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Purpose To assess the correlation between postimplant dosimetric quantifiers and the genitourinary (GU) toxicity of low-dose rate brachytherapy for prostate cancer. Methods and Materials The minimum urethral dose (UD10, 30, and 90) and the percent volume of the urethra receiving the prescription dose (V100, V150) were calculated from the postimplant dose-volume histograms of 182 patients. We then calculated various urethral biologically equivalent doses (uBEDs) using different values of the α/β ratio and tissue repair half-time (t1/2) and examined the correlations with GU toxicity. Results Common dosimetric quantifiers, such as UD90 (brachytherapy) + UD50 (external beam radiotherapy), showed no correlation with Grade ≥ 2 GU toxicity. There was a significant correlation between Grade ≥2 GU toxicity and uBED when the α/β value was 0.5 or 1 Gy and t1/2 was 0.5–2.5 h. An uBED (α/β = 1.0, t1/2 = 0.5) had the largest hazard ratio for GU toxicity, and it was also significantly correlated with Grade ≥ 2 GU toxicity according to multivariate analysis. Conclusions We observed a significant correlation of uBED with GU toxicity when α/β was 0.5 or 1.0 Gy and t1/2 was 0.5–2.5 h. As the simple formula we used has not been verified in basic experiments, more data are needed to validate our results.

An 18-year-old man presented with sudden vision loss in his left eye. Magnetic resonance imaging revealed a tumor that had invaded the left optic nerve, originating from the left posterior ethmoid sinus. Immunohistochemical analyses identified positive staining for NUT protein in the nuclei of tumor cells. We diagnosed locally advanced NUT carcinoma (NC) and initiated concurrent chemoradiotherapy (CCRT), consisting of chemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosphamide and etoposide, plus radiation therapy. The patient achieved a complete response. CCRT can be a useful treatment option for adolescent and young-adult patients with locally advanced unresectable NC.

Purpose Although proton therapy is controversial, it has been used to treat localized prostate cancer over the past 2 decades. The purpose of this study is to examine the long-term efficacy and toxicity of proton therapy for localized prostate cancer. Methods and Materials This was a retrospective observational study of 2021 patients from 2003 to 2014 at a single institution. Patients were classified using the risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019. Ninety-eight percent of the patients received 74 Gy (relative biological effectiveness) in 37 fractions. Fifty-one and 6% of the patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The outcomes were the time of freedom from biochemical relapse and the time to late toxicity by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The outcomes were estimated using the Kaplan-Meier method and were analyzed using multivariable Cox proportional hazards models. Results The median follow-up period was 84 months (interquartile range, 60-110). The 5- and 10-year freedom from biochemical relapse rates were 100% and 100%, 99% and 88%, 93% and 86%, 90% and 79%, 88% and 68%, and 76% and 63% for the very low, low, favorable intermediate, unfavorable intermediate, high, and very high-risk groups, respectively. Patients with higher risk experienced biochemical relapse after shorter periods. The 5-year rates of grade 2 or higher late genitourinary and gastrointestinal toxicity were 2.2% and 4.0%, respectively. The results of multivariable analyses indicate that younger patients more often experienced biochemical relapse. Conclusions This study demonstrates the favorable biochemical controls of proton therapy even in advanced localized prostate cancer patients with a low incidence of late toxicities, supporting the feasibility of conducting prospective clinical trials. The risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019, are useful to classify patients with localized prostate cancer. Our findings might suggest the necessity to develop a treatment strategy that accounts for the patient’s age.

Background The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution. Methods All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan–Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. Results The median follow-up was 71.5 months (range, 14–175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. Conclusions Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable.

