Hideo Niibe

Resistance of Differentiating Spermatogonia to Radiation-Induced Apoptosis and Loss in p53-Deficient Mice

The effect of the p53 gene on the survival of mouse testicular cells was evaluated by analysis of degenerating and terminal transferase-mediated end labeling (TUNEL)-positive cells and the subsequent production of further differentiated progeny. In p53 null mice, in contrast to wild-type mice, radiation induced negligible levels of degenerating or TUNEL-positive differentiating spermatogonia within 24 h. This was correlated with higher production of differentiated progeny of the differentiating spermatogonia in p53 null mice. Contrary to the differentiating spermatogonia, the stem spermatogonia of p53 null mice produced fewer differentiated progeny after irradiation than did the stem cells of wild-type mice. We conclude that, because the degeneration and TUNEL positivity of the differentiating spermatogonia in mice of different genotypes were correlated with each other and were dependent on p53, this process is indeed apoptosis. In the differentiating spermatogonia, p53-dependent apoptosis accounted for the bulk of the loss of their progeny after irradiation. Furthermore, whereas the differentiating spermatogonia died by apoptosis that was dependent on p53, the stem spermatogonia, which are more radioresistant, did not.

Limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer

The outcome of limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer (NSCLC) was analyzed to discuss the elective irradiation of regional lymph nodes. From 1976 through 1994, 36 patients with peripheral stage I NSCLC were treated with definitive radiation therapy (RT) alone at Gunma University hospital. The total dose ranged from 60 to 81 Gy with a 2 Gy-daily standard fractionation, although only one patient received 48 Gy. Ten patients received elective irradiation of the regional lymph nodes with a total dose of 40 Gy or more. The overall response rate was 97% with 31% complete responses. The overall survival rates at 3 and 5 years were 42 and 23%, and disease-specific survival rates were 56 and 39% at 3 and 5 years, respectively. In 26 patients without the elective regional irradiation, disease-specific survival rates at 3 and 5 years were 53 and 40%, respectively, whereas they were 64 and 39% in 10 patients with the regional nodal irradiation. The cumulative 5-year local progression rate was 28%, and the overall progression rate was 60% at 5 years. Four patients had a local recurrence as the only site of initial tumor progression. Combined local and regional progression was seen in two patients, and one patient had a local recurrence in combination with distant metastasis. Twelve patients had distant failure without evidence of local or regional progression. Only one patient without regional nodal irradiation developed an isolated regional failure. No patient had serious complications related to RT. High-dose limited field RT is justified for medically inoperable patients with peripheral stage I NSCLC. The regional nodal irradiation can be omitted in these pulmonary compromised patients because of the low regional relapse rate. Dose-escalation by a conformal RT with a small target volume can be expected to provide a better local control rate and better survival.

Outcome of radiation therapy for patients with Kasabach-Merritt syndrome

PURPOSE The efficacy of radiation therapy for Kasabach-Merritt syndrome, which is characterized by a huge hemangioma with consumption coagulopathy, remains controversial. In this study, we retrospectively investigated the treatment outcome of radiation therapy for seven neonates with Kasabach-Merritt syndrome. METHODS AND MATERIALS During the past 25 years we have seen seven children with Kasabach-Merritt syndrome who were treated with radiation therapy. Their ages ranged from 1 day to 5 months, with a median age of 1 month. The hemangioma was located in the extremities in four of seven children. Tumor sizes ranged from 70 cm to more than 150 cm in greatest diameter. Initial platelet counts were all less than 40,000/mm3 except for one patient. In principle, the total dose applied to the hemangioma was 8-10 Gy, with a daily dose of 1 Gy five times a week. RESULTS Four of seven hemangiomas responded dramatically, with a concomitant rise of the platelet count to radiation therapy. Although the remaining three hemangiomas, all of which were ill circumscribed by widespread overlying shiny, dusky purple skin, became less tense during radiation therapy. Disseminated intravascular coagulopathy was not improved, but they have responded favorably to two or three courses of radiation therapy with an extended radiation field by 1.5 years of age. As a result, all seven patients are now surviving with no evidence of hemangioma or hematological abnormalities. Shortening of the extremity was observed in three patients who received multiple courses of radiation therapy. CONCLUSIONS Radiation therapy appears to be one of the effective treatment options for Kasabach-Merritt syndrome despite the risk of growth delay and malignancy.

