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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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the efficacy and safety of proton beam therapy for patients with locally recurrent parotid cancer. Between 2009 and 2012, ten patients with locally recurrent parotid gland cancer were treated with proton beam therapy (70.2 Gy equivalents in 32 fractions) with or without intra-arterial infusion chemotherapy of cisplatin (50 mg/body/week, for a total of 5-8 weeks). The median follow-up was 24 months (range 10-49 months). The 1-year overall survival and local control rates were 80 %, and the 3-year overall survival and local control rates were 60 %. None of the patients experienced grade 3-5 toxicities in the treatment or the follow-up periods. These findings suggest that proton beam therapy could be applied effectively and safely for patients with locally recurrent parotid gland cancer., Competing Interests: Conflict of interestAll authors have no conflicts of interest to declare., (© Association of Otolaryngologists of India 2016.)

Aim: The purpose of this study was to clarify the efficacy and toxicities of re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy for recurrent oral cancer., Methods: Between October 2009 and July 2014, 34 patients who had recurrent oral cancer were treated by proton beam therapy combined with intra-arterial infusion chemotherapy at the Southern Tohoku Proton Therapy Center, Japan., Results: For all patients, the median follow-up was 25 months (range, 3-77 months). After treatment, 22 patients (65%) achieved a complete response, and 12 patients (35%) achieved a partial response at the primary tumor site. One-year and 2-year overall survival (OS) rates were 62% and 42%, respectively. One-year and 2-year LC rates were 77% and 60%, respectively. No treatment-related deaths were observed during the treatment and follow-up periods., Conclusion: Re-irradiation using proton beam therapy combined with weekly intra-arterial chemotherapy improved OS and local control rates compared with other treatment modalities and could become a new treatment modality for patients with recurrent oral cancer., (© 2016 John Wiley & Sons Australia, Ltd.)

Background: The efficacy, toxicity, and prognostic factors of high-dose proton beam therapy (PBT) for peripheral stage I non-small-cell lung cancer were assessed in this retrospective study., Materials and Methods: Fifty patients with peripheral stage I non-small-cell lung cancer, two of whom had heterochronic multiple lung cancers, underwent high-dose PBT between January 2009 and September 2014. The relative biological effectiveness of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned for the 90% isodose volume of the prescribed dosage to encompass the planning target volume. The cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events, version 4., Results: The study included 35 males and 15 females with a median age of 72.5 years. The median follow-up period was 22.8 months. The clinical stage was IA in 44 (85%) and IB in eight (15%) tumors. The total dose of PBT was 66 GyE in 10 fractions in all tumors. Three-year overall survival rate among all patients was 87.9% (95% confidence interval [CI], 94.8%-73.2%). Forty-five patients were alive, and 5 were dead. Three-year local control and progression-free survival rates were 95.7% (95% CI, 98.9%-83.8%) and 76.3% (95% CI, 86.9%-59.3%), respectively. Only one patient experienced Grade 2 pneumonitis., Conclusion: High-dose PBT may be an effective and safe treatment option for patients with stage I non-small-cell lung cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to evaluate the efficacy and toxicities of proton beam therapy combined with intra-arterial infusion chemotherapy via superficial temporal and occipital arteries for recurrent oral cavity squamous cell carcinoma (SCC)., Methods: Between October 2009 and June 2013, 46 patients with recurrent oral cavity SCC were treated by proton beam therapy combined with intra-arterial infusion chemotherapy of cisplatin (CDDP) and docetaxel. Treatment consisted of proton beam therapy (28.6-74.8 GyE in 13-34 fractions) and intra-arterial infusion chemotherapy (CDDP, 30-50 mg/body/week; docetaxel, 5-25 mg/body/week)., Results: One-year and 2-year overall survival (OS) rates were 65% and 46%, respectively. One-year and 2-year local control rates were 81% and 70%, respectively., Conclusion: These findings suggest that proton beam therapy combined with intra-arterial infusion chemotherapy could be applied effectively and safely for patients with recurrent oral cavity SCC. © 2016 Wiley Periodicals, Inc. Head Neck 38:1145-1151, 2016., (© 2016 Wiley Periodicals, Inc.)

Background: The purpose of this study is to retrospectively evaluate the incidence of lung toxicities after proton beam therapy (PBT) in patients with idiopathic pulmonary fibrosis (IPF)., Methods: Patients diagnosed with primary lung cancer or lung metastasis who were treated with PBT between January 2009 and May 2015 were recruited from our database retrospectively. Cases of pneumonitis (excluding infection-related pneumonitis) were evaluated using the Common Terminology Criteria for Adverse Events version 4.0, and the Fletcher-Hugh-Jones classification of respiratory status was used to evaluate pretreatment and posttreatment respiratory function., Results: Sixteen IPF patients received PBT for lung tumors, 15 received PBT for primary lung cancer, and one patient received PBT for metastasis from lung cancer. The cohort was composed of 14 men and 2 women, with a median age of 76 years (range: 63-89 years). The median follow-up time was 12 months (range: 4-39 months). The median dose of PBT was 80.0 Gy relative biological dose effectiveness (RBE) (range: 66.0-86.4 Gy [RBE]). The cumulative incidence of pneumonitis was 19.8 % (95 % confidence interval [CI]: 0-40.0 %), including one case of grade 5 pneumonitis. Reduced respiratory function was observed after PBT in seven patients, including one patient with pleural dissemination; five of these patients required home oxygen therapy., Conclusions: This study suggests that PBT can be performed more safely in IPF patients than surgery or X-ray irradiation. Although PBT has become a treatment choice for lung tumors of patients with IPF, the adverse events warrant serious attention.