This is the first multi‐institutional retrospective survey of the long‐term outcomes of proton therapy (PT) for prostate cancer in Japan. This retrospective analysis comprised prostate cancer patients treated with PT at seven centers between January 2008 and December 2011 and was approved by each Institutional Review Board. The NCCN classification was used. Biochemical relapse was based on the Phoenix definition (nadir + 2.0 ng/mL). Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. There were 215, 520, and 556 patients in the low‐risk, intermediate‐risk, and high‐risk groups, respectively. The median follow‐up period of surviving patients was 69 months (range: 7–107). Among all patients, 98.8% were treated using a conventional fractionation schedule and 1.2% with a hypofractionation schedule; 58.5% and 21.5% received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The 5‐year biochemical relapse‐free survival (bRFS) and overall survival rates in the low‐risk, intermediate‐risk, and high‐risk groups were 97.0%, 91.1%, and 83.1%, and 98.4%, 96.8%, and 95.2%, respectively. In the multivariate analysis, the NCCN classification was a significant prognostic factor for bRFS, but not overall survival. The incidence rates of grade 2 or more severe late gastrointestinal and genitourinary toxicities were 4.1% and 4.0%, retrospectively. This retrospective analysis of a multi‐institutional survey suggested that PT is effective and well‐tolerated for prostate cancer. Based on this result, a multi‐institutional prospective clinical trial (UMIN000025453) on PT for prostate cancer has just been initiated in order to define its role in Japan.

The aim of this retrospective study was to report long‐term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer‐specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow‐up period was 70 months (range, 4–145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low‐, intermediate‐, high‐, and very high‐risk groups, 5‐year FFBR was 99% (95% confidence intervals [CI], 96–100%), 91% (95% CI, 88–93%), 86% (95% CI, 82–89%), and 66% (95% CI, 53–76%), respectively, and 5‐year CSS was 100% (95% CI, 100–100%), 100% (95% CI, 100–100%) , 99% (95% CI, 97–100%), and 95% (95% CI, 94–98%), respectively. Patient age, T classification, Gleason score, prostate‐specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow‐up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high‐ and very high‐risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols.

Background and purpose Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. Materials and methods Four patients each with grade 0–1 or grade 2–3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. Results In the discovery cohort, grade 2–3 rectal bleeding was significantly higher in the Ku80 P =0.011). In radiation-induced expression of miR-99a, grade 2–3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(−) >0.93 group compared with ⩽0.93 group ( P =0.013). Most patients with grade 2–3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. Conclusion A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy.

Background and purpose The aim of this study was to retrospectively analyse the outcomes of cases of adenoid cystic carcinomas (ACCs) of the head and neck that were treated at a single institution with particle therapy consisting of either protons or carbon ions. Methods and materials Between February 2002 and March 2012, 80 patients were treated with proton therapy (PT) or carbon ion therapy (CIT) alone. PT and CIT were employed in 40 (50%) patients each, and more than half of the patients received 65.0 GyE in 26 fractions ( n =47, 59%). Results The median duration of follow-up was 38months (range, 6–115months). For all patients, the 5-year for overall survival (OS) rate, progression-free survival (PFS) rate, and local control (LC) rate were 63%, 39%, and 75%, respectively. No significant differences between PT and CIT were observed. The 5-year LC rates for T4 and inoperable cases were 66% and 68%, respectively. Twenty-one patients (26%) experienced grade 3 or greater late toxicities, including three patients who developed grade 5 bleeding from nasopharyngeal ulcers. Conclusions Particle radiotherapy for ACC achieves favourable LC, and its efficacy in inoperable or T4 cases is promising. There were no significant differences between PT and CIT in terms of OS, PFS and LC.

