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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.

Purpose: To investigate the differences between two rat yolk sac tumor cell lines with different radiosensitivities in etoposide sensitivity and in the sensitizing effect of etoposide in combination with irradiation., Materials and Methods: NMT-1 is a parent radiosensitive cell line and NMT-1R is a variant radioresistant cell line. The effects were assessed by clonogenic assay. Apoptosis was evaluated by DNA fragmentation to investigate the mechanism of cell death., Results: Etoposide potentiation of radiation sensitivity was manifested by elimination of the initial shoulder of the cell survival curve in radioresistant NMT-1R cells. However, there was no enhancement effect in radiosensitive NMT-1 cells. The incidence of apoptosis was elevated in NMT-1R cells treated with etoposide and radiation., Conclusion: Etoposide had a supra-additive effect in combination with irradiation for radioresistant NMT-1R cells due to the induction of apoptosis. However, a suppra-additive effect was not seen in radiosensitive NMT-1 cells.

Background: Two rat yolk sac tumor cell lines, NMT-1 and NMT-1R, are of the same origin and of different sensitivity to irradiation and to heat. The aim of this study was to investigate the sensitivities of these two cell lines to combined treatments of low-dose irradiation at 2 Gy and hyperthermia at 42 degrees C., Materials and Methods: The cell survival was assayed by soft agar clonogenic assay. After the survival curves of radiation alone and of heat alone at various temperatures were estimated, not only the effect of irradiation on heat, but the effect of heat on irradiation were evaluated with sequential treatments in both cell lines. These effects on survival curves were evaluated by the enhancement ratios at isosurvival levels of 37%, 10% and 1%, respectively., Results: NMT-1 was more sensitive to radiation but more resistant to heat than NMT-1R. For 1% survival level, radiosensitivity in NMT-1 was 1.32 times that in NMT-1R, while thermal sensitivity at 42 degrees C in NMT-1R was 2.73 times that in NMT-1. For sequential treatment, thermosensitization by a radiation dose of 2 Gy in radiosensitive NMT-1 was greater than that in radioresistant NMT-1R. Following heat at 42 degrees C for 1 hour, increased radiosensitivity in NMT-1R was significant, whereas the same heat treatment produced an increase in the radiation sensitivity of NMT-1 with a reduction of the survival curve shoulder but with less slope modification. There was no difference in the surviving fraction in the time-course of a combination of heat and irradiation at various intervals within 6 hours for NMT-1 except for heating immediately after irradiation. However a significant increase in survival was observed when heat was applied more than 3 hours after 2 Gy irradiation for NMT1-R., Conclusion: These results from our cell lines with the same origin were useful for investigation into the interaction of irradiation with heat.

Background: Recent biological research has shown that mild temperature hyperthermia (MTH) around 41 degrees C simultaneously combined with low dose-rate irradiation (LDRI) is an effective treatment modality for cancer. The aim of the study was to assess the clinical usefulness of a combination of MTH and simultaneous low dose-rate brachytherapy., Materials and Methods: Seven superficial and 8 deep-seated tumors were included in this protocol. Two tumors had no previous treatment and the remainder were recurrent tumors which had arisen from previously treated sites. The average major diameters of superficial and deep tumors were 8.6 and 7.0 cm, respectively. The average values for Tmin in superficial and deep tumors were 41.5 and 40.7 degrees C, respectively. Brachytherapy was delivered by 137Cs and/or 192Ir LDRI sources., Results: For superficial tumors, six of the seven tumors responded to the treatment (4 achieved CR, 2 PR, 1 NC) and four tumors did not recur within the follow-up period of 5-15 months. All of the deep tumors responded and 5 achieved CR, 3 PR. Four tumors recurred 4-17 months after the treatment and the remainder showed no local recurrence within the follow-up period of 4-31 months., Conclusion: MTH simultaneously combined with LDRI was an effective method for treating progressive and bulky tumors with a previous treatment history.

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 aim of this study was to investigate the effect of paclitaxel on radiation-induced p53-dependent apoptosis. A human ependymoblastoma transplanted to nude mice was used. They were treated with paclitaxel (40 mg/kg), irradiation (2 Gy), or a combination of both. Apoptosis was markedly increased in the irradiation group. p53 protein expression was well correlated with the frequency of radiation-induced apoptosis. There was only a slight increase in apoptosis in the paclitaxel group, with little p53 protein expression. In the combination group, the frequency of apoptosis varied with the time intervals, and the group irradiated 12 h after paclitaxel administration showed much less apoptosis than the irradiation group. The Ki-67 labeling index in the paclitaxel group was always higher than before administration. The present study indicates that p53-dependent apoptosis was frequently induced in the human tumor in vivo by irradiation, but not by paclitaxel alone. When combined with irradiation, the timing affected the frequency of apoptosis and the degree of p53 protein expression.