Proton beam therapy (PBT) is the preferred modality for early-stage lung cancer. Compared with X-ray therapy, PBT offers good dose concentration as revealed by the characteristics of the Bragg peak. Rib fractures (RFs) after PBT lead to decreased quality of life for patients. However, the incidence of and the risk factors for RFs after PBT have not yet been clarified. We therefore explored the relationship between irradiated rib volume and RFs after PBT for early-stage lung cancer. The purpose of this study was to investigate the incidence and the risk factors for RFs following PBT for early-stage lung cancer. We investigated 52 early-stage lung cancer patients and analyzed a total of 215 irradiated ribs after PBT. Grade 2 RFs occurred in 12 patients (20 ribs); these RFs were symptomatic without displacement. No patient experienced more severe RFs. The median time to grade 2 RFs development was 17 months (range: 9-29 months). The three-year incidence of grade 2 RFs was 30.2%. According to the analysis comparing radiation dose and rib volume using receiver operating characteristic curves, we demonstrated that the volume of ribs receiving more than 120 Gy3 (relative biological effectiveness (RBE)) was more than 3.7 cm(3) at an area under the curve of 0.81, which increased the incidence of RFs after PBT (P < 0.001). In this study, RFs were frequently observed following PBT for early-stage lung cancer. We demonstrated that the volume of ribs receiving more than 120 Gy3 (RBE) was the most significant parameter for predicting RFs.

Purpose: Proton beam therapy (PBT), compared with conventional radiotherapy, can deliver high-dose radiation to a tumor, while minimizing doses delivered to surrounding normal tissues. The better dose distribution of PBT may contribute to the improvement in local control rate and reduction in late adverse events. We evaluated therapeutic results and toxicities of PBT combined with selective intra-arterial infusion chemotherapy (PBT-IACT) in patients with stage III-IVB squamous cell carcinoma of the tongue., Materials and Methods: After 2 systemic chemotherapy courses and whole-neck irradiation (36 Gy in 20 fractions), we administered concurrent chemoradiotherapy comprising PBT for the primary tumor [28.6-33 Gy(RBE) in 13-15 fractions] and for the metastatic neck lymph node [33-39.6 Gy(RBE) in 15-18 fractions] with weekly retrograde intra-arterial chemotherapy by continuous infusion of cisplatin with sodium thiosulfate., Results: Between February 2009 and September 2012, 33 patients were enrolled. The median follow-up duration was 43 months. The 3-year overall survival, progression-free survival, local control rate, and regional control rate for the neck were 87.0, 74.1, 86.6, and 83.9 %, respectively. Major acute toxicities >grade 3 included mucositis in 26 cases (79 %), neutropenia in 17 cases (51 %), and dermatitis in 11 cases (33 %). Late grade 2 osteoradionecrosis was observed in 1 case (3 %)., Conclusions: PBT-IACT for stage III-IVB tongue cancer has an acceptable toxicity profile and showed good treatment results. This protocol should be considered as a treatment option for locally advanced tongue cancer.

The effect of proton beam therapy (PBT) on various cancers is controversial. We aimed to evaluate the efficacy and safety of PBT with alternating chemoradiotherapy (ACRT) for patients with stage I-III esophageal cancer. Two cycles of systemic chemotherapy with a continuous infusion of 5-fluorouracil (5-FU) on days 1-5 and a 5h infusion of nedaplatin (NDP) on day 6 were accompanied by thoracic irradiation using X-ray therapy and PBT. During the first half of the treatment, X-rays were delivered to the prophylactic area. During the second half of the treatment, proton beams were used to irradiate the involved field. To reduce the dose of cardiac irradiation, proton beams were delivered with posterior and posterior oblique angles. Between January 2009 and December 2012, 47 patients were enrolled in this study. The median follow-up duration was 29 months for all patients and 40 months for survivors. The 3 year overall survival rate, progression-free survival rate, and local control rate were 59.2%, 56.3%, and 69.8%, respectively. With respect to grade 3-4 late toxicities, there were no pleural or pericardial effusions, but two patients (4.3%) had esophageal stenosis, one patient (2.1%) had fistula, and two patients (4.3%) developed radiation pneumonitis. PBT with ACRT might have the potential to reduce the risk of cardiac damage and might become one of the primary methods of esophageal cancer treatment., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: This study aimed to evaluate the efficacy and toxicity of proton beam therapy combined with cisplatin intra-arterial infusion via a superficial temporal artery as treatment for maxillary sinus carcinoma., Methods: Twenty-six patients with confirmed maxillary sinus carcinoma were enrolled in this study from May 2009 to April 2011. Patients underwent proton beam therapy and intra-arterial infusion chemotherapy with cisplatin., Results: The median total dose was 70.4 GyE per 32 fractions, and the median dose of cisplatin was 300 mg/body for six cycles of intra-arterial infusion. The 3-year overall survival rate was 58% for all patients (n = 26), 58% for patients with stage T4 disease (n = 12), 57% for patients with

Purpose: To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC)., Methods and Materials: Eligibility criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients., Results: Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6%-68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed., Conclusions: Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In an aging society, increasing number of older patients are diagnosed with esophageal cancer. The purpose of this study was to assess the clinical efficacy and safety of proton beam therapy for older patients with esophageal cancer., Patients and Methods: Older patients (age: ≥ 65 years) newly diagnosed with esophageal cancer between January 2009 and June 2013 were enrolled in this study. All patients underwent either proton beam therapy alone or proton beam therapy with initial X-ray irradiation. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0., Results: Twenty patients were eligible for this study and all completed the treatment. The median age was 78 years (range: 65-89 years) and the median follow-up time was 26.5 months (range: 6-62 months). Seven patients had lymph node metastases and 10 had stage II/III cancer. The median dose of proton beam therapy was 72.6 Gy relative biological dose effectiveness (RBE) (range: 66-74.8 Gy [RBE]) for proton beam therapy alone and 33 Gy (RBE) (range: 30.8-39.6 Gy [RBE]; total dose range: 66.8-75.6 Gy [RBE]) for proton beam therapy with initial X-ray irradiation. The 2-year overall survival rate was 81.8% (95% confidence interval [CI]: 62.4%-100%), and the 2-year local control rate was 89.4% (95% CI: 75.5%-100%). Grade 2 or 3 toxicities occurred in some cases; however, no grade 4 or 5 toxicity was observed., Conclusions: High-dose (66-75.6 Gy [RBE]) proton beam therapy without chemotherapy was an efficacious and safe treatment for older patients with esophageal cancer.