In patients undergoing radiotherapy for localized prostate cancer, dose–volume histograms and clinical variables were examined to search for correlations between radiation treatment planning parameters and late rectal bleeding. We analyzed 129 patients with localized prostate cancer who were managed from 2002 to 2010 at our institution. They were treated with 3D conformal radiation therapy (3D-CRT, 70 Gy/35 fractions, 55 patients) or intensity-modulated radiation therapy (IMRT, 76 Gy/38 fractions, 74 patients). All radiation treatment plans were retrospectively reconstructed, dose–volume histograms of the rectum were generated, and the doses delivered to the rectum were calculated. Time to rectal bleeding ranged from 9–53 months, with a median of 18.7 months. Of the 129 patients, 33 patients had Grade 1 bleeding and were treated with steroid suppositories, while 25 patients with Grade 2 bleeding received argon plasma laser coagulation therapy (APC). Three patients with Grade 3 bleeding required both APC and blood transfusion. The 5-year incidence rate of Grade 2 or 3 rectal bleeding was 21.8% for the 3D-CRT group and 21.6% for the IMRT group. Univariate analysis showed significant differences in the average values from V65 to V10 between Grades 0–1 and Grades 2–3. Multivariate analysis demonstrated that patients with V65 ≥ 17% had a significantly increased risk (P = 0.032) of Grade 2 or 3 rectal bleeding. Of the 28 patients of Grade 2 or 3 rectal bleeding, 17 patients (60.7%) were cured by a single session of APC, while the other 11 patients required two sessions. Thus, none of the patients had any further rectal bleeding after the second APC session.

This study sought to demonstrate the feasibility of estimating the source strength during implantation in brachytherapy. The requirement for measuring the strengths of the linked sources was investigated. The utilized sources were (125)I with air kerma strengths of 8.38-8.63 U (μGy m(2) h(-1)). Measurements were performed with a plastic scintillator (80 mm × 50 mm × 20 mm in thickness). For a source-to-source distance of 10.5 mm and at source speeds of up to 200 mm s(-1), a counting time of 10 ms and a detector-to-needle distance of 5 mm were found to be the appropriate measurement conditions. The combined standard uncertainty (CSU) with the coverage factor of 1 (k = 1) was ∼15% when using a grid to decrease the interference by the neighboring sources. Without the grid, the CSU (k = 1) was ∼5%, and an 8% overestimation due to the neighboring sources was found to potentially cause additional uncertainty. In order to improve the accuracy in estimating source strength, it is recommended that the measurment conditions should be optimized by considering the tradeoff between the overestimation due to the neighboring sources and the intensity of the measured value, which influences the random error.

The post-implantation dosimetry for brachytherapy using Monte Carlo calculation by EGS5 code combined with the source strength regression was investigated with respect to its validity. In this method, the source strength for the EGS5 calculation was adjusted with the regression, so that the calculation would reproduce the dose monitored with the glass rod dosimeters (GRDs) on a water phantom. The experiments were performed, simulating the case where one of two (125)I sources of Oncoseed 6711 was lacking strength by 4-48%. As a result, the calculation without regression was in agreement with the GRD measurement within 26-62%. In this case, the shortage in strength of a source was neglected. By the regression, in order to reflect the strength shortage, the agreement was improved up to 17-24%. This agreement was also comparable with accuracy of the dose calculation for single source geometry reported previously. These results suggest the validity of the dosimetry method proposed in this study.

The aim of this study is to demonstrate the feasibility of estimating the strength of the moving radiation source during patient implantation. The requirement for the counting time was investigated by comparing the results of the measurements for the static source with those for the source moving at 2, 5, 10 and 20 cm s(-1). The utilized source was (125)I with an air-kerma strength of 0.432 U (μGym(2)h(-1)). The detector utilized was a plastic scintillation detector (8 cm × 5 cm × 2 cm in thickness) set at 8 cm away from the needle to guide the source. Experiments were conducted in order to determine the most desirable counting time. Analysis using the maximum of the measured values while the source passed through the needle indicated that the results for the moving source increased more than those for the static source as the counting time decreased. The combined standard uncertainty, with the coverage factor of 1, was within 4% at the counting time of 100 ms. This investigation supported the feasibility of the method proposed for estimating the source strength during the implantation procedure, regardless of the source speed. The method proposed is a potential option for reducing the risk of accidental replacements of sources with those of incorrect strengths.

