Differences of Extracellular Cues and Ca2+ Permeable Channels in the Signaling Pathways for Inducing Amphibian Sperm Motility.

Low osmolality of freshwater and/or sperm motility-initiating substance (SMIS) induce amphibian sperm motility through increases in intracellular Ca2+. In the internally fertilizing newt Cynops pyrrhogaster, the sperm motility-initiating substance engages T type voltage-dependent Ca2 + channels and N-methyl D-aspartate-type glutamate receptors to initiate sperm motility and L type voltage-dependent Ca2+ channels to enhance motility. In the present study, differences in the usages of SMIS and Ca2+ permeable channels for sperm motility regulation were examined in amphibians that undergo different reproductive modes. Proteins of 14-17 kDa were detected by antibody against the active site peptide of SMIS in the oviduct secretion of internal fertilizers (C. pyrrhogaster, Cynops ensicauda, and Ambystoma mexicanum) and arboreal fertilizers (Rhacophorus arboreus and Rhacophorus schlegelii), but not in Buergeria japonica, an external fertilizer in freshwater. In the pharmacological study, a blocker of some transient receptor potential channels (RN1734) additionally suppressed enhancement of sperm motility in C. pyrrhogaster. In R. schlegelii, blockers of four types of channels differently suppressed sperm motility induced by low osmolality with or without the active site peptide of SMIS. Notably, blockers of L type voltage-dependent Ca2+ channels (nifedipine) and N-methyl D-aspartate-type glutamate receptors (MK801) suppressed sperm motility in the presence and the absence of the peptide, respectively. Low osmolality-induced sperm motility was suppressed by RN1734 and MK801 in B. japonica, but not in Xenopus laevis. These results reveal complex differences in the signaling pathways for inducing sperm motility that may be partly related to reproductive modes in amphibians.

Health-related quality of life in Japanese patients with prostate cancer following proton beam therapy: an institutional cohort study.

OBJECTIVE: Many treatment options have guaranteed long-term survival in patients with localized prostate cancer and health-related quality of life has become a greater concern for those patients. The purpose of this study was to reveal the health-related quality of life after proton beam therapy and to clarify the differences from other treatment modalities for prostate cancer. METHODS: Between January 2011 and April 2016, 583 patients were enrolled in the study and health-related quality of life outcomes using the Expanded Prostate Cancer Index Composite questionnaire were evaluated and compared with previous research targeted at Japanese patients. RESULTS: We found a significant decrease in the least square mean scores for urinary and bowel domains excluding the incontinence subscale after proton beam therapy (P < 0.0001) and recovery at a year following treatment. The scores for sexual function in patients without androgen deprivation therapy decreased each year after proton beam therapy (P < 0.0001). The scores for hormones in patients without androgen deprivation therapy remained high and those of patients with androgen deprivation therapy were lower before treatment but were comparable to those of non-androgen deprivation therapy patients at 2 years post-treatment. We found that the impact of radiotherapy including proton beam therapy on urinary condition and sexual function was lower than that of surgery. CONCLUSIONS: For the first time in Japan, we investigated health-related quality of life using Expanded Prostate Cancer Index Composite questionnaires in patients with prostate cancer after proton beam therapy and compared it with other treatment modalities.

Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer.

OBJECTIVES: We compared the clinical outcomes of proton beam radiotherapy (PBRT) and those of conventional chemoradiotherapy via hyper-fractionated acceleration radiotherapy (HART) after induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). METHODS: Twenty-five consecutive patients with LAPC received induction chemotherapy comprising gemcitabine and S-1 before radiotherapy. Of these, 15 and 10 were enrolled in the HART and PBRT groups, respectively. RESULTS: Moderate hematological toxicities were observed only in the HART group, whereas two patients in the PBRT group developed duodenal ulcers. All patients underwent scheduled radiotherapy, with overall disease control rates of 93% and 80% in the HART and PBRT groups, respectively. Local progression was observed in 60% and 40% of patients in the HART and PBRT groups, respectively. However, there was no statistical significance between the two groups regarding the median time to progression (15.4 months in both) and the median overall survival (23.4 v.s. 22.3 months). CONCLUSIONS: PBRT was feasible and tolerable, and scheduled protocols could be completed with careful attention to gastrointestinal ulcers. Despite the lower incidence of local recurrence, PBRT did not yield obvious progression control and survival benefits relative to conventional chemoradiotherapy.