Background: We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer., Methods: Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events., Results: Median age of the patients was 72 years (range: 57-91 years), and median follow-up was 15.4 months (range: 7.8-36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66-86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1-year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1-year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis., Conclusions: For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option.

Purpose: Accurate analysis of the correlation between deformation of the prostate and displacement of its center of gravity (CoG) is important for efficient radiation therapy for prostate cancer. In this study, we addressed this problem by introducing a new analysis approach., Method: A planning computed tomography (CT) scan and 7 repeat cone-beam CT scans during the course of treatment were obtained for 19 prostate cancer patients who underwent three-dimensional conformal radiation therapy. A single observer contoured the prostate gland only. To evaluate the local deformation of the prostate, it was divided into 12 manually defined segments. Prostate deformation was calculated using in-house developed software. The correlation between the displacement of the CoG and the local deformation of the prostate was evaluated using multiple regression analysis., Results: The mean value and standard deviation (SD) of the prostate deformation were 0.6 mm and 1.7 mm, respectively. For the majority of the patients, the local SD of the deformation was slightly lager in the superior and inferior segments. Multiple regression analysis revealed that the anterior-posterior displacement of the CoG of the prostate had a highly significant correlation with the deformations in the middle-anterior (p < 0.01) and middle-posterior (p < 0.01) segments of the prostate surface (R2 = 0.84). However, there was no significant correlation between the displacement of the CoG and the deformation of the prostate surface in other segments., Conclusion: Anterior-posterior displacement of the CoG of the prostate is highly correlated with deformation in its middle-anterior and posterior segments. In the radiation therapy for prostate cancer, it is necessary to optimize the internal margin for every position of the prostate measured using image-guided radiation therapy.

Background: Evidence has suggested that radiation therapy with a lower dose per fraction may be a reasonable option for the treatment of centrally located non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of two proton beam therapy (PBT) protocols for stage I NSCLC and to determine prognostic factors., Material and Methods: This study included patients clinically diagnosed with stage I NSCLC. Based on the location of the tumor, one of the two PBT protocols was administered. Patients with peripherally located tumors were given 66 Gy relative biological dose effectiveness (RBE) over 10 fractions (Protocol A) while patients with centrally located tumors were given 80 Gy (RBE) over 25 fractions (Protocol B)., Results: Between January 2009 and May 2012, 56 eligible patients were enrolled (protocol A: 32 patients; protocol B: 24 patients). The three-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 81.3% [95% confidence interval (CI) 75.9-86.7%], 73.4% (95% CI 67.2-79.6%), and 96.0% (95% CI 93.2-98.8%), respectively. There were no significant differences in outcomes between the two protocols. Late grade 2 and 3 pulmonary toxicities were observed in nine patients (13.4%) and one patient (1.5%), respectively; no grade 4 or 5 toxicities were observed. Sex, age, performance status, T-stage, operability, and tumor pathology were not associated with OS and PFS. Only maximum standardized uptake value (SUVmax; <5 vs. ≥5) was identified as a significant prognostic factor for OS and PFS., Conclusion: Both high-dose PBT protocols achieved high LC rates with tolerable toxicities in stage I NSCLC patients, and SUVmax was a significant prognostic factor.

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., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

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 Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

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.

Background: We examined the efficacy and toxicity of proton beam therapy (PBT) for treating advanced cholangiocarcinoma., Methods: The clinical data and outcomes of 28 cholangiocarcinoma patients treated with PBT between January 2009 and August 2011 were retrospectively examined. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and local control (LC) rates, and the log-rank test to analyze the effects of different clinical and treatment variables on survival. Acute and late toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0., Results: The median age of the 17 male and 11 female patients was 71 years (range, 41 to 84 years; intrahepatic/peripheral cholangiocarcinoma, n = 6; hilar cholangiocarcinoma/Klatskin tumor, n = 6; distal extrahepatic cholangiocarcinoma, n = 3; gallbladder cancer, n = 3; local or lymph node recurrence, n = 10; size, 20-175 mm; median 52 mm). The median radiation dose was 68.2 Gy (relative biological effectiveness [RBE]) (range, 50.6 to 80 Gy (RBE)), with delivery of fractions of 2.0 to 3.2 Gy (RBE) daily. The median follow-up duration was 12 months (range, 3 to 29 months). Fifteen patients underwent chemotherapy and 8 patients, palliative biliary stent placement prior to PBT. OS, PFS, and LC rates at 1 year were 49.0%, 29.5%, and 67.7%, respectively. LC was achieved in 6 patients, and was better in patients administered a biologically equivalent dose of 10 (BED10) > 70 Gy compared to those administered < 70 Gy (83.1% vs. 22.2%, respectively, at 1 year). The variables of tumor size and performance status were associated with survival. Late gastrointestinal toxicities grade 2 or greater were observed in 7 patients <12 months after PBT. Cholangitis was observed in 11 patients and 3 patients required stent replacement., Conclusions: Relatively high LC rates after PBT for advanced cholangiocarcinoma can be achieved by delivery of a BED10 > 70 Gy. Gastrointestinal toxicities, especially those of the duodenum, are dose-limiting toxicities associated with PBT, and early metastatic progression remains a treatment obstacle.

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).

DNA double-strand break (DSB) is one of the most serious forms of damage induced by ionizing irradiation. Non-homologous end-joining (NHEJ) is a key mechanism of DNA DSB repair. The immunohistochemical analysis of proteins involved in NHEJ may have potential as a predictive assay for tumor radiosensitivity. We examined the correlation between the expression of proteins involved in DNA DSB in biopsy specimens and the results of chemoradiotherapy in hypopharyngeal cancers. Fifty-seven patients with previously untreated squamous cell carcinoma of the hypopharynx were treated between March 2002 and December 2009. Most patients (75%) had stage III or IV disease. The chemotherapy consisted of cisplatin plus 5FU or S-1. A tumor dose of 50 Gy was usually administered to the primary tumor and regional lymph nodes. Doses of 10-20 Gy were usually added to the primary tumor with reduced fields after 50 Gy. The 5-year disease-free survival rate was 100% for patients in stage I, 90% in stage II, 64% in stage III and 50% in stage IV. In stages I-III, patients with a lower expression of Ku70 or XRCC4 tended to have better locoregional control. These results indicated that a lower expression of Ku70 or XRCC4 may be correlated with higher radiosensitivity. Two patients had distant metastasis alone, of which one had 0% expression of Ku70 and the other had 0% expression of Ku86. The absence of Ku70 or Ku86 expression indicates low DNA-PK activity. Low DNA-PK activity due to a low expression of Ku may result in the genetic alteration of cancer cells, leading to a higher tendency of distant metastasis. This finding suggests that proteins involved in NHEJ may have an impact on the treatment results of chemoradiotherapy in hypopharyngeal cancer.

