Yukio Akagi

Radiation-induced apoptosis and necrosis in Molt-4 cells : a study of dose-effect relationships and their modification

Cell death induced by various radiation doses in Molt-4 and L5178Y cells was studied. Molt-4 cells have a low threshold for induction of interphase death while L5178Y cells have a high threshold. Interphase death in Molt-4 cells at doses > 100 Gy and in L5178Y cells at doses > 300 Gy showed typical necrosis. In contrast, cell death in Molt-4 cells after 2-30 Gy had features of both apoptosis and necrosis; the appearance of orcein-stained cells in the light microscope was suggestive of apoptosis, showing chromatin margination and apoptotic bodies. The concomitant appearance of non-viable cells as estimated by either orcein staining or eosin dye staining correlated well with this. Early cell swelling and a diffuse smear pattern in DNA gel electrophoresis were however suggestive of necrosis. Detailed electron microscopic observations revealed that events leading to the interphase death of Molt-4 cells after 2-30 Gy involved complicated pathways which included both apoptotic changes in the nucleus and necrotic changes in the cytoplasm. TPA not only had a protective effect on the interphase death of Molt-4 cells, but also converted the mode of cell death from interphase death to mitotic death after low doses of radiation. Cycloheximide and H-7, known to inhibit apoptosis in irradiated thymocytes, had no protective effect on the interphase death of Molt-4 cells, suggesting that the events leading to interphase death in Molt-4 cells might be different from those in thymocytes. BrdUrd-labelling had a sensitizing effect on the radiation response, but no effect on interphase death in Molt-4 cells thus suggesting that DNA damage may not be responsible for interphase death.

Optimum fractionation for high-dose-rate endoesophageal brachytherapy following external irradiation of early stage esophageal cancer

PURPOSE To establish the optimum fractionation for high-dose-rate (HDR) endoesophageal brachytherapy (EBT) for early stage esophageal cancer from retrospective data of patients treated with different HDR schedules following external beam irradiation (EBI). METHODS AND MATERIALS The study population consisted of 35 consecutive early stage esophageal cancer patients who received EBI to the mediastinum, plus EBT, between May 1992 and November 1995 at the Hiroshima University Medical Center and Hiroshima City Hospital. All patients were treated with EBI, with doses ranging from 50 to 61 Gy. The spinal cord was spared after 44-45 Gy. HDR EBT was performed using a double-balloon applicator in conjunction with an Ir-192 remote afterloading system. One group of 10 patients was given a weekly endoesophageal boost of 4 or 5 Gy at a distance of 5 mm from the applicator surface over a period of 1-2 weeks. Another group of 25 patients was treated with 4 or 5 endoesophageal boosts with a fraction dose of either 2.5 or 2 Gy for 1 week. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) for tumor (Gy10) and esophageal mucosa (Gy3); Gy10 means alpha/beta equals 10 Gy, and Gy3 means alpha/beta equals 3 Gy. The Kaplan-Meier method was used to calculate the local control and late complication rates, while the Cox-Mantel test was used to evaluate statistical significance (p < 0.01). RESULTS Nine (26%) of the 35 patients recurred locally and 7 (20%) had late complications (esophageal ulcer grade by RTOG/EORTC criteria > 1). The 5-year overall survival, local control, and late complication rates were 38%, 57%, and 26%, respectively. The probability of local recurrence was not affected by the treatment parameters. Results from the LQ formula significantly correlate with data on late complications. A BED > 134 Gy3 and a fraction number = < 3 were associated with late complications (grade > 1). BED analysis showed that the fractionation dose should be decreased to 2.5 or 2.0 Gy at a distance of 5 mm from the applicator surface, and the number of doses increased to 4 or 5, respectively, to yield a satisfactory BED (< 134 Gy3). CONCLUSION A significant reduction in endoesophageal brachytherapy dose per fraction is necessary to reduce late complications. Our current treatment protocol for early-stage esophageal cancer consists of EBI of 60 Gy followed by 4 EBT doses at a fraction dose of 2.5 Gy applied over 1 week.