Potential proton beam therapy for recurrent endometrial cancer in the vagina.

Proton beam radiotherapy mainly has been used in the gynecological field in patients with cervical cancer. The efficacy of proton beam therapy in patients with recurrent endometrial cancer has not yet been determined. A 77-year-old endometrial cancer patient presented with recurrence in the vagina without distant metastasis following hysterectomy. A hard mass measuring 6 cm originated from the apex of the vagina, surrounded the vaginal cavity, and infiltrated the proximal and distal vagina. The patient received proton beam radiotherapy using a less invasive particle treatment system while minimizing the dose to the surrounding normal tissues. The dose to the planning target volume was 74 Gy (relative biological effectiveness) with 37 fractions. The patient was treated with 150-210-MeV proton beams for 53 days. Proton beam therapy led to the disappearance of tumors without any complications except for grade 1 cystitis although evidence of further complications is not available past our 6-month follow-up period. Proton beam therapy may become a useful treatment modality for recurrent endometrial cancer as well as cervical uterine cancer.

A Japanese registry study and systematic review of particle therapy for renal cell carcinoma.

The feasibility and efficacy of particle beam therapy (PBT) using protons or carbon ions were compared with those of photon-based stereotactic body radiotherapy (SBRT) for primary renal cell carcinoma (RCC) via a systematic review and nationwide registry for PBT (Japanese Society for Radiation Oncology [JASTRO] particle therapy committee). Between July 2016 and May 2019, 20 patients with non-metastatic RCC who were treated at six Japanese institutes (using protons at three, using carbon ions at the other three) were registered in the nationwide database and followed up prospectively. The 20 patients comprised 15 men and had a median age of 67 (range: 57-88) years. The total radiation dose was 66-79.6 Gy (relative biological effectiveness [RBE]). Over a median follow up of 31 months, the 3-year rates of overall survival (OS) and local control (LC) were 100% and 94.4%, respectively. No grade ≥ 3 toxicities were observed. Based on a random effects model, a meta-analysis including the present results revealed 3-year OS rates after SBRT and PBT of 75.3% (95% CI: 57.3-86.6) and 94.3% (95% CI: 86.8-97.6), respectively (P = 0.005), but the difference in LC rates between the two methods was not observed (P = 0.63). PBT is expected to have similar if not better treatment results compared with SBRT for primary renal cancer. In particular, PBT was shown to be effective even for large RCC and could provide a therapeutic option when SBRT is not indicated.

Proton beam therapy for extrahepatic biliary tract cancer: Analysis with prospective multi-institutional patients' registration database, Proton-Net.

Background and purpose: To examine the role of proton beam therapy (PBT) in the treatment of extrahepatic biliary tract cancer (EBC). Methods and materials: We analyzed the data accumulated in the Proton-Net database, which prospectively registered all individual patient data treated with PBT in all Japanese proton institutions from May 2016 to June 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS), and toxicity. Results: Ninety-three patients with unresectable and/or recurrent EBC were treated with PBT using a median prescribed dose of 67.5 Gy (RBE) (range, 50-72.6 Gy) in 25 (22-30 fractions). With a median follow-up of 16.3 months, the median survival time was 20.1 months and the 2-year OS was 37.8%. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Poor liver function (Child-Pugh B, C), a narrower distance between the tumor and digestive tract (2 cm >), and a larger tumor diameter (2 cm <) were identified as poor prognostic factors for OS. PBT-related grade 3 ≤ acute and late adverse events occurred in 5.4% and 4.3% of patients, respectively, including one gastrointestinal late toxicity (duodenal ulcer). Conclusions: This is the largest prospectively accumulated series of PBT for EBC, and PBT showed favorable outcomes with acceptable toxicity profiles.

Particle Beam Therapy for Intrahepatic and Extrahepatic Biliary Duct Carcinoma: A Multi-Institutional Retrospective Data Analysis.

