is important.

p53 protein expression, apoptosis and growth delay induced by nedaplatin, a novel platinum compound, were investigated in vivo, and compared with those induced by ionizing radiation. A human ependymoblastoma with wild-type p53 was transplanted subcutaneously to the thighs of nude mice. The incidences of p53 protein-positive cells and apoptosis in tumors increased following exposure to ionizing radiation. In tumors treated with nedaplatin, they also increased, but the incidences of p53 protein-positive cells and apoptosis induced by 32 mg/kg nedaplatin, 1/2 LD50, were lower than those induced by 1 Gy irradiation. However, growth-delay assay showed no significant difference between the efficacy of 32 mg/kg nedaplatin and that of 1 Gy irradiation. These results suggest that the main antineoplastic activity caused by nedaplatin may be mediated through different mechanisms than those of the p53-dependent early apoptosis.

The present study was undertaken to investigate cell death (particularly apoptosis) induced by etoposide, radiation, and both, and to examine p53 protein expression in relation to cell death. Nude mice transplanted with a human tumor (ependymoblastoma) were treated with etoposide (5-40 mg/kg) or 1-2 Gy X-ray irradiation or both. The tumor was excised at different points after treatment, and tumor tissue specimens were used to check for apoptosis and p53 protein expression by TUNEL, p53 protein staining, etc. Induction of p53-dependent apoptosis was observed in the etoposide treatment group, the X-ray irradiation group, and the combined (etoposide + X-ray irradiation) group. Etoposide 10 mg/kg was found to be approximately equivalent to 1 Gy X-ray irradiation in ability to induce apoptosis. When etoposide treatment was combined with X-ray irradiation at intervals of 3-6 hours, an approximately additive effect was observed.

The occurrence of placental metastasis from maternal primitive neuroectodermal tumor (PNET) is extremely rare. A 33-year-old woman at 33 weeks' gestation was admitted to the hospital. She died of the disease on hospital day 28 because the unresectable tumor was located over a wide area of the retroperitoneum. A neonate was delivered by a caesarean section without evidence of disease and has survived to 1 year of age. Pathologically, the tumor consisted of monotonous small round cells with a high nuclear cytoplasmic ratio, including several pseudorosettes and Homer-Wright-type rosettes. On immunohistochemical examination, the tumor cells were positively stained for neuron-specific enolase. Microscopically, the placenta showed intervillous metastasis from the maternal PNET. This case may be the first one of placental metastasis from PNET ever reported in the literature.

The effect of heavy ion (carbon beam) on apoptosis in vivo was studied. The human brain tumors xenografts of different radiosensitivities were used. The results demonstrated that the effect of carbon beam on apoptosis was similar to photon in radiosensitive tumors; however, carbon beam had the advantage on apoptosis in radioresistant tumors. In ependymoblastoma, a radiosensitive tumor, the incidence of apoptosis induced by photon and by carbon at 6 hours after irradiation were 34.5 +/- 7.85% and 32.5 +/- 7.04%, respectively. In glioblastoma (radioresistant tumor), the incidence of apoptosis induced by photon and by carbon at 6 hours after irradiation were 1.35 +/- 1.68% and 4.4 +/- 2.47%, respectively. Therefore, the incidence of apoptosis was increased more than 3-fold (RBE 3.0) at 6 hours after irradiation in glioblastoma. The heavy ion (carbon) beam is effective in radioresistant tumors in vivo.

Relationships between p53 protein expression and radiation-induced apoptosis in five human tumors transplanted to nude mice were studied immunohistochemically. They were irradiated with 200 kV X-rays. Six hours after 2, 5, 10, or 20 Gy irradiation, tumors were excised and fixed. Tumors were also examined 1-48 hours after 10 Gy. Immunohistochemical studies were performed for analysis of p53 protein expression. TUNEL and electron microscopic studies were performed to identify apoptosis. In non-irradiated control groups, the incidence of apoptosis was very low in all of the five tumors. Most tumor cells of the ependymoblastoma were p53 protein negative, but the other four tumors were p53 positive. Following irradiation, most tumor cells of the ependymoblastoma became p53 positive, and the incidence of apoptosis increased. However, we could not find significant changes in the percentage of p53 positive cells in the other tumors, and radiation-induced apoptosis in them was low or negligible. These results suggest that radiation-induced apoptosis in a radiosensitive human tumor is related to wild-type p53 protein expression. In contrast, the p53 protein expression of the other four human tumors should be mutant type, and it does not lead to radiation-induced apoptosis.