Purpose: The purpose of this study was to clarify the utility of 1-(1',3',4'-Trihydroxy-2'-Butoxy) Methyl-2-Nitroimidazol (PR-350) as a hypoxic cell radiosensitizer in an in vivo human tumor. We examined the effect of PR-350 on the changes of tumor volume and microscopic features following irradiation., Methods and Materials: Tissue from a human small-cell lung cancer was transplanted to 136 nude mice. They were given 200 mg/kg of PR-350, as a hypoxic cell radiosensitizer, or saline, for the control. One hundred mice were used to evaluate the effect of PR-350 on tumor volume after irradiation, and the other mice were used for histological study: hematoxylin and eosin staining, immunohistochemistry (Ki-67 and p53), TUNEL staining, and electromicroscopy., Results: Respective 10, 15, and 20 Gy irradiation groups showed some tendency of a sensitizing effect of PR-350, compared with the saline group. A statistically significant difference was observed between PR-350- and saline-treated groups with 15 Gy of irradiation (p < 0.05). Apoptotic cells counts were slightly increased in both PR-350 and saline groups at 6 h after 15 Gy of irradiation. Massive necrotic areas were noted in both groups at 72 h after irradiation. p53 was intensely positive in most tumor cells with or without irradiation. However, no significant difference was found between PR-350 and saline groups in these microscopic features., Conclusion: PR-350 was an effective hypoxic cell radiosensitizer for a human small cell lung cancer in vivo, in which necrotic change was dominant following irradiation.

The effect of irradiation either alone or in combination with cytokine (IFN-gamma) on the expression of carcinoembryonic antigen (CEA) on the surface of the human lung cancer cell line, GLL-1, was studied in vitro. The results demonstrated that CEA expression on GLL- 1 cells increased after irradiation with a single dose of 10 Gy. In a time-course study the peak of CEA expression was observed at the 4th day after irradiation. The relative CEA expression on the 1st to 5th day after irradiation were 1.2, 1.2, 1.2, 1.4 and 1.3, respectively. Irradiation in combination with IFN-gamma showed an additional effect on the expression of CEA. A 1.7 fold increase in CEA expression was detected. A cell cycle study showed that the change in the relative CEA expression of the G1 cell fraction was similar to that of all cell fractions. The relative CEA expression of GLL-1 cells treated by irradiation in combination with IFN-gamma in the G1 cell fraction was much higher than those treated differently.

This study was performed to clarify whether changes in the metabolites observed by phosphorous-31 magnetic resonance spectroscopy (31P-MRS) could indicate an optimum interval between two doses of radiation in a murine tumor model. Murine mammary carcinoma cells, FM3A, were irradiated 7 days after transplantation with a single 5 Gy dose without anesthesia. 31P spectra were measured with a spectrometer up to 30 days. The beta-ATP/Pi and PCr/Pi values were calculated from the peak area of each spectrum. In a fractionation experiment, two fractions of irradiation at a 5 Gy per fraction were given at 0, 1, 2, 3 and 6 day intervals. Tumor growth delay was also scored to determine the fractionated radiation effect. In the control group, beta-ATP/Pi and PCr/Pi decreased with tumor growth. In the single irradiation group, the tumor did not grow up to day 6, and an initial rise and subsequent decrease in beta-ATP/Pi and PCr/Pi were observed. Maximum beta-ATP/Pi and PCr/Pi were observed on day 2 after irradiation. In a fractionation experiment, the greatest growth delay was observed in the two day interval group, in which maximum beta-ATP/Pi and PCr/Pi were demonstrated in 31P-MRS. Our results suggested that changes in the metabolites observed by 31P-MRS could be useful indicators for determining the fractionation schedule in radiation therapy.