To examine the efficacy and toxicity of particle beam therapy (PT) for biliary duct carcinoma (BDC) and compare the outcomes between extrahepatic BDC (eBDC) and intrahepatic BDC (iBDC). We analyzed multi-institutional data from May 2009 to December 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS) and toxicity. We included 150 patients with unresectable BDC treated with PT using a median prescribed dose of 70.2 GyRBE (range, 44-77 GyRBE) in 25 fractions (range, 10-38 fractions). With a median follow-up of 13.0 months, median survival time (MST) was 21 months, and 2-year OS was 44.8%. For eBDC and iBDC, the MSTs were 20 and 23 months, respectively. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Vascular invasion, prescribed dose and serum tumor marker level (carcinoembryonic antigen: CEA) were identified as poor prognostic factors for OS. A higher radiation dose EQD2 ≥ 67 Gy showed superior OS, with a hazard ratio of 0.341. The radiation dose of PT is an important predisposing factor for overall survival. The MST for patients with eBDC given a higher radiation dose was 25 months, compared to 15 months for those given the lower dose and 23 months for patients with iBDC (all iBDC given higher doses). iBDC and eBDC duct carcinomas showed equivalent outcomes with PT, especially when treated with a high radiation dose. In detailed analysis, baseline CEA level in iBDC, and radiation dose and GTV in eBDC were statistically significant predicators for OS. Acute and late toxicity grade ≥3 occurred in 2.2% and 2.7% of patients, respectively, including two late grade-5 toxicities. In conclusion, PT showed good efficacy for BDC, both eBDC and iBDC, with a low incidence of severe toxicity.

Particle therapy using protons or carbon ions for cancer patients with cardiac implantable electronic devices (CIED): a retrospective multi-institutional study.

PURPOSE: To evaluate the outcomes of particle therapy in cancer patients with cardiac implantable electronic devices (CIEDs). MATERIALS AND METHODS: From April 2001 to March 2013, 19,585 patients were treated with proton beam therapy (PBT) or carbon ion therapy (CIT) at 8 institutions. Of these, 69 patients (0.4%, PBT 46, CIT 22, and PBT + CIT 1) with CIEDs (64 pacemakers, 4 implantable cardioverter defibrillators, and 1 with a cardiac resynchronization therapy defibrillator) were retrospectively reviewed. All the patients with CIEDs in this study were treated with the passive scattering type of particle beam therapy. RESULTS: Six (13%) of the 47 PBT patients, and none of the 23 CIT patients experienced CIED malfunctions (p = 0.105). Electrical resets (7) and over-sensing (3) occurred transiently in 6 patients. The distance between the edge of the irradiation field and the CIED was not associated with the incidence of malfunctions in 20 patients with lung cancer. A larger field size had a higher event rate but the test to evaluate trends as not statistically significant (p = 0.196). CONCLUSION: Differences in the frequency of occurrence of device malfunctions for patients treated with PBT and patients treated with CIT did not reach statistical significance. The present study can be regarded as a benchmark study about the incidence of malfunctioning of CIED in passive scattering particle beam therapy and can be used as a reference for active scanning particle beam therapy.

[A Study on Radiation Dermatitis Grading Support System Based on Deep Learning by Hybrid Generation Method].

PURPOSE: Radiation dermatitis is one of the most common adverse events in patients undergoing radiotherapy. However, the objective evaluation of this condition is difficult to provide because the clinical evaluation of radiation dermatitis is made by visual assessment based on Common Terminology Criteria for Adverse Events (CTCAE). Therefore, we created a radiation dermatitis grading support system (RDGS) using a deep convolutional neural network (DCNN) and then evaluated the effectiveness of the RDGS. METHODS: The DCNN was trained with a dataset that comprised 647 clinical skin images graded with radiation dermatitis (Grades 1-4) at our center from April 2011 to May 2019. We created the datasets by mixing data augmentation images generated by image conversion and images generated by Poisson image editing using the hybrid generation method (Hyb) against lowvolume severe dermatitis (Grade 4). We then evaluated the classification accuracy of RDGS based on the hybrid generation method (Hyb-RDGS). RESULTS: The overall accuracy of the Hyb-RDGS was 85.1%, which was higher than that of the data augmentation method generally used for image generation. CONCLUSION: Effectiveness of the Hyb-RDGS using Poisson image editing was suggested. This result shows a possible supporting system for objective evaluation in grading radiation dermatitis.