Treatment results of stage I and II oral tongue cancer with interstitial brachytherapy: Maximum tumor thickness is prognostic of nodal metastasis

PURPOSE To evaluate the prognostic importance of T classification and maximum tumor thickness (MTT) on the treatment results of Stage I and II oral tongue cancer treated with interstitial brachytherapy. METHODS AND MATERIALS Between January 1981 and December 1993, 173 cases were eligible for this retrospective analysis. Of 173 patients, 75 were classified as Stage I and 98 as Stage II: maximum tumor length ranged from 6 to 40 mm. MTT, which ranged from 2 to 38 mm, was measured with ultrasonography and/or palpation. Brachytherapy was performed with iridium hairpins or radium needles following external irradiation in 66 patients, or exclusively in 107 patients. RESULTS The 5-year local recurrence rates were Stage I, 7%; Stage II, 22%; MTT < 8 mm, 8%; and MTT > or = 8 mm, 28%. The 5-year regional recurrence rates were Stage I, 15%; Stage II, 29%; MTT < 8 mm, 18%; and MTT > or = 8 mm, 31%, respectively. The 5-year local recurrence rates of the patients with Stage I and MTT < 8 mm of the brachytherapy only group were significantly better than those of Stage II and MTT > or = 8 mm (5% and 6% vs. 16% and 24%). The 5-year regional recurrence rates of the patients with Stage I and MTT < 8 mm of the brachytherapy-only group were significantly better than those of Stage II and MTT > or = 8 mm (14% and 16% vs. 34% and 46%). There was no significant difference in the 5-year regional recurrence rates between the two groups of Stage I and Stage II, MTT < 8 mm. However, there was a significant difference in the 5-year regional recurrence rates between the two groups of MTT > or = 8 mm (p < 0.005). CONCLUSIONS For patients with Stage I and II oral tongue cancer, tumor thickness as well as T classification were prognostic for nodal metastasis and prognosis. Patients with MTT > or = 8 mm are more likely to fail in the neck region. These findings suggest that MTT should be considered along with T stage in determining strategies for Stage I and II oral tongue cancer.

Interstitial brachytherapy for stage I and II squamous cell carcinoma of the oral tongue: factors influencing local control and soft tissue complications.

PURPOSE Our aim was to study the treatment parameters that influence local control and soft tissue complications (STC) in a series of 207 Stage I and II squamous cell carcinomas of the oral tongue treated by interstitial brachytherapy (BRT) alone (127 patients), or by a combination using external beam irradiation (EBI) (80 patients) between 1980 and 1993. METHODS AND MATERIALS The patient distribution was 93 T1, 72 T2a, and 42 T2b. The prescribed BRT dose at the plane 5 mm from the plane of the radioactive sources was 65-70 Gy in BRT alone, and 50-60 Gy in the combined treatment using EBI. Generally, an EBI dose of 30 Gy was used. No prophylactic neck treatment was performed. RESULTS The 5-year local recurrence-free rate for T1, T2a, and T2b was 92.9%, 81.9%, and 71.8%, respectively (p < 0.05). The lesions of endophytic appearance and those located in the posterior half of the mobile tongue had a significantly lower local control rate than those of other macroscopic appearances (p = 0.02) and those in other localizations (p < 0.01). Most local recurrences (66.7%) occurred within 2 years after treatment. However, 8 of 14 recurrences of T1 and 6 of 15 recurrences among patients treated by BRT alone occurred after 5 years. Statistical analysis showed that, in BRT alone treatment, a dose rate < = 1.0 Gy/h was related to better local control (p = 0.04). There was no significant relationship between BRT dose and local control; however, the incidence of local recurrence was lowest in a BRT dose 65-70 Gy. In the combined treatment, a total dose > 85 Gy (p = 0.01), BRT dose > 55 Gy (p = 0.04), and a dose rate < 0.55 Gy/h (p = 0.03) were significantly related to better local control. The incidence of more severe STC were 11.5% and was significantly higher in T2a (p = 0.03) and T2b (p < 0.01) than in T1. Statistical analysis revealed that a dose rate > = 0.6 Gy/h was significantly related to more STC in BRT alone (p = 0.03), and that a dose rate > = 0.55 Gy/h (p < 0.03) and a BRT dose > 70 Gy ( < 0.05) and a total dose > 100 Gy (p < 0.05) were significantly related to more STC in the combined treatment. Neck metastases occurred in 25% in T1N0, 27% in T2aN0, and 31% in T2bN0 (NS). Eighty-eight percent were found within 12 months. Thirty-three secondary cancers including 12 head and neck, 8 esophageal, and 3 gastric were found after treatment. The 5-year crude survival rate for T1, T2a, and T2b was 83.4%, 66.0%, and 70.9%, respectively. CONCLUSION To acheive better local control and fewer STC, we recommend the following relationships between dose and dose rate. In BRT alone, dose rate should be maintained at < 0.6 Gy/h with a preferable BRT dose 65-70 Gy. In the combined treatment, total dose, BRT dose and dose rate should be kept between > 85 Gy and < = 100Gy, between > 55 Gy and < = 70 Gy, and < 0.55 Gy/h, respectively. We also recommend longer follow-up periods; more than 5 years might be necessary for late local recurrences and for secondary cancers.