We investigated the sensitizing effects of AK-2123 (Senazole) on the interaction of radiation, cisplatin and hyperthermia under aerobic conditions in the rat yolk sac cell line NMT-1R in vitro. The effects were assessed by clonogenic assay. A cytotoxic effect of AK-2123 after 24 hours exposure was observed as a function of the dose. For NMT-1R cells, the ID70 of AK-2123 was 400 micrograms/ml for 24 hours exposure, which was employed for subsequent combined treatments. Although a statistically significant increase in the G1 cell fraction was observed after AK-2123 treatment with a dose of ID70 (p = 0.02) no enhancing effect of AK-2123 on radiation, cisplatin or heat response curves was detected under aerobic conditions in vitro.

Concurrent intra-arterial infusion chemotherapy and radiation therapy following alteration of pelvic blood flow was performed in 15 patients with invasive bladder cancer (T2: 2, T3a: 4, T3b: 5, T4: 4). Infusion chemotherapy consisted of a daily low-dose of cisplatin with a dose range of 7 to 9 mg per patient. Of the 15 patients, 11 achieved complete response (73%) and other had partial response. Four of those with CR developed recurrence (local recurrence in three and distant metastasis in one patient). Cause specific and disease-free survival at 3-years were 56% and 49.9%, respectively, and the bladder preservation rate at 3-year was 47%. Toxic reactions related to the treatment was of a reasonable level, and cisplatin-induced renal dysfunction was not experienced, even in the patients with poor renal function, although transient neutropenia and thrombocytopenia occurred in all patients at the latter stage of the treatment. This treatment modality is considered to be effective and feasible even in patients with locally advanced disease and/or those unsuited for cisplatin-based systemic chemotherapy.

The prognostic significance of nuclear p53 protein expression in survival and local control was investigated immunohistochemically in 36 patients with inoperable or unresectable non-small cell lung cancer who were treated with radiation therapy (RT). Formalin-fixed, paraffin-embedded sections obtained by bronchoscopy were used to examine the expression of nuclear p53 protein with immunohistochemistry. In 25 cases (69%), p53 protein expression was detected. There was no relation between p53 expression and other pretreatment characteristics. Response to RT was found in all p-53 negative cases versus 72% in p53-positive cases (p < 0.05). The 2-year survival rate for p53-negative cases was 51% with a median survival time of 21 months. The corresponding rate for p53-positive cases was 31% with a median survival time of 9 months. This difference, however, did not reach a statistically significant level because of the small sample size. In conclusion, the results of this study suggest that p53 protein expression may be of predictive value on response to RT in non-small cell lung cancer.

Purpose: The aim of this study was to investigate the cell killing induced by low dose-rate irradiation (LDRI) simultaneously combined with long duration mild hyperthermia in LK87 human lung cancer cells. Cell cycle alteration due to this combined treatment was also observed., Materials and Methods: Human lung adenocarcinoma cells, LK87, were treated with concurrent LDRI (50 cGy/hr) and mild hyperthermia (38 to 42 degrees C). Cell survival was estimated by clonogenic assay. Flow cytometry was performed with FACScan. The treatments were simultaneously performed for up to 48 hr (24 Gy)., Results: Survival curves of mild hyperthermia alone revealed development of chronic thermotolerance up to 48 hr, whereas LDRI plus hyperthermia caused an exponential decrease in survival. The LDRI cytotoxicities were enhanced by mild hyperthermia over a non-lethal temperature range. The Do values calculated from dose response curves at 37, 38, 39, 40, 41 41.5 and 42 degrees C were 6.55, 5.25, 4.24, 3.99, 3.46, 1.83 and 0.70 Gy, respectively. Cell cycle analysis demonstrated a remarkable G2 and a mild G1 block for LDRI alone, but only a G1 block was observed for LDRI combined with 41 degrees C hyperthermia., Conclusion: The LDRI cytotoxicity was enhanced by long duration mild temperature hyperthermia. The suppression of chronic thermotolerance was considered to be a mechanism involved in this sensitization.

Background: We investigated the utility of clinical FDG-PET in patients with nasopharyngeal tumor treated by radiotherapy, retrospectively., Materials and Methods: Fifteen patients with known or suspected nasopharyngeal tumors underwent FDG-PET. PET images were evaluated with visual interpretation qualitatively. Semiquantitative analysis was also performed on the metabolic ratios (MRs)., Results: The sensitivity and specificity of FDG-PET based on visual inspection were 92.9% (13/14) and 83.3% (10/12), respectively. There was a statistically significant difference between histological types in the mean MR. MR was significantly decreased by radiotherapy in patients with poorly differentiated squamous cell carcinoma. PET scans obtained 1-3 months after radiotherapy indicated decreased levels of FDG uptake in all tumors but one scan did not accurately reflect the status of the disease., Conclusion: These results are encouraging as to the clinical usefulness of FDG-PET for evaluating radiation effects in patients with nasopharyngeal tumor.