Multi-Institutional Retrospective Analysis of the Outcomes of Proton Beam Therapy for Patients With 1 to 3 Pulmonary Oligometastases From Various Primary Cancers.

PURPOSE: Our purpose was to evaluate the efficacy of proton beam therapy (PBT) in patients with 1 to 3 pulmonary oligometastases from various primary cancers in Japan. METHODS AND MATERIALS: This multi-institutional retrospective survey included 118 patients with 141 metastatic lung tumors from miscellaneous primary cancers, across 6 Japanese institutions, and involved the analyses of local progression-free rate (LPF), distant progression-free rate, progression-free survival rate, cause-specific survival rate, and overall survival rate (OS). Treatment-induced adverse effects of grade ≥2 were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0). Cox proportional hazards regression models were used in univariable analysis and multivariable analysis (MVA) for the identification of the prognostic factors of LPF and OS. RESULTS: The median follow-up duration from the time of PBT was 25.5 months. The major primary disease sites included colorectal cancer (42.4%), lung cancer (11.9%), head and neck cancer (8.5%), and kidney cancer (8.5%). For years 1, 2, and 3, LPFs were 92.2%, 86.3%, and 78.4%; distant progression-free rates were 59.1%, 44.1%, and 34.0%; progression-free survival rates were 49.6%, 31.7%, and 24.2%; cause-specific survival rates were 83.4%, 72.5%, and 64.8%; and OS rates were 79.0%, 67.8%, and 59.6%, respectively. Eight patients developed acute adverse effects (grade ≥2). Ten patients developed radiation pneumonitis (grade 2) as a late adverse effect. None of the patients developed severe late toxicity (grade ≥3). Colorectal cancer as the primary disease was the only prognostic factor associated with LPF that remained independently significant in the MVAs performed using 3 sets of parameters (hazard ratio [HR], 3.31-4.76 in 3 MVA sets). In the MVA, the significant prognostic factors for OS were performance status (HR, 2.78; 95% confidence interval, 1.01-7.67) and total tumor volume (HR, 1.01; 95% confidence interval, 1.00-1.02). CONCLUSIONS: PBT provides promising outcomes for pulmonary oligometastasis with acceptable toxicities.

Clinical Outcomes of Proton Beam Therapy for Ground-Glass Opacity-Type Lung Cancer.

PURPOSE: Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC), including ground-glass opacity (GGO)-type lung cancer. However, some patients are inoperable or refuse to undergo surgery. To explore whether proton beam therapy (PBT) can be an alternative to surgical resection in these patients, this study aimed to examine the retrospective treatment outcomes of patients with GGO-type lung cancer who underwent PBT. PATIENTS AND METHODS: Patients with stage I NSCLC and GGOs who underwent PBT at the Medipolis Proton Therapy and Research Center (Kagoshima, Japan) between April 2011 and September 2015 were included. Patients were treated with a total dose of 66 GyE delivered in 10 fractions. Survival curves were calculated using the Kaplan-Meier method, and treatment-related adverse events (AEs) were assessed. RESULTS: A total of 48 patients (median age: 70.9 ± 9.2 years; men: 54.2%) were analyzed, among whom 53 tumors were observed. The 3-year overall survival rate after PBT was 91.7% (95% confidence interval [CI], 79.3-96.8%), the 3-year disease-free survival rate was 85.4% (95% CI: 71.8-92.8%), and the 3-year local control rate among 53 tumors was 92.5% (95% CI: 81.1-97.1%). During the 3-year follow-up period, 4 patients died, and 3 survived despite recurrence or metastasis. Common AEs were radiation pneumonitis (89.6%), rib fracture (27.1%), and cough (27.1%). None of the patients developed grade ≥3 treatment-related AEs. CONCLUSION: The results of this study suggest that PBT may be a promising alternative for patients with GGO-type lung cancer when surgical resection is not feasible, with excellent survival outcomes and tolerable treatment-related AEs.

Proton Therapy for Primary Renal Cell Carcinoma: The First Nationwide Retrospective Study in Japan.