We investigated the uncertainty in patient set-up margin analysis with a small dataset consisting of a limited number of clinical cases over a short time period, and propose a method for determining the optimum set-up margin. Patient set-up errors from 555 registration images of 15 patients with prostate cancer were tested for normality using a quantile-quantile (Q-Q) plot and a Kolmogorov-Smirnov test with the hypothesis that the data were not normally distributed. The ranges of set-up errors include the set-up errors within the 95% interval of the entire patient data histogram, and their equivalent normal distributions were compared. The patient set-up error was not normally distributed. When the patient set-up error distribution was assumed to have a normal distribution, an underestimate of the actual set-up error occurred in some patients but an overestimate occurred in others. When using a limited dataset for patient set-up errors, which consists of only a small number of the cases over a short period of time in a clinical practice, the 2.5% and 97.5% intervals of the actual patient data histogram from the percentile method should be used for estimating the set-up margin. Since set-up error data is usually not normally distributed, these intervals should provide a more accurate estimate of set-up margin. In this way, the uncertainty in patient set-up margin analysis in radiation therapy can be reduced.

Objective: To evaluate for how long patients should be isolated after I-131 treatment for thyroid cancer according to the guidelines issued by the Japanese Ministry of Welfare., Methods: We reviewed 92 therapies performed in 76 patients who were administered I-131 at our hospital from July 2007 to September 2009. Fifty-six patients were given 2220 or 2960 MBq I-131 at the first therapy, and 29 patients underwent 36 repeated therapies using 2960, 3700, 5550 or 7400 MBq I-131. We surveyed radioactivity for a 1 cm dose equivalent rate at 1 m intervals at 30 and 48 h after administration of I-131, obtained planar scintigrams at 48 h, and surveyed radioactivity repeatedly until it fell to under 30 μSv/h., Results: The radioactivity was under 30 μSv/h at 30 h in 51 out of 92 cases (55%). Among the remaining 41 (45%) cases, 27 (29%) and 32 (35%) cases showed decreased radioactivity under 30 μSv/h at 48 and 72 h, respectively, and it remained higher than 30 μSv/h at 72 h in another 9 cases (10%). In 5 (38%) of the 13 cases with bone metastasis, the radioactivity remained over 30 μSv/h after 72 h, and scintigrams showed strong accumulation in bone metastases. Among the 27 cases demonstrating below 30 μSv/h at 48 h, 26 showed radioactivity being below 50 μSv/h at 30 h, while it was above 50 μSv/h at 30 h in all 14 cases which demonstrated above 30 μSv/h at 48 h. We compared the radioactivity levels of 27 cases under 30 μSv/h at 48 h and 14 cases over 30 μSv/h at 48 h using a cutoff value of under 50 μSv/h at 30 h to release patient at 48 h, the positive predictive value and negative predictive value were 100 and 93%, respectively, and radioactivity was found to differ significantly (P < 0.001)., Conclusions: To predict external radiation levels at 48 h, it is helpful to consider external radiation levels at 30 h after treatment. Consideration of intracellular uptake in thyroid cancer, especially in cases of bone metastases, digestive tract function, and renal function, is important for predicting isolated period.

Background: Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent., Methods: DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT., Results: A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings., Conclusion: Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization.

Although heat stress induces a variety of illnesses, there have been few studies designed to uncover the molecular mechanisms underlining the illnesses. We here demonstrate that heat activates ER stress, which inhibits heat shock responses (HSR) via translational block. In heat-stressed rats, ER stress responses, as represented by eIF2α phosphorylation and XBP1 splicing, occurred mainly in the cortex, where the HSR was substantially inhibited. Heat exposure also activated ER stress signals in primary cortical neurons. Since HSF1 knockdown enhanced heat-induced ER stress and subsequent cell death, HSR inhibition in turn augments ER stress, implying a vicious spiral of both stresses. Taken together, heat-induced ER stress impairs the HSR and enhances cell damage, thereby manifesting its unique effect on heat stress.

We aimed to optimize internal margin (IM) determination for respiratory-gated radiotherapy using end-expiratory phase assessments using a motion phantom. Four-dimensional computed tomography (4D CT) data were acquired using a GE LightSpeed RT CT scanner, a respiratory-gating system, and a motion phantom designed to move sinusoidally. To analyze the accuracy of 4D CT temporal resolution, a 25.4 mm diameter sphere was inserted into the motion phantom, and we measured the differences in sphere diameters between static and end-exhalation phase images. In addition, the IM obtained from the maximum intensity projection within the gating window (MIP(GW)) image was compared to theoretical value. Cranial-caudal motion displacement ranged from 5.0 to 30.0 mm, and the respiratory period ranged from 2.0 to 6.0 sec. Differences in sphere diameters between static and end-exhalation phase images ranged from 0.37 to 4.6 mm, with 5.0-mm and 30 mm target displacements, respectively. Differences between the IM obtained from the MIP(GW) and the theoretical values ranged from 1.12 to 6.23 mm with 5.0mm and 30 mm target displacements, respectively. These differences increased in proportion to the target velocity due to a motion artifact generated during tube rotation. In this study, the IMs obtained using the MIPGW image were overestimated in all cases. We therefore propose that the internal target volume (ITV) for respiratory-gated radiotherapy should be determined by adding the calculated value to the end-exhalation phase image. We also demonstrate a methodology for subtracting motion artifacts from the ITV using a motion phantom.