Background: To evaluate potential of misonidazole (MISO) as a probe for hypoxia, the biodistribution of 14C-MISO was investigated in a murine tumor model., Materials and Methods: Following intraperitoneal injection of 14C-MISO in C57BL/6 mice with implanted meningial sarcoma tumors in the thighs, the animals were sacrificed at various times (0.5-120 hours), and 14C labeling was measured by a liquid-scintillation counter. The necrotic zone of tumor was identified by its appearance and separated from the non-necrotic tissue., Results: Concentration-time curves revealed a higher 14C label in the hypoxic areas, and the difference in 14C label between hypoxic and oxic areas widened as time elapsed., Conclusions: These results suggest that MISO bound the hypoxic cells more firmly, and the difference in 14C label reflects differences in the bioreductive ability of MISO in these cells. These promising results indicate the feasibility of MISO analogues as a non-invasive probe for hypoxic cell identification.

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.

The aim of this study was to compare the survival and recurrence rates of patients undergoing breast-conserving therapy with the rates of those undergoing mastectomy. Between August 1991 and June 1994, 229 patients were enrolled in this study, although one was later excluded because the tumor was histologically diagnosed as benign. A total of 119 patients with clinical stage TIS, I or II underwent breast-conserving therapy and 109 patients received mastectomy. Mastectomy was utilized more than breast-conserving therapy in the case of clinical stage II, greater age, larger tumor size or shorter distance between the tumor and the nipple. Twenty-seven patients (23.1%) of the 117 receiving breast-conserving surgery were surgical margin positive. There was no significant difference in the distance between the tumor and the nipple, tumor size or clinical stage in the incidence of surgical margin positive cases. Mean follow-up time of the breast-conserving therapy group and the mastectomy group was 42.4 and 39.7 months, respectively. There was no significant difference in the overall survival and disease-free survival between breast-conserving therapy and mastectomy. After adjustment for the clinical stage, there was no significant difference in the prognosis between breast-conserving therapy and mastectomy.

Two rat yolk sac tumour cell lines with different radiosensitivities were used to quantify the extent of apoptosis following irradiation by using a DNA fragmentation assay in vitro. Apoptosis was also confirmed by fluorescence analysis of nuclear morphological changes by using Hoechst 33258. A radiosensitive cell line, NMT-1 cells, showed morphological changes characteristic of apoptosis by fluorescence microscopic observation at 24 hours after irradiation with a single dose of 10 Gy. Development of apoptosis in NMT-1 cells was observed as a function of time within 24 hours after irradiation. There was a significant increase in the amount of apoptosis between 2 and 5 Gy only in NMT-1 cells but increasing the radiation dose from 5 Gy to 10 Gy did not result in increased apoptosis. A radioresistant NMT-1R cells, on the other hand, displayed a small apoptotic response to an irradiation dose of 10 Gy at 24 hours after irradiation.

To evaluate the treatment-related late sequelae including gonadal function and second malignancy 94 patients with stage I and II testicular seminoma treated with postorchiectomy radiation therapy were analyzed retrospectively. The 10-year cause specific, disease free and actuarial survival rates were 100, 98.5 and 96.1% for stage II and 91.7, 83.3 and 91.7% for stage II, respectively. The most common late sequelae of gastrointestinal tract was peptic ulcer, developing in 16% of all patients with a median interval of 12 months, but severity was mild except one who needed subtotal gastrectomy. Second malignancies developed in 9 patients (9.5%) with a median interval of 13 years, but calculated O/E ratio excluding 2 patients with secondary germ cell tumor of contralateral testis was 2.3 and did not reach a significant level statistically. Concerning gonadal function assessed from the number of the children, 79% of the patients who wanted to have children after the treatment were successful in fathering children. No fatal complications were observed.