High-dose radiation therapy for elderly patients with inoperable or unresectable non-small cell lung cancer

PURPOSE To evaluate definitive radiation therapy delivering doses in excess of 60 Gy for elderly patients aged 75 years or over with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS The treatment results for 97 patients aged 75 years or older (mean age 78 years; elderly group) with inoperable or unresectable NSCLC were retrospectively analyzed and compared with those for 206 patients younger than 75 year old (mean age 64 years; younger group). The elderly patients were classified into two groups; 67 patients aged 75-79 years (the elderly A) and 30 patients aged 80 years or older (the elderly B). Most of all patients were treated with a total dose of 60 Gy or more in 2 Gy daily standard fractionation. RESULTS The overall 2 and 5 year survival rates were 32 and 13% for the elderly A group, and 28 and 4% for the elderly B group, respectively, compared with 36 and 12% for the younger group. There was not a statistically significant difference in survival rates among three groups. In stage I-II NSCLC patients there was also no significant difference in survival curves among the three groups. In patients with stage III disease, however, the survival curve of the elderly B was inferior to those of the younger group and the elderly A group, although the difference was not statistically significant. After the treatment the deterioration rate of the performance status was only 5% in the younger group and 8% in the elderly group. Only three younger and two elderly patients died of late pulmonary insufficiency associated with high-dose irradiation to the proximal bronchus. No other treatment-related event was observed except for mild acceptable acute complications in the elderly groups. CONCLUSIONS Definitive radiation therapy is recommended to the elderly aged 75 years or older with inoperable or unresectable NSCLC, especially early stage disease, as an acceptable choice of treatment.

Treatment results of radiotherapy for malignant lymphoma of the orbit and histopathologic review according to the WHO classification

PURPOSE To analyze the results of radiotherapy (RT) for malignant lymphoma of the orbit and to evaluate them compared with the World Health Organization (WHO) classification published in 2001. METHODS AND MATERIALS The data from 29 patients with malignant lymphoma of the orbit treated with RT at Gunma University Hospital between 1978 and 2001 were retrospectively analyzed. Pathologic slides from 23 cases were available and were reviewed by a hematopathologist according to the WHO classification. The original and reviewed diagnoses, patient characteristics, treatment results, and complications were analyzed. In principle, patients with low-grade or indolent lymphoma were treated with RT alone, using 30 Gy as the tumor dose. Survival data were calculated using the Kaplan-Meier method. RESULTS One case that proved to be a pseudotumor was excluded from evaluation. Of the 28 cases, 25 were Stage IAE, 1 was Stage IIAE, and 2 were Stage IVAE. The median follow-up was 71 months. According to the original classification and the Working Formulation, the 5- and 10-year overall survival rate of patients with low-grade lymphoma was 94% and 73%, respectively. The corresponding rates for those with intermediate-grade lymphoma were 67% and 67% (p = 0.15). In contrast, the WHO classification showed a significant difference in the survival curves. The 5- and 10-year overall survival rate of patients with mucosa-associated lymphoid tissue (MALT) lymphoma was 100% and 88%, respectively; for diffuse large B-cell patients, the rates were both 0% (p < 0.001). In patients with MALT lymphoma, one local and four distant relapses developed; two of them >10 years after initial treatment. All of the relapsed MALT lymphomas were controlled by salvage therapy. CONCLUSION Excellent local control and survival can be achieved for patients with orbital MALT lymphoma using RT alone. A precise histopathologic diagnosis using the WHO classification and long-term follow-up for >10 years is recommended.

Clinical study of the radioprotective effects of amifostine (YM-08310, WR-2721) on chronic radiation injury☆

We have previously reported that Amifostine, a radioprotective agent, was effective in treating acute radiation mucositis in the head and neck region. We found that when a considerable amount of Amifostine accumulates in the salivary glands, it may be useful in preventing chronic disturbances of salivary secretion. We have observed an increase in the uptake of Ga-67-citrate to the salivary glands when they were irradiated. In this paper, the radioprotective effects of Amifostine, in treating chronic radiation injury of the salivary glands, were studied, using the cessation of an increase in uptake of Ga-67-citrate after radiotherapy as the criterion. The subjects were 105 patients, (280 salivary glands in Ga-scintigrams) with malignancy of the head and neck region treated by irradiation from 1978 to 1984. Ga-negative glands were recognized in 97%, that is, 36 out of 37 glands, before irradiation, and the figure decreased to 19%, seven out of 37, within 1 to 2 weeks (10Gy less than or equal to) after the start of radiotherapy. In patients who were irradiated with more than 30 Gy and in whom scintigraphy was performed at 6 months or more after radiotherapy, Ga-negative glands were recognized in 18 out of 41 glands, 44%, with Amifostine, compared with 13%, four out of 32 glands, without Amifostine. A difference was recognized between these two groups in the negative change in Ga-67 uptake after radiotherapy (p less than 0.05). These facts suggest that Amifostine may have a radioprotective effect on chronic radiation injury.