Purpose: 5-chloro-2,4-dihydroxypyridine (gimeracil) is a component of the oral fluoropyrimidine derivative S-1. Gimeracil was originally added to S-1 to yield prolonged 5-fluorouracil (5-FU) concentrations in serum and tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We previously demonstrated that gimeracil enhances the efficacy of radiotherapy through the suppression of homologous recombination (HR) in DNA double strand repair. The goal of this paper was to examine the effects of gimeracil on the sensitivity of anticancer drugs and hyperthermia in order to obtain effective radiosensitization., Materials and Methods: Various cell lines, including DLD 1 (human colon carcinoma cells) and cells deficient in HR or nonhomologous end-joining (NHEJ), were used in clonogenic assays. The survival of these cells after various treatments (e.g., drug treatment, heat treatment, and radiation) was determined based on their colony-forming ability., Results: Gimeracil enhanced cell-killing effects of camptothecin (CPT), 5-FU, and hydroxyurea. Gimeracil sensitized effects of CPT or 5-FU to cells deficient in HR or NHEJ to a similar extent as in other cells (DLD1 and a parent cell), indicating that its sensitizing mechanisms may be different from inhibition of HR or NHEJ. Combination of gimeracil and CPT or 5-FU sensitized radiation more effectively than each modality alone. Gimeracil also enhanced heat sensitivity at 42°C or more. The degree of heat sensitization with gimeracil increased as the temperature increased, and the combination of gimeracil and heat-sensitized radiation was more effective than each modality alone., Conclusion: Gimeracil enhanced sensitivity of CPT, 5-FU, and hyperthermia. Combination of these modalities sensitized radiation more efficiently than each modality alone.

The post-exposure density growth (PEDG) is one of the characteristics of radiochromic film (RCF). In film dosimetry using RCF and a flatbed scanner, pixel values read out from the RCF are converted to dose (hereafter, film dose) by using a calibration curve. The aim of this study is to analyze the relationship between the pixel value read out from the RCF and the PEDG, and that between the film dose converted from the RCF and the PEDG. The film (GAFCHROMIC EBT) was irradiated with 10-MV X-rays in an ascending 11-dose-step arrangement. The pixel values of the irradiated EBT film were measured at arbitrary hours using an Epson flatbed scanner. In this study, the reference time was 24 h after irradiation, and all dose conversions from the pixel values read out from the EBT film were made using a calibration curve for 24 h after irradiation. For delivered doses of 33 and 348 cGy, the measured pixel values at 0.1 and 16 h after irradiation represented ranges of -9.6% to -0.7% and -3.9% to -0.3%, respectively, of the reference value. The relative changes between the pixel values read out from the EBT film at each elapsed time and that at the reference time decreased with increasing delivered dose. However, the difference range for all the film doses had a width of approximately -10% of the reference value at elapsed times from 0.1 to 16 h, and it showed no dependence on the delivered dose.

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase (DPYD), partially inhibits homologous recombination (HR) repair and has a radiosensitizing effect as well as enhanced sensitivity to Camptothecin (CPT). DPYD is the target protein for radiosensitization by Gimeracil. We investigated the mechanisms of sensitization of radiation and CPT by DPYD inhibition using DLD-1 cells treated with siRNA for DPYD. We investigated the focus formation of various kinds of proteins involved in HR and examined the phosphorylation of RPA by irradiation using Western blot analysis. DPYD depletion by siRNA significantly restrained the formation of radiation-induced foci of Rad51 and RPA, whereas it increased the number of foci of NBS1. The numbers of colocalization of NBS1 and RPA foci in DPYD-depleted cells after radiation were significantly smaller than in the control cells. These results suggest that DPYD depletion is attributable to decreased single-stranded DNA generated by the Mre11/Rad50/NBS1 complex-dependent resection of DNA double-strand break ends. The phosphorylation of RPA by irradiation was partially suppressed in DPYD-depleted cells, suggesting that DPYD depletion may partially inhibit DNA repair with HR by suppressing phosphorylation of RPA. DPYD depletion showed a radiosensitizing effect as well as enhanced sensitivity to CPT. The radiosensitizing effect of DPYD depletion plus CPT was the additive effect of DPYD depletion and CPT. DPYD depletion did not have a cell-killing effect, suggesting that DPYD depletion may not be so toxic. Considering these results, the combination of CPT and drugs that inhibit DPYD may prove useful for radiotherapy as a method of radiosensitization.

Purpose: To evaluate the actual work environment of radiation oncologists (ROs) in Japan in terms of working pattern, patient load, and quality of cancer care based on the relative time spent on patient care., Methods and Materials: In 2008, the Japanese Society of Therapeutic Radiology and Oncology produced a questionnaire for a national structure survey of radiation oncology in 2007. Data for full-time ROs were crosschecked with data for part-time ROs by using their identification data. Data of 954 ROs were analyzed. The relative practice index for patients was calculated as the relative value of care time per patient on the basis of Japanese Blue Book guidelines (200 patients per RO)., Results: The working patterns of RO varied widely among facility categories. ROs working mainly at university hospitals treated 189.2 patients per year on average, with those working in university hospitals and their affiliated facilities treating 249.1 and those working in university hospitals only treating 144.0 patients per year on average. The corresponding data were 256.6 for cancer centers and 176.6 for other facilities. Geographically, the mean annual number of patients per RO per quarter was significantly associated with population size, varying from 143.1 to 203.4 (p < 0.0001). There were also significant differences in the average practice index for patients by ROs working mainly in university hospitals between those in main and affiliated facilities (1.07 vs 0.71: p < 0.0001)., Conclusions: ROs working in university hospitals and their affiliated facilities treated more patients than the other ROs. In terms of patient care time only, the quality of cancer care in affiliated facilities might be worse than that in university hospitals. Under the current national medical system, working patterns of ROs of academic facilities in Japan appear to be problematic for fostering true specialization of radiation oncologists., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (© 2011 Japanese Cancer Association.)