An analysis of mandibular bone complications in radiotherapy for T1 and T2 carcinoma of the oral tongue

PURPOSE To examine the incidence of mandibular bone complication in patients who underwent radiotherapy for T1 and T2 carcinomas of the oral tongue and to analyze the factors contributing to its occurrence. METHODS AND MATERIALS The clinical records of 148 patients with T1 and T2 carcinoma of the oral tongue treated with radiotherapy alone between 1978 and 1989 were examined retrospectively. Interstitial brachytherapy, used as the major treatment modality, was performed using cobalt needles, radium needles, or iridium hairpins. The prescribed dose at the plane 5 mm from the plane of the radioactive sources was 65-70 Gy in interstitial brachytherapy alone, and 50-60 Gy in the combined treatment with external irradiation. An external irradiation dose of 30 Gy was usually used. RESULTS Eleven of the patients showed radiation-induced mandibular bone complication. Two (1 T1, 1 T2) had been treated with interstitial brachytherapy alone, and nine (2 T1, 7 T2) with the combination of external irradiation and interstitial brachytherapy. The incidence of radiation complication of bone was significantly higher in the patients with T2 tumors (p = 0.04) and in those who received the combined treatment (p < 0.01). Multivariate analysis revealed that the total dose (p = 0.04) and dose rate of interstitial brachytherapy (p = 0.03) were significant factors contributing to radiation bone complication. A significant difference in the incidence of bone complication was also seen between patients who received a total dose of 90 Gy or more and those who received less than 90 Gy (p < 0.01), as well as between patients who were treated with 0.55 Gy/h or higher and those who were treated with less than 0.55 Gy/h (p = 0.03). CONCLUSION A significant increase in the incidence of bone complication was found at the total dose of 90 Gy or more and at the dose rate of 0.55 Gy/h or higher. In combined treatment with external irradiation and interstitial brachytherapy, the interstitial brachytherapy dose of 60 Gy appears to be the threshold at which mandibular bone complication is induced when the external irradiation dose is 30 Gy.

Experimental and clinical studies on dose reduction effects of spacers in interstitial brachytherapy for carcinoma of the mobile tongue

The difference of radiation dose reduction effect with spacers of different materials, a heat-curing denture base resin and a silicon impression material, was examined experimentally and clinically. Radium needles and iridium hairpins were used as radioactive sources. In both studies, it was revealed that a dose reduction effect of silicon impression material was greater than that of denture base resin. Silicon impression material was thought to be a better material for spacers because of its larger radiation dose reduction effect and the time saving to produce the spacer.