BACKGROUND/AIM: This multi-institutional study aimed to investigate the efficacy and feasibility of proton beam therapy (PBT) for renal cell carcinoma (RCC) in Japan. PATIENTS AND METHODS: The survival, local control, and toxicities in 22 RCC patients treated between 2001 and 2016 at 6 Japanese PBT institutes were analyzed. RESULTS: The 22 patients comprised 20 men and had a median age of 67 (range=42-88) years. The total irradiation dose was 60-79.6 Gy (relative biological effectiveness). Over a median follow-up of 37 months, the 3-year overall and disease-specific survival rates were 95% and 100%, respectively, and no recurrence occurred. No patient experienced grade 3 or higher adverse events. The serum blood urea nitrogen (p=0.25) and creatinine levels (p=0.95) were not significantly affected, although the mean estimated glomerular filtration rate was reduced by 7.1±11.2 ml/min/1.73 m2 Conclusion: Despite the small number of patients, high-dose PBT can control RCC while maintaining their renal function with high probability, and could be and alternative curative therapy especially for inoperable patients.

Optimal Androgen Deprivation Therapy Combined with Proton Beam Therapy for Prostate Cancer: Results from a Multi-Institutional Study of the Japanese Radiation Oncology Study Group.

BACKGROUND: Androgen deprivation therapy (ADT) combined with radiation therapy benefits intermediate- and high-risk prostate cancer (PC) patients. The optimal ADT duration in combination with high-dose proton beam therapy (PBT) remains unknown. METHODS: Intermediate- and high-risk PC patients treated with PBT combined with ADT for various durations were analyzed retrospectively. To assess the relationship between ADT and biochemical relapse-free (bRF) rate, Cox proportional hazards models including T stage, prostate specific antigen (PSA) level, Gleason score (GS), and total radiation dose were used. RESULTS: In the intermediate-risk PC patients (n = 520), ADT use improved bRF (HR 0.49, 95% CI 0.26-0.93; p = 0.029), especially in those with multiple intermediate-risk factors (T2b-2c, PSA 10-20 ng/mL, and GS 7). In the high-risk PC patients (n = 555), a longer ADT duration (>6 months) conferred a benefit for bRF (HR 0.54, 95% CI 0.32-0.90; p = 0.018), which was most apparent in patients with multiple high-risk factors (T3a-4, PSA > 20 ng/mL, and GS ≥ 8) treated with ADT for ≥21 months. CONCLUSIONS: Short-term (≤6 months) ADT is beneficial for intermediate-risk PC patients, but likely unnecessary for those with a single risk factor, whereas ADT for >6 months is necessary for high-risk PC patients and ADT for ≥21 months might be optimal for those with multiple risk factors in combination of high-dose PBT.

Proton Beam Therapy for Histologically or Clinically Diagnosed Stage I Non-Small Cell Lung Cancer (NSCLC): The First Nationwide Retrospective Study in Japan.

PURPOSE: To investigate the efficacy and safety of proton beam therapy (PBT) for the treatment of stage I non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Six hundred sixty-nine patients with 682 tumors histologically or clinically diagnosed stage I NSCLC according to the seventh edition of Union for International Cancer Control who received passive-scattering PBT from April 2004 and December 2013 in Japan were retrospectively reviewed to analyze survival, local control, and toxicities. RESULTS: Of 669 patients, 486 (72.6%) were men, with a median age of 76 years (range, 42-94 years). NSCLC was histologically confirmed in 440 patients (65.7%). Clinical T stages included T1a (n = 265; 38.9%), T1b (n = 216; 31.7%), and T2a (n = 201; 29.4%). The total irradiation doses of PBT ranged from 74.4 to 131.3 biological effective dose GyE (median, 109.6 biological effective dose GyE). The median follow-up period was 38.2 months (range, 0.6-154.5 months) for all patients. The 3-year overall survival and progression-free survival rates for all patients were 79.5% and 64.1%, respectively. For patients with stage IA tumors, the 3-year overall survival and progression-free survival rates were 82.8% and 70.6%, respectively, and the corresponding rates for patients with stage IB tumors were 70.8% and 47.3%, respectively. The 3-year local progression-free rates for all, stage IA, and stage IB patients were 89.8%, 93.5%, and 79.4%, respectively. The incidence of grade 2, 3, 4, and 5 pneumonitis was 9.8%, 1.0%, 0%, and 0.7%, respectively. The incidence of grade ≥3 dermatitis was 0.4%. No grade 4 or severe adverse events, other than pneumonitis, were observed. CONCLUSIONS: PBT appears to yield acceptable survival rates, with a low rate of toxicities.