To determine if histological type was a prognostic factor for non-small cell lung cancer (NSCLC), 67 two-year survivors were analyzed retrospectively after definitive radiation therapy (RT) for inoperable or unresectable Stage I-III NSCLC. There was no difference in short-term outcome (within 2 years) between patients with squamous cell carcinoma and patients with adenocarcinoma. After 2 years, the 5-year survival rate for the 2-year survivors was 56% for squamous cell carcinoma (n = 55) and 34% for adenocarcinoma (n = 12). According to degree of histologic differentiation, patients with poorly differentiated adenocarcinoma had a poorer outcome compared than those with well differentiated adenocarcinoma and squamous cell carcinoma as a whole. Among progression-free patients at the end of 2 years, 97% of patients with squamous cell carcinoma survived without evidence of disease for more than 5 years. Disease-free 2-year survival should be substituted for 5-year survival in patients with squamous cell carcinoma treated with RT.

Unlabelled: A retrospective analysis of para-aortic lymph node (PALN) metastasis in patients with cervical squamous cell cancer who received prophylactic postoperative irradiation to the pelvis, was carried out., Patients and Methods: Sixty-seven patients had no intra-pelvic lymph node (IPLN) metastasis (n 0), whereas 33 had IPLN (n 1). All patients received prophylactic external beam irradiation with a total dose of 50 Gy to the entire pelvis followed by intravaginal boost. Only 5 patients received a prophylactic PALN irradiation with a total dose of 30-50 Gy., Results: No patients with n 0 developed para-aortic recurrence. However, 6 of 33 patients with n 1 developed PALNs recurrence but only 3 patients developed isolated PALN recurrence. There was no difference in survival between patients with PALNs irradiation and patients without PALNs irradiation., Conclusions: Routine prophylactic irradiation to PALNs is not necessary even for patients with IPLN metastasis except for the selected patients in the management of cervical cancer.

The effect of hyperthermia and cytokine (IFN-gamma) in the expression of carcinoembryonic antigen (CEA) on the surface of cells was studied in vitro. The human lung cancer cell line, GLL-1, was used. The results demonstrate increase in CEA expression after hyperthermia. The magnitude of elevated CEA expression increased with increasing temperature (41-43 degrees C). Time-course study demonstrated that the peak CEA expression was 3 days after heating at 43 degrees C. The relative CEA expression was 1.3 at 1 day, 1.6 at 2 days, 1.9 at 3 days, 1.8 at 4 days, and 1.5 at 5 days, respectively. Hyperthermia plus IFN-gamma showed a synergistic effect in the expression of CEA. The four fold marked increase of CEA expression was detected. Furthermore, the pattern of time-course of CEA expression in hyperthermia combined with IFN-gamma was different from that in hyperthermia alone.

The purpose of this study was to evaluate the effect of adjuvant radiotherapy for advanced rectal cancers on the human neuro-immuno-endocrine system. Fifty-seven patients with rectal cancer were investigated. Abdominoperineal resection (APR) was carried out on all of them. The levels of serum IAP in 4-12 weeks after operation were significantly higher in the preoperative radiotherapy group compared with those of non-preoperatively irradiated (p < 0.05). With preoperative radiotherapy, serum IAP levels in patients with postoperative intracavitary cone irradiation returned to normal values within three months of operation; however, those with postoperative external pelvic irradiation continued to be significantly elevated until six months after operation. We conclude that preoperative radiotherapy combined with post-operative external pelvic irradiation is likely to exert unfavorable effects on the human immuno-endocrine system.

From 1976 to 1985, 185 patients with non-small cell lung cancer at stages I-III were treated with definitive radiotherapy in Gunma University Hospital. As a result of analyzing the long-term survivors treated with radiotherapy, suitable conditions of the patients for radical radiotherapy were as follows; 1) stage I or II, and some stage III, 2) as regards the histologic type epidermoid carcinoma or well-differentiated adenocarcinoma, 3) as regards the primary sites, the upper lobe and the superior segment of the lower lobe, 4) the optimum dose was 60-70Gy, 5) the size of the radiation fields given > 40Gy was 100 cm2 or less, and 6) the host condition was satisfactory (BRM combined use). In particular, as a result of administering PSK as adjuvant treatment to patients with epidermoid carcinoma of the lung showing satisfactory tumour shrinkage after radiotherapy, the five year survival rate of the patients with stages I or II disease, as well as stage III was 39% and 22% respectively, compared with the non-administered group's 16% and 5%. These differences are statistically significant. Although an improvement in the results of treatment with the combined use of appropriate BRMs is anticipated in the future, when clinical trials for combined BRM and radiotherapy are planned, the subjects should be patients with satisfactory tumour regression after radiotherapy.