Rapid rise in FDG uptake in an irradiated human tumour xenograft

In order to investigate early changes in the glucose metabolism of irradiated tumours, tumour uptake of 2-[18F]fluoro-2-deoxy-d-glucose (18FDG) was studied in human tumour xenografts. Three human tumour lines [ependymoblastoma (NNE), small cell lung cancer (GLS), and glioblastoma (KYG)] showing different radiosensitivities and incidences of radiation-induced apoptosis were subcutaneously transplanted into nude mice, and were irradiated at a single dose of 10 Gy. Then 0.5 mCi of18FDG was intravenously administered 1 h before sacrifice. The animals were sacrificed at 2, 4 and 6 h following irradiation, and18FDG accumulation in the tumours was examined. Before irradiation, GLS and KYG tumours showed significantly higher rates of18FDG accumulation compared with NNE tumours (P <0.004 andP <0.001, respectively). NNE (the most radiosensitive tumour with the highest incidence of radiation-induced apoptosis), however, displayed a 2.3-fold higher rate of18FDG accumulation at 2 h following irradiation compared with a non-irradiated group (P <0.01), and thereafter showed a plateau up to 6 h. The accumulation did not increase significantly in the other tumours with lower radiosensitivity and much less radiation-induced apoptosis. The rapidity of the increase in18FDG accumulation in the most radiosensitive tumour line, occurring as early as 2 h following irradiation, suggests that the increase was independent of recovery phenomena following radiation damage.

Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone: patterns of recurrence, latent periods, and prognosis

PURPOSE A retrospective analysis was performed with emphasis on the patterns of recurrence, latent period, and prognosis in patients with cervical squamous cell carcinoma of the uterus treated with definitive radiation therapy alone. Late recurrence, which was observed more than 5 years after the initial radiation therapy, was finally focused on and discussed. MATERIALS AND METHODS Between 1976 and 1994, 256 patients with squamous cell carcinoma of the uterine cervix without hematogenous metastasis were treated with definitive radiation therapy alone. The patients were staged as follows according to the FIGO classification: 26 in Stage I, 56 in Stage II, 124 in Stage III, 28 in Stage IVa, and 22 in Stage IVb. All the patients were treated with external beam irradiation and low-dose-rate intracavitary brachytherapy. RESULTS A total of 74 patients had recurrence. The recurrence appeared in 67 cases (90.5%) within 5 years. Metastasis to para-aortic and/or supraclavicular nodes developed later than other types of recurrence. Among patients with lymphogenous metastasis, there were more 5-year survivors after recurrence than with other types of recurrence. Patients with early recurrence, within 2 years of the initial therapy, had a worse prognosis than those with recurrence more than 2 years after treatment. Seven patients (2.7%) in all developed late recurrence more than 5 years after the treatment. The first site of recurrence was an abdominal para-aortic or supraclavicular node in all patients, excluding one patient who developed intrapelvic lymph node metastasis. Six patients had pelvic node metastasis detected with lymphangiography at the initial treatment. Median survival after late recurrence was 16.0 months. Two of 7 patients survived more than 3 years after secondary radiation therapy, and the remainder died of recurrent disease. CONCLUSION Patients with para-aortic and/or supraclavicular node metastasis that developed late after the initial treatment are more likely to survive due to secondary radiation therapy. Careful follow-up is emphasized for long-term survivors.

Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion

Purpose : Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated. Materials and methods : Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60-70Gy was administered to both groups. Hyperthermia was performed for 45-60min immediately after irradiation for two-four sessions with radiofrequency capacitive heating devices. Results : For primary response, 10 of the 13 tumours responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumours responded (1 CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumours histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.4%, respectively. No severe pulmonary complication was observed in either group. Conclusions : Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.

An interaction of cisplatin and radiation in two rat yolk sac tumour cell lines with different radiosensitivities in vitro

We investigated the interaction of cisplatin and radiation in two rat yolk sac tumour cell lines with different radiosensitivities in vitro. The effects were assessed by clonogenic assay. D0 for the radiosensitivity of the radioresistant variant cell line, NMT-1R was 139 cGy, which was 1.3 times larger than that for the parent radiosensitive cell line, NMT-1 (D0 = 107 cGy). The concentration of cisplatin required to reduce colony formation by 50% at 1 h treatment (ID50 of cisplatin) was 0.25 microgram/ml for NMT-1, whereas that for NMT-1R was 1.0 microgram/ml. Cisplatin potentiation of radiation sensitivity was manifested by the decrease in the slope of the radiation dose-response curve. D0s for NMT-1 and NMT-1R were 83 and 100 cGy in combined treatment with ID50 of cisplatin immediately before radiation. The enhancement ratios of cisplatin were therefore 1.30 for NMT-1 and 1.39 for NMT-1R respectively in D0. No different enhancement ratio for cisplatin was observed in the time course of combination treatment with cisplatin and radiation within the interval of 6 h. There was no clear change in cell cycle distribution within 6 h after treatment with ID50 of cisplatin for both cell lines. In conclusion, cisplatin had a synergistic effect on both cell lines which was independent of the time course and sequence in combination with radiation within 6 h.