Xenografts of a human malignant glioma subcutaneously transplanted into nude mice were irradiated with graded single doses (2, 5, 10 or 20 Gy) or five types of fractionation schedules in two weeks: conventional [20 Gy in 10 fractions (fr)], hyperfractionated [24 Gy in 20 fr (two fractions per day)], and hypofractionated-1, 2, 3 [20 Gy, 18 Gy, 16 Gy in 4 fr]. All of the fractionated irradiation groups showed tumor regression. The hypofractionation-1 group (20 Gy in 4 fr) demonstrated the most prominent tumor regression, while the hyperfractionation group (24 Gy in 20 fr) showed the least effect. The hypofractionation-2 group (18 Gy in 4 fr) showed similar regression to the conventional fractionation group (20 Gy in 10 fr). Histologically, tumors in the control groups consisted of a homogenous population of small anaplastic cells, and only a small number of tumor cells were glial fibrillary acidic protein (GFAP)-positive. Following irradiation, the population of small anaplastic cells decreased and the percentage of GFAP-positive cells increased. Cellular pleomorphism became much more prominent after irradiation in all of the fractionated irradiation groups as compared with the graded single dose irradiation groups. In this study, hyperfractionation was not effective against human glioma xenografts compared with conventional fractionation and hypofractionation. This indicates that care is needed in applying hyperfractionation regimens to human malignant gliomas.

This report describes an unusual case of a long-term survivor with small cell lung cancer (SCLC), treated with radiation therapy alone having a late relapse with solitary brain metastasis 6.5 years after the initial treatment. He received radiation therapy and died of the brain metastasis 8.5 years after the initial treatment. Autopsy revealed no tumor recurrence at the primary site and no distant metastases except for the brain. The histology of the brain tumor was small cell carcinoma.

201Tl, 123I-IMP-SPECT were performed in 17 patients with brain tumors before and after radiation therapy, compared with X-CT. 15 of 17 patients showed enhanced areas on X-CT and higher accumulations on 201Tl-SPECT in the same lesions before radiation therapy. There was significant correlation between enhanced lesions on X-CT and lesions of higher accumulation on 201Tl-SPECT before and after radiation therapy. But, the patients with residual enhanced lesions on X-CT did not always show higher accumulation on 201Tl-SPECT after radiation therapy. And, 2 patients with radiation injury after radiation therapy for brain tumor did not show higher accumulation on 201Tl-SPECT, though one patient showed enhanced lesion on X-CT. 201Tl-SPECT was expected to evaluate viability of brain tumor. 123I-IMP-SPECT was useful to recognize the site of higher 201Tl accumulation and evaluate blood flow around brain tumor. It is concluded that 201Tl, 123I-IMP-SPECT is useful for the evaluation of treatment effect of brain tumor and for the differentiation of cerebral radiation injury from recurrent tumor.

Eight cases of primary malignant lymphoma of the brain were examined clinically and immunohistopathologically. According to the LSG classification the patients were subclassified into 5 with diffuse large cell type, 2 with diffuse medium-sized cell type and one with diffuse mixed cell type. Immunohistological stainings demonstrated that all of them were of B lymphocyte origin. Two cases had multiple lesions which were seen in the periventricular area. Tumor response for the treatment consisted of surgery followed by radiation therapy was excellent except for one. Only 2 patients were alive and well at 24 months and 27 months.

Rat glioma model was used to evaluate the effect of hyperthermia with and without radiation therapy. The animal model was induced by left frontal burr hole opening and inoculation of a small piece of G-XII glioma tissue to 6- to 8-week-old rats. The therapeutical experiments were given 10-14 days after inoculation of the tumor. Interstitial heating at 44 and 45 degrees C at the surface of the inserting probe using 2450 MHz microwave was delivered for 30 minutes. Deep X-ray whole head irradiation of 800 R using Stabilipan 2 (Siemens) was given just after the hyperthermia therapy. The survival of treated animals of hyperthermia, radiation, and combination of hyperthermia and radiation was significantly superior to that of non-treated control group. There was no significant difference of survival among the treated groups, though median survival was longest in the group of combination therapy of hyperthermia and radiation. Large tumors developed at the time of death in all the control and the treated animals. Histological examination showed some tendencies of macrophage infiltration in tumor tissue of hyperthermia therapy.

The results of radiation therapy in 31 patients with intracranial germ cell tumors have been analyzed. The five-year survival rates were 70.1% for germinomas and 38.1% for teratomas. Three patients with germinoma have since died of spinal seeding. The prophylactic irradiation of the spinal canal has been found effective in protecting spinal seeding, since no relapse of germinoma has been observed in cases that received entire neuraxis irradiation, whereas teratomas and marker (AFP, HCG) positive tumors did not respond favorably to radiation therapy, and the cause of death in these patients has been local failure. Long-term survivors over 3 years after radiation therapy have been determined as having a good quality of life.

Twenty-four adults with glioblastoma multiforme (astrocytoma, grade 4) underwent postoperative large dose fraction radiotherapy (LDFR; 5 Gy twice weekly) with Linac X-rays. The outcome in this group was compared with that of 26 patients who received conventional fractionated radiotherapy (CFR; 2 Gy 5 times weekly). The time, dose, and fractionation (TDF) factor was about 100 in both groups. The survival rates following LDFR and CFR were, respectively, 63% vs 65% at 1 year; 36% vs 8% at 2 years; 17% vs 4% at 3 years; and 4% vs 0% at 5 years. Although the survival curve for LDFR was superior to that for CFR, the difference was not statistically significant. Autopsies of nine LDFR and 13 CFR patients showed no residual tumor in one case and no cases, respectively; small residual tumor in three cases in each group; extensive coagulation necrosis of the tumor and surrounding brain tissue in one LDFR and four CFR patients; tumor proliferation in three LDFR and four CFR cases; and mixed glioblastoma and fibrosarcoma in one LDFR and two CFR patients. These results suggest that maximum tumor removal followed by LDFR may offer a better prognosis for patients with glioblastoma than that offered by surgery plus CFR.