This study investigated the maximum tolerated dose (MTD) of S-1 with concurrent radiotherapy in patients with head and neck cancer, based on the frequency of dose-limiting toxicities (DLT). S-1 was administered orally at escalating doses from 40 mg/m(2) b.i.d. on the days of delivering radiotherapy, which was given at a total dose of 64-70 Gy in 32-35 fractions over 6-7 weeks. A total of 12 patients (3 patients at 40 mg/m(2), 6 patients at 60 mg/m(2), and 3 patients at 80 mg/m(2)) were enrolled in this trial. At the dose of 80 mg/m(2), two of the three patients developed DLT (Grade 3 anorexia and rhabdomyolysis) due to S-1, so the MTD was determined to be 80 mg/m(2). Among the 12 enrolled patients, 9 (75%) showed a complete response and 3 (25%) showed a partial response. The overall response rate was 100%. The recommended dose of S-1 with concurrent radiotherapy is 60 mg/m(2).

Background and purpose 5-Chloro-2,4-dihydroxypyridine (Gimeracil) is a component of an oral fluoropyrimidine derivative S-1. Gimeracil is originally added to S-1 to yield prolonged 5-FU concentrations in tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We found that Gimeracil by itself had the radiosensitizing effect. Methods and materials We used various cell lines deficient in non-homologous end-joining (NHEJ) or homologous recombination (HR) as well as DLD-1 and HeLa in clonogenic assay. γ-H2AX focus formation and SCneo assay was performed to examine the effects of Gimeracil on DNA double strand break (DSB) repair mechanisms. Results Results of γ-H2AX focus assay indicated that Gimeracil inhibited DNA DSB repair. It did not sensitize cells deficient in HR but sensitized those deficient in NHEJ. In SCneo assay, Gimeracil reduced the frequency of neo-positive clones. Additionally, it sensitized the cells in S-phase more than in G0/G1. Conclusions Gimeracil inhibits HR. Because HR plays key roles in the repair of DSBH caused by radiotherapy, Gimeracil may enhance the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways.

Hyperfractionated accelerated radiotherapy without a split (AF) has been performed to improve the local control probability of early glottic carcinomas since 1990 in the authors’ institution. Here, they report their experience treating early glottic cancer patients with AF in a single institution who have a long follow-up period. 131 T1 N0 M0 glottic cancers and 65 T2 N0 M0 glottic cancers were treated with conventional fractionation (CF) from 1984 to 1989 and with AF since 1990. CF consisted of five daily fractions of 2 Gy per week, to a total dose of 64 Gy. AF consisted of 1.72 Gy per fraction, two fractions per day, 5 days a week, to a total dose of 55 or 58.5 Gy. The 5-year local control probability for T1 tumors was 94% with 58.5 Gy and 87% with 55 Gy of AF, whereas it amounted to 80% with CF. For T2 tumors, it was 56% with 58.5 Gy and 68% with 55 Gy of AF, whereas it amounted to 64% with CF. The data of T2 should be evaluated with caution due to the small number of patients. Patients with AF had more severe mucosal reactions but no severe late reactions. AF significantly improved the local control rates for T1 glottic cancer.

Background. The purpose of the present study was to present the treatment outcomes of particle therapy for indeterminate pulmonary nodules (IPNs) diagnosed as stage I non-small cell lung cancer, including a comparative analysis involving pathologically proven lung cancer (PPLC).Material and methods. A total of 54 patients (57 lesions) who underwent particle therapy for IPNs were enrolled in this study. Median patient age was 76 (range 52–87) years. T-classification was: T1a, 30; T1b, 16; and T2a, 11. Particle therapy using protons or carbon ions was delivered at total doses of 52.8–80 Gy equivalent in 4–26 fractions. The PPLC cohort included 111 patients.Results. The median follow-up time was 41 (range 7–90) months. For all IPN patients, the three-year overall survival, progression-free survival, local control and distant progression-free survival rates were 90%, 72%, 94% and 79%, respectively. Grade 2 toxicities were radiation pneumonitis (19%), dermatitis (9%), rib fracture (2%), chest wall pain (2%) and neuropathy (2%). No ≥ grade 3 toxicities were observed. In univariate analysis, the IPN group showed significantly better survival relative to the PPLC group. However, after adjustment for baseline imbalances between these two groups in multivariate analysis, pathological confirmation did not correlate with survival.Conclusions. Particle therapy for IPNs provided favorable outcomes with minimal toxicities, which may be comparable to those for PPLC patients. Further studies are needed to clarify the optimal management of IPN patients.