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: Repair of various types of DNA damages is critical for genomic stability. DNA-dependent protein kinase (DNA-PK) has an important role in DNA double-strand break repair. We examined whether there may be a correlation between DNA-PK activity in peripheral blood lymphocytes (PBLs) and survival percentages in various cancer patients. We also investigated the changes of DNA-PK activity in PBLs after radiotherapy., Methods: A total of 167 of untreated cancer patients participated in this study. Peripheral blood was collected, separated, and centrifuged. DNA-PK activity was measured by DNA-pull-down assay. Chromosomal aberrations were examined by cytogenetic methods., Results: DNA-PK activity of PBLs in advanced cancer patients was significantly lower than that in early stage. The patients with lower DNA-PK activity in PBLs tended to have the lower disease-specific survivals and distant metastasis-free survivals than those with higher DNA-PK activity in advanced stages. There was also a tendency of inverse correlation between DNA-PK activity and excess fragments. The DNA-PK activity of PBLs in most patients decreased in response to radiation as the equivalent whole-body dose increased., Conclusion: Cancer patients in advanced stage, with lower DNA-PK activity of PBLs might have higher distant metastasis and exhibit poorer prognosis. Therefore, DNA-PK activity in PBLs could be used as a marker to predict the chromosomal instability and poorer prognosis.

Background and Purpose: The structure of radiation oncology in designated cancer care hospitals in Japan was investigated in terms of equipment, personnel, patient load, and geographic distribution. The effect of changes in the health care policy in Japan on radiotherapy structure was also examined., Material and Methods: The Japanese Society of Therapeutic Radiology and Oncology surveyed the national structure of radiation oncology in 2007. The structures of 349 designated cancer care hospitals and 372 other radiotherapy facilities were compared., Results: Respective findings for equipment and personnel at designated cancer care hospitals and other facilities included the following: linear accelerators/facility: 1.3 and 1.0; annual patients/linear accelerator: 296.5 and 175.0; and annual patient load/full-time equivalent radiation oncologist was 237.0 and 273.3, respectively. Geographically, the number of designated cancer care hospitals was associated with population size., Conclusion: The structure of radiation oncology in Japan in terms of equipment, especially for designated cancer care hospitals, was as mature as that in European countries and the United States, even though the medical costs in relation to GDP in Japan are lower. There is still a shortage of manpower. The survey data proved to be important to fully understand the radiation oncology medical care system in Japan.

Gandolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a hepatobiliary contrast agent for MRI. It was reported that Gd-EOB-DTPA is useful to detect liver tumors and differentially diagnose benign and malignant pathologies in the liver. Since Gd-EOB-DTPA partially accumulates in the hepatocytes and bile via various transporters after intravenous injection, signal intensity in the liver increases on T1-weighted images. The signal intensity of the liver after Gd-EOB-DTPA injection depends on the Gd-EOB-DTPA uptake by hepatocytes and bile excretion. It is known tha the Gd-EOB-DTPA accumulating in the kidney is excreted to the urine through glomerular filtration. Because Gd-DTPA is concentrated in the renal tubules after being filtered at the Bowman's capsule, and since it is neither secreted nor reabsorbed the concentrating and diluting function of the renal tubules can be studied by imaging techniques. since renal function can be evaluated with Gd-EOB-DTPA can also be used to evaluate renal function. Eith the development of MRI equipment and rapid imaging techniques, temporal resolution had improved greatly. However, no previous study has been carried out on renal function using Gd-EOB-DTPA dynamic MR study that was correlated with estimated glomerular filtration rate (eGFR) and stage of chronic kidney disease (CKD) in the Japan Association of chronic kidney disease initiative.

Purpose: To evaluate the ongoing structure of radiation oncology in Japan in terms of equipment, personnel, patient load, and geographic distribution to identify and improve any deficiencies., Methods and Materials: A questionnaire-based national structure survey was conducted from March to December 2008 by the Japanese Society of Therapeutic Radiology and Oncology (JASTRO). These data were analyzed in terms of the institutional stratification of the Patterns of Care Study., Results: The total numbers of new cancer patients and total cancer patients (new and repeat) treated with radiation in 2007 were estimated at 181,000 and 218,000, respectively. There were 807 linear accelerator, 15 telecobalt, 46 Gamma Knife, 45 (60)Co remote-controlled after-loading, and 123 (192)Ir remote-controlled after-loading systems in actual use. The linear accelerator systems used dual-energy function in 539 units (66.8%), three-dimensional conformal radiation therapy in 555 (68.8%), and intensity-modulated radiation therapy in 235 (29.1%). There were 477 JASTRO-certified radiation oncologists, 826.3 full-time equivalent (FTE) radiation oncologists, 68.4 FTE medical physicists, and 1,634 FTE radiation therapists. The number of interstitial radiotherapy (RT) administrations for prostate, stereotactic body radiotherapy, and intensity-modulated radiation therapy increased significantly. Patterns of Care Study stratification can clearly identify the maturity of structures based on their academic nature and caseload. Geographically, the more JASTRO-certified physicians there were in a given area, the more RT tended to be used for cancer patients., Conclusions: The Japanese structure has clearly improved during the past 17 years in terms of equipment and its use, although a shortage of personnel and variations in maturity disclosed by Patterns of Care Study stratification were still problematic in 2007., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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. gamma-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 gamma-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., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The purpose of the present study is to investigate anticancer efficacy and apoptosis confirmed by caspase under several exposure conditions of high-intensity focused ultrasound (HIFU)., Materials and Methods: Twenty-five rats with KDH-8 hepatoma were treated by HIFU at several acoustic energies to evaluate treatment efficacy. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Hoechst 33258 staining, and caspase 3, 8, and 9/6 activity was respectively assayed., Results: The KDH-8 subcutaneous tumors were reduced by HIFU, and these rats survived longer than the nontreatment rats (P < 0.01). The minimal threshold of HIFU energy was 30 W × 1.0 s for tumor control and long-term survival. The tumors exposed to HIFU exhibited marked apoptotic features under conditions of less than 10 W × 1.0 s. In cultured KDH-8 cells, apoptosis was caused at less than 30 W × 1.0 s (P < 0.01), and more was induced as the energy went down. Caspase 3, 8, and 9/6 were more activated at low energy under 10 W × 1.0 s (P < 0.01), and caspase 8, which is death receptor dependent, was significantly more activated than caspase 9/6, which is mitochondria dependent (P < 0.01)., Conclusion: HIFU-induced apoptosis in vivo and in vitro is one of the mechanisms for tumor control and is mediated by caspase 3, 8, and 9/6. The significantly greater activation of caspase 8 than of caspase 9/6 suggests that the apoptosis pathway induced by HIFU might be more mitochondria dependent than death receptor dependent. However, further examination will be needed.