Results of a preliminary study using hypofractionated involved-field radiation therapy and concurrent carboplatin/paclitaxel in the treatment of locally advanced non-small-cell lung cancer

BackgroundWe aimed to evaluate the feasibility and efficacy of hypofractionated involved-field radiation therapy (IFRT) omitting elective nodal irradiation (ENI) with concurrent chemotherapy for locally advanced non-small-cell lung cancer (NSCLC).MethodsBetween July 2004 and July 2006, ten patients with locally advanced NSCLC were included in this study. One had stage IIIA and 9 had stage IIIB disease. The treatment consisted of IFRT in fractions of 2.5 Gy and weekly carboplatin (CBDCA)/paclitaxel (PTX). Hypofractionated IFRT with a median total dose of 65 Gy with median percent total lung volume exceeding 20 Gy (V20) of 20.2%, and a median of five courses of chemotherapy with weekly CBDCA (area under the curve, 1.5−2.0)/PTX (30−35 mg/m2) were given to all patients.ResultsThe median survival time and the 1-, 2-, and 3-year overall survival rates were 29.5 months and 90.0%, 58.3%, and 43.8%, respectively. No elective nodal failure was encountered during the median follow up of 18.2 months. No acute or late toxicities of grade 3 or worse were observed. No in-field recurrence occurred in the group with a total dose of 67.5 Gy or more, but there was such recurrence in 83.3% of those in the group with less than 67.5 Gy.ConclusionHypofractionated IFRT with weekly CBDCA/PTX was a feasible treatment regimen. Hypofractionated IFRT with a total dose of 67.5 Gy or more could be a promising modality to improve the treatment results in patients with locally advanced NSCLC.

Dose-reducing effect of lipowitz metal-embedded spacers in interstitial brachytherapy for carcinoma of the mobile tongue

Dose-reducing effects of spacers with and without a Lipowitz metal plate for the purpose of decreasing osteoradionecrosis after interstitial brachytherapy for tongue cancers were examined experimentally and clinically. The thicker the sample or spacer and the thicker the metal plate, the greater was the dose reduction achieved. A more marked dose reduction was achieved with iridium than with radium because of lower gamma ray energy of iridium. Iridium has been used widely as a radioactive source for interstitial brachytherapy. It was concluded therefore that a metal plate should be used as a shield into the spacer in interstitial brachytherapy both to reduce the radiation dose to surrounding normal tissues and to help prevent osteoradionecrosis.

Clinical results of external beam radiotherapy alone with a concomitant boost program or with conventional fractionation for cervical cancer patients who did not receive intracavitary brachytherapy

A combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) is well established as the standard radical radiotherapy (RT) for cervical cancer. However, it is sometimes necessary to perform EBRT alone for patients where ICBT is not feasible. For these patients, we initiated EBRT alone with three-dimensional conformal radiotherapy (3DCRT). The purpose of this study is to evaluate the results of EBRT alone without ICBT for patients with cervical cancer. Sixteen patients were treated with EBRT alone between 2002 and 2009. There were three stage IIB, six stage IIIB and seven patients with stage IVA disease. A total of 10 patients were treated with a median dose of 66 Gy with a median overall treatment time (OTT) of 40 days delivered by a concomitant boost (CCB), and a median dose of 60 Gy with a median OTT of 47 days was administered for six patients by conventional fractionation (CF). The 3-year overall survival (OAS) and local control (LC) rates were 43.8% and 75.0%, respectively. The 3-year LC rate was 90.0% for the CCB group, 50.0% for the CF group (P = 0.0692); 100% for OTT ≤42 days, 42.9% for OTT ≥43 days (P = 0.0095). No severe acute and late adverse effects were encountered for any of the patients. These outcomes suggest that EBRT with a CCB program may be a promising radical treatment for cervical cancer that provides better LC with minimal complications, especially in cases where ICBT cannot be performed.