Background: Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. Many inflammatory cytokines such as tumor necrosis factor (TNF) are produced rapidly in the brain by experimental or clinical injury. Method: To investigate whether genetic polymorphism of TNF was related to alcoholic brain atrophy, we determined restriction fragment-length polymorphisms of the TNF-β genes in 72 male alcoholics. Computed tomography was used to determine the severity of brain atrophy. Results: Digestion with NcoI and MspI after polymerase chain reaction amplification showed that the TNFB 1 allele frequency was significantly higher in patients with brain atrophy than in those without brain atrophy (X 2 = 10.20, p = 0.0034). A multivariate analysis that included age, total alcohol intake, ADH2 genotype, and TNF-β genotype showed that the ADH2 1 /2 1 genotype and TNFB 1 /B 1 genotype are independently associated with alcoholic brain atrophy. These findings suggest that the TNFB 1 allele may be associated with alcoholic brain atrophy.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Victor R. Preedy and Junko Adachi. The presentations were (1) Alcoholic myopathy: Past, present and future, by Timothy J. Peters and Victor R. Preedy; (2) Protein adducts in the type I and II fiber-predominant muscles of the ethanol-fed rat, by Simon Worrall, Seppo Parkkila, and Onni Niemela; (3) Hydroperoxides and changes in alcoholic myopathy, by Junko Adachi, Migiwa Asamo, and Yasuhino Ueno; and (4) A close association between testicular atrophy, muscle atrophy, and the increase in protein catabolism after chronic ethanol administration, by Kunihiko Takeda, Masayoshi Yamauchi, Kazuhiko Sakamoto, Masaru Takagi, Hisato Nakajima, and Gotaro Toda.

This study retrospectively evaluated the efficacy and toxicity of particle therapy using carbon ions or protons for primary sacral chordomas.We evaluated 23 patients with primary sacral chordoma treated with carbon ion therapy (CIT) or proton therapy (PT) between July 2005 and June 2011 at the Hyogo Ion Beam Medical Center, Hyogo, Japan. The median patient age was 72 years. 14 patients were treated with 70.4 Gy equivalents (GyE) in 16 fractions and 9 were treated with 70.4 GyE in 32 fractions. CIT was used for 16 patients, and PT was used for 7 patients.The median follow-up period was 38 months. At 3 years, local control (LC), overall survival (OS) and progression-free survival (PFS) for all patients were 94%, 83% and 68%, respectively. The log-rank test revealed that male sex was significantly related to better PFS (p=0.029). No other factors, including dose fractionation and ion type, were significant for LC, OS or PFS. In nine patients, ≥ Grade 3 acute dermatitis was observed, and ≥ Grade 3 late toxicities were observed in nine patients. The 32-fraction protocol reduced severe toxicities in both the acute and late phases compared with the 16-fraction protocol.Particle therapy for patients with sacral chordoma showed favourable LC and OS. Severe toxicities were successfully reduced by modifying the dose fractionation and treatment planning in the later treatment era. Thus, this therapeutic modality should be considered useful and safe.This is the first study including both CIT and PT for sacral chordomas.