Purpose: Image-guided biopsy occasionally fails to diagnose small lung lesions, which are highly suggestive of primary lung cancer. The aim of the present study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) for small lung lesions that were clinically diagnosed as primary lung cancer without pathologic confirmation., Methods and Materials: A total of 115 patients were treated with SBRT in 12 institutions. Tumor size ranged from 5 to 45 mm in diameter, with a median of 20 mm., Results: The 3-year and 5-year overall survival rates for patients with a tumor size < or =20 mm in diameter (n = 58) were both 89.8%, compared with 60.7% and 53.1% for patients with tumors >20 mm (n = 57) (p <0.0005), respectively. Local progression occurred in 2 patients (3.4%) with a tumor size < or =20 mm and in 3 patients (5.3%) with tumors >20 mm. Among the patients with a tumor size < or =20 mm, Grade 2 pulmonary complications were observed in 2 (3.4%), but no Grade 3 to 5 toxicity was observed. In patients with a tumor size >20 mm, Grades 2, 3, and 5 toxicity were observed in 5 patients (8.8%), 3 patients (5.3%), and 1 patient (1.8%), respectively., Conclusion: In patients with a tumor < or =20 mm in diameter, SBRT was reasonably safe in this retrospective study. The clinical implications of the high local control rate depend on the accuracy of clinical/radiologic diagnosis for small lung lesions and are to be carefully evaluated in a prospective study.

Background: Secondary cancers are severe complications in patients who have had allogeneic bone marrow transplantation for childhood leukemia. We describe here a case of squamous cell carcinoma (SCC) of the buccal mucosa in a young adult patient who had had allogeneic bone marrow transplantation for childhood acute leukemia., Methods and Results: The primary tumor was treated with interstitial brachytherapy, and lymph node metastasis was treated by supraomohyoid neck dissection. The patient had a history of acute lymphoblastic leukemia (ALL) at 11 years of age and had received an allogeneic bone marrow transplant from a female donor. Further investigation of the tissue specimens by fluorescent in situ hybridization (FISH) revealed that an XX chromosome pattern was dominant in the tumor region, and this suggested that donor-derived cells might affect carcinogenesis in the recipient., Conclusions: This case presents an incidence of secondary oral cancer associated with allogeneic bone marrow transplantation.

The purpose of this study is to evaluate tumor vascularity of pancreatic carcinoma noninvasively by contrast-enhanced ultrasound (US) and clarify the diagnostic value of tumor vascularity in subjects with nonresectable advanced pancreatic carcinoma. The study was approved by our institutional review board and written informed consent was obtained from all subjects. Twenty-seven subjects with advanced pancreatic ductal carcinoma were treated by chemoradiotherapy. Contrast-enhanced US, US guided biopsies and dynamic computed tomography (CT) were performed before and after the therapy. We assigned the intratumoral enhancement pattern of US as an enhanced ultrasound (EU) score, from 1 to 4, according to the degree of enhancement area. Intratumoral microvessel density (IMD) and average vessel diameter (AVD) were calculated by means of CD 34 immunostaining. Vascular endothelial growth factor (VEGF) staining was graded on a scale of 1 to 3. EU scores before chemoradiotherapy were compared with IMD, AVD, VEGF, histological grading and hepatic metastasis. After the therapy, local treatment response was evaluated by dynamic CT calculating the maximum area of the tumor, by comparing it with its size in pre- therapy. Subjects who had at least a 50% or more decrease of tumor size lasting more than 4 wk were estimated as partial response (PR), more than a 50% of increase progressive disease (PD) and if neither PR nor PD criteria were met, they were classified as stabled disease (SD). Next, EU scores were compared with IMD, AVD, VEGF and treatment response. Statistically significant differences were evaluated by Pearson's correlation, post-hoc, Spearman's rank correlation, Wilcoxon rank sum and Student's t-test. A p < 0.05 was defined as being statistically significant. Before the therapy, the EU score and IMD were significantly correlated (r = 0.50, p < 0.02), as was VEGF (r = 0.45, p < 0.05). The EU score and AVD were negatively correlated (r = - 0.56, p < 0.02). Significant correlation was found between the EU score and histological grading (p < 0.004). The EU score was higher in subjects who had hepatic metastasis compared with subjects who had no hepatic metastasis (p < 0.05). After chemoradiotherapy, 14 subjects exhibited PR, while 13 showed SD. None of the subjects showed PD. The EU score was smaller in PR than SD (p < 0.05). The EU score significantly decreased after the therapy in PR (p < 0.01) but not in SD. IMD and AVD did not significantly decrease in either PR or SD; however, VEGF decreased significantly in PR (p < 0.01) but not in SD. Contrast-enhanced US could reveal tumor vascularity of pancreatic ductal carcinoma and could be potentially useful to evaluate treatment effect of subjects who receive chemoradiotherapy. Further investigation will be needed to prove the usefulness of contrast-enhanced US.

Purpose: We evaluated the efficacy of magnetic resonance angiography (MRA) for detecting the artery of Adamkiewicz (AKA) and the vertebral level of its feeding arteries branching from the aorta., Materials and Methods: Eighty-two patients (67 men, 15 women; aged 34 to 86 years, mean age 68.6 years) with thoracic descending and thoracoabdominal aortic lesions (aneurysm in 55, dissection in 25, coarctation in 2) underwent MRA to detect AKA. MRA was performed using 6-phase, dynamic-enhanced, 3-dimensional, fast spoiled gradient recalled acquisition in steady state (GRASS) on a 1.5-tesla (T) system, with double-dose bolus contrast injection. The vertebral levels of AKA branching and the AKA feeder artery branching from the aorta were determined., Results: The AKA was detected in 67 patients (81.7%). Branching of AKA occurred at levels T7 to T12 on the left side (n=52) and on the right (n=15). Vascular continuity from the aorta to the anterior spinal artery was demonstrated in 55 patients (67.1%). Comparing the vertebral level of arterial branching from the aorta to that of the AKA at the intervertebral foramen, the AKA branched at the same vertebral level in 44 patients (80.0%), one vertebral level above/below in 10 (18.2%), and 2 vertebral levels above in one (1.8%)., Conclusion: MRA can be useful in the preoperative work-up of patients with thoracoabdominal aortic lesions to localize AKA and the segmental trajectories of vessels supplying blood to the AKA.