Proton Beam Therapy Alone for Intermediate- or High-Risk Prostate Cancer: An Institutional Prospective Cohort Study.

The role of proton beam therapy (PBT) as monotherapy for localized prostate cancer (PCa) remains unclear. The purpose of this study was to evaluate the efficacy and adverse events of PBT alone for these patients. Between January 2011 and July 2014, 218 patients with intermediate- and high-risk PCa who declined androgen deprivation therapy (ADT) were enrolled to the study and were treated with PBT following one of the following protocols: 74 Gray (GyE) with 37 fractions (fr) (74 GyE/37 fr), 78 GyE/39 fr, and 70 GyE/28 fr. The 5-year progression-free survival rate in the intermediate- and high-risk groups was 97% and 83%, respectively (p = 0.002). The rate of grade 2 or higher late gastrointestinal toxicity was 3.9%, and a significant increased incidence was noted in those who received the 78 GyE/39 fr protocol (p < 0.05). Grade 2 or higher acute and late genitourinary toxicities were observed in 23.5% and 3.4% of patients, respectively. Our results indicated that PBT monotherapy can be a beneficial treatment for localized PCa. Furthermore, it can preserve the quality of life of these patients. We believe that this study provides crucial hypotheses for further study and for establishing new treatment strategies.

Risk factors for radiation pneumonitis after stereotactic radiation therapy for lung tumours: clinical usefulness of the planning target volume to total lung volume ratio.

OBJECTIVE: To identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic radiation therapy (SRT) for lung tumours. METHODS: We retrospectively evaluated 68 lung tumours in 63 patients treated with SRT between 2011 and 2015. RP was graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0. SRT was delivered at 7.0-12.0 Gy per each fraction, once daily, to a total of 48-64 Gy (median, 50 Gy). Univariate analysis was performed to assess patient- and treatment-related factors, including age, sex, smoking index (SI), pulmonary function, tumour location, serum Krebs von den Lungen-6 value (KL-6), dose-volume metrics (V5, V10, V20, V30, V40 and VS5), homogeneity index of the planning target volume (PTV), PTV dose, mean lung dose (MLD), contralateral MLD and V2, PTV volume, lung volume and the PTV/lung volume ratio (PTV/Lung). Performance of PTV/Lung in predicting symptomatic RP was also analysed using receiver operating characteristic (ROC) analysis. RESULTS: The median follow-up period was 21 months. 10 of 63 patients (15.9%) developed symptomatic RP after SRT. On univariate analysis, V10, V20, PTV volume and PTV/Lung were significantly associated with occurrence of RP  ≥Grade 2. ROC curves indicated that symptomatic RP could be predicted using PTV/Lung [area under curve (AUC): 0.88, confidence interval (CI: 0.78-0.95), cut-off value: 1.09, sensitivity: 90.0% and specificity: 72.4%]. CONCLUSION: PTV/Lung is a good predictor of symptomatic RP after SRT. Advances in knowledge: The cases with high PTV/Lung should be carefully monitored with caution for the occurrence of RP after SRT.

Long-term outcomes of proton therapy for prostate cancer in Japan: a multi-institutional survey of the Japanese Radiation Oncology Study Group.

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.

A feasibility study of a hybrid breast-immobilization system for early breast cancer in proton beam therapy.