Background and purpose This retrospective study aimed to compare the clinical outcomes and late toxicities of proton therapy (PT) with those of carbon ion therapy (CIT) for stage I non-small cell lung cancer (NSCLC). Material and methods A total of 111 patients who underwent particle therapy for stage I NSCLC between April 2003 and December 2009 were enrolled in this study. PT ( n= 70) and CIT ( n= 41) were delivered to total doses of 52.8–80GyE in 4–26 fractions and 52.8–70.2GyE in 4–26 fractions, respectively. The median follow-up time was 41months. Results Differences in outcome between the PT and CIT groups regarding 3-year overall survival (72% and 76%, respectively), progression-free survival (44% and 53%, respectively), and local control (81% and 78%, respectively) were not statistically significant. In multivariate analysis, the type of treatment beam did not correlate with overall survival. The severity of late toxicities was comparable between the two groups. Conclusions Clinical results in the PT group were comparable to those in the CIT group. However, this study was a retrospective analysis of a highly heterogeneous population. Consequently, more homogeneous prospective data, large multicentric databases and, ideally, randomized trials are warranted.

The aim of this study was to develop a dose calculation method which is applicable to the interseed attenuation and the geometry lacking the equilibrium radiation scatter conditions in brachytherapy.The dose obtained from measurement with a radiophotoluminescent glass rod dosimeter (GRD) was compared to the dose calculated with the Monte Carlo (MC) code "EGS5," using the 125I source structure detailed in by Kennedy et al. The GRDs were irradiated with 125I Oncoseed 6711 in a human head phantom. The phantom was a cylinder made of 2 mm thick PMMA with a diameter of 18 cm and length of 16 cm. Some of the GRD positions were so close to the phantom surface that the backscatter margin was less than 5 cm, insufficient for photons.The EGS5 simulations were found to reproduce the relative dose distributions as measured with the GRDs to within 25% uncertainty in the geometry lacking the equilibrium radiation scatter conditions. The absolute value of the GRD measurement agreed with the American Association of Physicist in Medicine Task Group No 43 Updated Protocol (AAPM-TG43U1) formalism to within 3% of the reference point (r = 1 cm, theta = 90 degrees), where the TG43U1 is especially reliable because of the abundant data accumulation in composing the formalism. The factor to normalize the measured or calculated dose to the TG43U1 estimate at the reference point was evaluated to be 0.97 for the GRD measurement and 1.8 for the MC calculation, which uses the integration of the apparent activity with the time as the amount of disintegration during the irradiation. Also, F(r,theta) and g(r) estimated by this calculation method were consistent with those proposed in the TG43U1.The results of this investigation support the validity of both the MC calculation method and GRD measurement in this study as well as the TG-43U1 formalism. Also, this calculation is applicable to interseed attenuation and the geometry lacking the equilibrium radiation scatter.

Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. siRNA for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair. (Cancer Sci 2011; 102: 1712‐1716)

Altered fractionation schedules are based on two different concepts of radiobiology. One concept is that the radiation repair capability of cells in late responding tissues is higher than that of cells in acute responding tissues which include tumor tissues. Hyperfractionation utilizes this concept. The other concept is that accelerated repopulation of tumor cells occurs in a later period of radiation therapy. In order to overcome repopulation of tumor cells, accelerated hyperfractionation is proposed. These two concepts are independent and some fractionation methods include both concepts. Clinical results of altered fractionation schedules of radiation therapy could be predicted with a biological model (the linear quadratic model theory)for fractionated radiation. When this biological model is applied to tumors in which the tumor cell repopulation during radiotherapy period is negligible, the correction for tumor proliferation is required. Since the calculation of the biological effect dose with this model uses several assumptions, we should consider the biological effect dose as a crude approximation. Especially, in case of concomitant chemotherapy and altered fractionation, it is difficult to predict its results with a simple radiobiology model. The randomized trial is required to examine the significance of chemoradiotherapy using altered fractionation.