Fifty-three patients with intracranial metastases from pulmonary carcinoma were treated with cranial irradiation between 1976 and 1983. There was improvement in neurologic symptoms in 80%, and the one and two-year survival rates for the entire group of patients were 21% and 4%. Those or patients without metastasis tumor in other organs were 38% and 9%, respectively. It was suggested that the total dose should be in excess of 40 Gy. Histologically, adenocarcinoma and epidermoid carcinoma showed better prognosis than other types of cancer.

The patients of malignant glioma mostly consisting of anaplastic astrocytoma (AA) and glioblastoma (GM) were surveyed at the Committee for Compiling the Manual of Radiotherapy in the Treatment of Brain Tumors, organized by Japanese Association for Radiotherapy Research. Total 286 patients were treated at ten institutes during the period from January 1985 through December 1987. Numbers of cases with AA and GM were 130 and 156, respectively. Concerning the treatment volume, the medium field (50-100 cm2) was applied to 127 patients (37.4%) and the whole brain to 25 one (7.4%). The total dose was given by the range from 56 Gy to 65 Gy in 158 patients (47.6%). One-year survival ratio of AA and GM were 60-75% and 40-65%, respectively. For obtaining the improvement of local control rate, it is considered that the beam focusing onto the target lesion and the sufficient removal of the tumor are necessary and essential.

Single and combined treatment of interstitial microwave hyperthermia (HT) and radiation therapy (RT) were delivered to rat glioma models. The animal model tumors were induced by intracerebral inoculation of a small piece of G-XII glioma tissue to 6-8 week-old rats. Heating to about 44 degrees C at the surface of the inserting antenna using a 2450 MHz microwave was carried on for 30 minutes. A single dose of 800 r to the whole head was delivered by deep X-ray apparatus. In combined treatment, heating immediately preceded irradiation. Following treatment, animals were sacrificed at 1, 3, 6, 12, 24, 48, 72 and 96 hours. BUdR was administered intraperitoneally 1 hour before sacrifice. Microscopically, in HT, tumor cells became eosinophilic and separated from each other. Some of them were necrotic. Macrophage infiltration in tumor tissue was recognized after 72 hours. BUdR labelling indices were less than 1% till 24 hours had passed, then became 25% at 48 hours, nearly equal to that of the control animals. In RT, ballooning of the tumor cells was prominent, and some of the tumors became necrotic. Lymphocyte infiltration of the tumor tissue was occasionally seen. BUdR labeling indices decreased slowly; less than 10% in 24 hours, but continued until 96 hours had passed. Combined treatment of HT and RT showed addictive effect of histological changes and suppression of tumor cell growth.

Retrospective analysis of patients with malignant lymphoma of the brain was carried out. All cases were mainly treated with radiation therapy. Overall survival was 44% and 37% at two and five year. Survival was statistically better for patients with diffuse medium-sized cell or diffuse mixed type compared with diffuse large cell type by the LSG classification, for the age group less than 50 years compared with greater than or equal to 50 years, and for the group with Karnofsky Index greater than or equal to 50% compared with less than or equal to 40%. In 11 of 15 patients the first recurrent site was the central nervous system.

Rat brain tumor was used as a model to evaluate radiation therapy with and without misonidazole. BD-IX rats were implanted intracerebrally with an ethylnitrosourea-induced glioma. Three series of experiments were performed, with radiation given 14 days after inoculation of the glioma clone. In each series, the following radiation doses were given: 500 rads once, 1,000 rads once; and 1,000 rads twice, every time with or without two different doses of misonidazole. Radiation therapy significantly prolonged survival when compared to the longevity of the control group. The dose of 1,000 rads given twice was highly effective and the life-span of tumor-bearing rats increased from 72% to 121%. Misonidazole plus irradiation negated the prolongation of survival, achieved with radiation therapy alone.

Six autopsy cases of glioblastoma multiforme in cerebral hemisphere were examined by large histological preparations. They were treated by surgery and high-dose fractionated radiation therapy (5 Gy twice weekly). Their morphological changes were compared to the last CT and radiation field and total doses. Four out of six cases showed small residual tumor. One case showed extensive necrosis of the tumor and brain. The other case exhibited no tumor tissue at all. Spongy degeneration of the white matter associated with astrocytosis and macrophage infiltration extended sometimes beyond the local irradiation field. These white matter changes were easily occurred in the previous peritumoral edema where tumor cell infiltration was frequently observed. Residual tumor cells consisted of small anaplastic cells, which might be radioresistant and recur. Enhancement effect of CT scan showed tumor tissue and radiation necrosis with vascular proliferation.