Background: Treatment outcome was evaluated in patients who underwent breast-conserving therapy and tangential irradiation. After verifying background factors including systemic therapy, the clinical efficacy of postoperative irradiation was investigated., Method: There were 708 study subjects, all of whom had early breast cancer treated between 1992 and 2002. The median follow-up period was 83 months. After breast-conserving surgery, in patients with negative surgical margins, only tangential irradiation at 48 Gy/24 fr was performed. In contrast, in those with positive surgical margins, 10 Gy of radiation boost to the tumor bed with electrons was administered after tangential irradiation with 50 Gy/25 fr. Treatment outcome was analyzed using the Kaplan-Meier method and Cox's proportional hazards regression model., Results: The disease-free survival and no-recurrence rates within the ipsilateral breast after 5 years were 93.4 and 97.2%, respectively. Risk factors for recurrence within the ipsilateral breast included younger age of patient, the number of positive lymph nodes, and no endocrine therapy. However, the surgical margin was not a risk factor. Risk factors for relapse outwith the ipsilateral breast included younger age, the number of positive lymph nodes, and recurrence within the ipsilateral breast., Conclusions: From our analysis of 708 Japanese women who received breast-conserving therapy, which can be regarded as a standard method in Japan, the treatment outcome was compatible with previous reports from other countries.

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.

Purpose: Severe acute radiation dermatitis is observed in approximately 5% to 10% of patients who receive whole-breast radiotherapy. Several factors, including treatment-related and patient-oriented factors, are involved in susceptibility to severe dermatitis. Genetic factors are also thought to be related to a patient's susceptibility to severe dermatitis. To elucidate genetic polymorphisms associated with a susceptibility to radiation-induced dermatitis, a large-scale single-nucleotide polymorphism (SNP) analysis using DNA samples from 156 patients with breast cancer was conducted., Experimental Design: Patients were selected from more than 3,000 female patients with early breast cancer who received radiotherapy after undergoing breast-conserving surgery. The dermatitis group was defined as patients who developed dermatitis at a National Cancer Institute Common Toxicity Criteria grade of > or =2. For the SNP analysis, DNA samples from each patient were subjected to the genotyping of 3,144 SNPs covering 494 genes., Results: SNPs that mapped to two genes, ABCA1 and IL12RB2, were associated with radiation-induced dermatitis. In the ABCA1 gene, one of these SNPs was a nonsynonymous coding SNP causing R219K (P = 0.0065). As for the IL12RB2 gene, the strongest association was observed at SNP-K (rs3790568; P = 0.0013). Using polymorphisms of both genes, the probability of severe dermatitis was estimated for each combination of genotypes. These analyses showed that individuals carrying a combination of genotypes accounting for 14.7% of the Japanese population have the highest probability of developing radiation-induced dermatitis., Conclusion: Our results shed light on the mechanisms responsible for radiation-induced dermatitis. These results may also contribute to the individualization of radiotherapy.

Background and Purpose: Flow voids within the cavernous sinuses and/or certain venous drainage on spin-echo MR imaging and time-of-flight (TOF) flow enhancement on MR angiography (MRA) have indicated high-velocity shunt flow and have been used for screening patients with dural arteriovenous fistulas (DAVFs) of the cavernous sinuses. In this investigation, the capabilities of 3D dynamic MRA as a flow-independent approach and those of conventional MR imaging techniques were compared with selective angiography for the diagnosis of DAVFs of the cavernous sinuses., Materials and Methods: This retrospective study involved 18 patients with angiographically proved DAVFs of the cavernous sinuses and 12 control subjects. Sixteen partially overlapping sequential MR images were acquired on contrast-enhanced 3D dynamic MRA between the petrosal bone and the orbital roof. Two experienced observers blinded to the clinical data and results of angiography independently graded 3D dynamic MRA, fast spin-echo T2-weighted imaging (FSE T2WI), and TOF MRA., Results: The average area under the receiver operating characteristic curve values and interobserver kappa scores for the diagnosis of DAVFs on 3D dynamic MRA, FSE T2WI, and TOF MRA were 0.99, 0.89, and 0.95; and 0.92, 0.71, and 0.73, respectively. Those for the diagnosis of anterior, posterior, and retrograde cortical venous drainage on 3D dynamic MRA were 0.72, 0.95, and 0.81; and 0.56, 0.50, and 0.49, respectively., Conclusion: In this small series, screening 3D dynamic MRA directly demonstrates DAVFs of the cavernous sinuses and has improved diagnostic capability.

Purpose: The purpose of this study was to elucidate the wall layer appearance of the human hepatic artery shown by intravascular ultrasound (IVUS)., Methods: We evaluated the wall layer appearance of 57 human hepatic arteries from 36 cadavers. The thickness of the inner high-echoic layer and the second low-echoic layer of the arteries was measured by IVUS, and it was compared with that of the arterial intima and media, respectively., Results: The thickness of the inner high-echoic layer was 0.2 ± 0.1 mm and that of the second low-echoic layer was 0.4 ± 0.1 mm, on IVUS. However, the histological thickness of the intima was 120 ± 45 μm and that of the media was 258 ± 71 μm. The media of the hepatic artery correlated significantly with the second low-echoic layer on IVUS (r = 0.62, P < 0.01). The diameter of the vessels measured on IVUS correlated significantly with that of the histological specimens (r = 0.89, P < 0.01)., Conclusion: From our results, the three layers of the hepatic artery detected with IVUS may correspond to the intima, media, and adventitia, respectively.