Objective: Low-dose-rate (LDR) brachytherapy is an effective treatment for tongue cancer. However, little is known about the biological mechanism underlying this therapy, characterized by delivery of continuous exposures of LDR irradiation. It is reported that lower microvessel density (MVD), lower Ki-67 index or higher expression of endogenous hypoxic markers such as carbonic CA IX and Glut-1 are related to the poor control of tumors treated with external irradiation. To elucidate the biological characteristics of LDR brachytherapy, we analyzed our results in cases of tongue cancer treated with LDR brachytherapy by using immunohistochemical stainings with antibodies against Ki-67 and MVD, Glut-1 and CA IX. Methods: The prognostic value of Ki-67 index, MVD and the expression of CA IX and Glut-1 was assessed in 68 tongue cancers treated with LDR brachytherapy. The specimens were taken from tongue cancers before radiation therapy and immunohistochemical staining was performed. Results: The local recurrence-free survival rates were significantly different between T1þT2 and T3 (P ¼ 0.00067), but not between low and high Ki-67 indexes (P ¼ 0.54), between low and high MVD (P ¼ 0.071), low and high CA IX indexes (P ¼ 0.062) or low and high Glut-1 indexes (P ¼ 0.107). T stage, the size of the tumor was the only significant factor for local control in multivariate analyses (P ¼ 0.0377). Conclusion: LDR could overcome the radioresistence of non-cycling and hypoxic cells; however, we cannot draw firm conclusions due to the limited number of patients.

To examine the relationship between shiftwork experience and quality of sleep after retirement, we carried out a self-reported questionnaire survey on 777 retired workers of a manufacturing company. Questionnaire items included past illness, current health status, dietary habit, alcohol drinking, smoking, regular exercise, sleep, working condition (job, shift work experience, shift work periods and side job), current working status, social activity, educational background, sex, age and number of years since retirement. Present health status (adjusted odds ratio 4.318, 95% CI 2.475-7.534), shift work experience (2.190, 1.211-3.953), present working status (1.913, 1.155-3.167) and dietary habit (1.653, 1.055-2.591) were significantly related to sleep disturbance after retirement by multiple logistic regression analysis. To prevent sleep disturbance after retirement, people should keep a regular lifestyle and good health status, especially ex-shift workers.

Background and purpose This study was conducted to analyze the influence of radiotherapy doses and chemotherapy doses and clinical parameters on in-field disease control in order to assess the optimal radiation doses for treatment of mature T/NK-cell lymphomas according to the newly proposed WHO classification. Patients and methods Subjects consisted of 62 patients with mature T/NK-cell lymphomas treated with radiotherapy at four Japanese institutions between 1983 and 2002. We reevaluated all histopathological specimens of non-Hodgkin's lymphomas (NHL), using the WHO classification. Radiation therapy was usually delivered to the involved field. The majority of patients also received adriamycin-based chemotherapy such as CHOP, modified CHOP, or more intensive chemotherapy. Results There were no significant differences in radiosensitivity among subtypes of mature T/NK-cell lymphomas, at least between extranodal NK/T-cell lymphomas, nasal type and peripheral T-cell lymphomas, unspecified. There was a radiation dose-response in non-bulky mature T/NK-cell lymphomas, indicating that radiation doses of more than 52 Gy may be required to obtain in-field control. However, it was difficult to obtain local control of bulky T-cell lymphomas, even with high doses of irradiation. Conclusions Mature T/NK-cell lymphomas were more radioresistant than B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). The chemotherapy including adriamycin did not improve the in-field control of mature T/NK-cell lymphomas. These results were obtained by using non-randomized data and the significance of these results is limited by bias in data. However, our results suggest that the treatment strategy which is usually used for DLBCL, that is, a combined modality of CHOP and around 40 Gy of radiotherapy, may not be sufficiently effective for mature T/NK-cell lymphomas.

Background We previously reported that levels of multiubiquitin chains, representing ubiquitin-protein conjugates, were significantly higher in sera of patients with alcoholic liver cirrhosis than in normal subjects and patients with other types of alcoholic liver disease. Methods To characterize them, ubiquitin-immunoreactive proteins were purified from sera of healthy human volunteers and patients with alcoholic liver diseases by using affinity chromatography on a Sepharose column containing an immobilized monoclonal antibody recognizing conjugated ubiquitin. Results SDS-PAGE analysis followed by Western blotting revealed that the immunoaffinity-purified proteins mainly contained multiple components with molecular masses greater than 60 kDa, almost all of which were immunostained with the ubiquitin antibody. This size heterogeneity was in agreement with the property of ubiquitin-protein conjugates in all cells examined. These results indicate that the immunoaffinity-purified serum proteins are polyubiquitinated proteins presumably derived from some somatic cells. These ubiquitinated proteins obtained from the alcoholic cirrhosis patients were stained more strongly than those from the normal subjects and patients with other types of alcoholic liver disease, although equal amounts of multiubiquitin chains were analyzed simultaneously. In addition, marked differences were observed in the two-dimensional PAGE pattern of the ubiquitin-protein conjugates purified from the alcoholic cirrhosis patient serum compared with those from the normal human serum: four distinct broad spots (presumably polyubiquitin-protein complexes) were observed only in the former. Conclusions This is the first report on isolation of ubiquitin-protein conjugates from human serum, and it indicates that not only their levels, but also their molecular compositions, were greatly affected by alcoholic cirrhosis.

Serum concentrations of free ubiquitin and multiubiquitin chain as determined by immunoassays were compared between 10 healthy subjects, and 11 patients with alcoholic hepatic fibrosis, 10 with alcoholic cirrhosis, and 6 with viral liver cirrhosis. All measurements of multiubiquitin chains were expressed in terms of a standard multiubiquitin chain reference preparation 1. Serum concentrations (mean +/- SD) of free ubiquitin and multiubiquitin chains were significantly higher in patients with alcoholic cirrhosis (63.5 +/- 33.7 ng/ml and 7.5 +/- 4.6 ng/ml) than in the normal subjects (29.6 +/- 6.6 ng/ml, p < 0.05 and 4.1 +/- 1.7 ng/ml, p < 0.05), and those with alcoholic hepatic fibrosis (34.8 +/- 16.3 ng/ml, p < 0.05 and 3.0 +/- 0.7 ng/ml, p < 0.05) and viral liver cirrhosis (28.8 +/- 7.5 ng/ml, p < 0.05 and 4.2 +/- 1.3 ng/ml, p < 0.05). Serum levels of both forms of ubiquitin in six patients with alcoholic cirrhosis showed a tendency to decline after 3 months of abstinence. In a total of 14 patients with alcoholic liver damage, 11 with brain atrophy had significantly higher serum levels of both ubiquitin forms than did three patients without brain atrophy (p < 0.05). No correlation was seen between serum concentrations of either form of ubiquitin and liver function test results in the patients with alcoholic liver damage. However, serum levels of both forms of ubiquitin levels correlated significantly with cumulative alcohol intake (p < 0.05). A significant correlation (p < 0.05) also was observed between serum levels of multiubiquitin chains and mean corpuscular volume, a marker of alcohol consumption. These results suggest that the serum concentrations of ubiquitin, especially multiubiquitin chain is a good marker for the diagnosis of alcoholic cirrhosis.

In order to clarify the risk factors for stroke from an epidemiological viewpoint, 314 men (aged 50-79) in the fishing village of Ushibuka were evaluated over an 8-year period (1970-1978) by means of multivariate analysis. At the systematic re-examination in 1970, the following 11 variables were determined: age, systolic blood pressure, electrocardiographic (ECG) abnormalities, serum cholesterol, serum triglyceride, serum alpha-lipoprotein fraction, serum albumin, serum uric acid, drinking habits, smoking habits and body mass index. Thirty men experienced stroke during the 8-year period. The mean value of age, systolic blood pressure and serum uric acid were significantly higher in men who experienced stroke, while serum cholesterol, triglyceride, alpha-lipoprotein fraction and albumin were not seen as statistically significant. The high level of serum uric acid correlated with the high incidence of stroke. According to stepwise discriminant analysis of the 11 variables. ECG abnormalities, systolic blood pressure and serum uric acid discriminated 73.9% of the men who experienced stroke. In conclusion, a high serum uric acid concentration is noted to be an important risk factor for stroke in the fishing village of Ushibuka where high intake of fish protein is common.