PURPOSE: We aimed to develop a new breast-immobilizing system for proton beam therapy (PBT) of early breast cancer (EBC) that would provide the optimum breast shape during the treatment as well as increased fixation reliability by reducing the influence of respiratory movement. METHODS: The breast-immobilizing system (HyBIS; hybrid breast-immobilizing system) consists of a whole body immobilization system (WBIS), position-converting device (to change patient position), photo-scanning system, breast cup (made using a three-dimensional printer), breast cup-fitting apparatus, breast cup-holding device (to ensure the breast remains lifted in the supine position), and dedicated stretcher fixed to the WBIS (to carry the patient). We conducted a phantom experiment to evaluate the effect of the HyBIS on breast immobilization during the respiratory cycle. Thirteen markers were embedded in the right breast of a female phantom that simulated respiratory thoracic movement at an amplitude of 15 mm, and their displacements on four-dimensional computed tomography were compared between conditions with and without immobilization by HyBIS. RESULTS: When immobilization was applied with the HyBIS, breast protrusion was maintained in the phantom in the supine treatment position. The mean values of the anteroposterior, superoinferior, lateral, and three-dimensional (3D) displacement of the markers were 2.7 ± 1.7, 0.3 ± 0.5, 0.9 ± 0.8, and 3.1 ± 1.6 mm with HyBIS, and 5.5 ± 2.9, 0.6 ± 0.8, 0.5 ± 0.4, and 5.6 ± 2.9 mm without HyBIS, respectively; thus, the anteroposterior (P = 0.014) and 3D (P = 0.007) displacements significantly improved with HyBIS. CONCLUSIONS: We demonstrated that the HyBIS can help retain the protruded breast shape in the supine position during treatment and can reduce the influence of respiratory movement. Thus, the HyBIS can help to reliably and precisely perform PBT for EBC.

HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases.

Nanomedicine allows achievement of tumor-selective drug delivery because of the enhanced permeability and retention (EPR) effect of solid tumors. We report here the first clinical application of a new agent-HPMA copolymer-conjugated pirarubicin (P-THP)-with a molecular size of about 8 nm, or 38.5 kDa. A patient had advanced prostate cancer with multiple metastases in the lung, pelvis, femur, and perhaps the sacrum. In April 2013, this 60-year-old patient started treatment with leuprorelin and estradiol, which continued until July 2014, but the patient became refractory to this treatment. So the patient underwent proton beam radiotherapy targeted to the primary prostate cancer, and P-THP was administered for numerous metastatic tumor nodules concomitantly with radiotherapy. This combination therapy had remarkable results, with complete remission of multiple metastases in the lung and bone. The prostate-specific antigen (PSA) value was decreased from about 1000 ng/mL on April 30, 2013, to about 100 ng/mL on June 24, 2013, with hormone therapy, but rose again to 964.2 ng/mL and then to 1472 ng/mL in July 2013, during leuprorelin administration. P-THP treatment administered concomitantly with proton beam irradiation was started in August 2013. The PSA value was decreased to 102 ng/mL on August 26, 2013, and then to 0.971 ng/mL on October 8, 2013, and 0.277 ng/mL on January 15, 2015. The P-THP doses ranged from 30 to 75 mg of free THP equivalent/patient every 2-3 weeks without signs of serious toxicity, such as cardiovascular side effects or a reduction in quality of life. No evidence of relapse was found more than 20 months after P-THP administration. This case demonstrates the value of hydrazone-bonded polymeric drugs in multimodal therapy.

Effect of Film Dressing on Acute Radiation Dermatitis Secondary to Proton Beam Therapy.

PURPOSE: Acute radiation dermatitis (ARD) is one of the most common adverse events of proton beam therapy (PBT), and there is currently no effective method to manage ARD. The purpose of this study was to examine the prophylactic effect of a film dressing using Airwall on PBT-induced ARD compared with standard skin managements. METHODS AND MATERIALS: A total of 271 patients with prostate cancer who were scheduled for PBT at our center were divided into 2 groups based on their own requests: 145 patients (53%) chose Airwall (group A) and 126 patients (47%) received standard treatments (group B). We evaluated irradiated skin every other day during PBT and followed up once a week for a month after completion of PBT. RESULTS: Grade 0, 1, 2, and 3 dermatitis were seen in 2, 122, 21, and 0 and 0, 65, 57, and 4 patients in groups A and B, respectively (P<.001). Numbers of days to grades 1 and 2 ARD development were 34.9 ± 14.3 and 54.7 ± 10.3 and 31.8 ± 11.3 and 54.4 ± 11.6 in groups A and B, respectively. There were no significant differences between the 2 groups. Eighteen patients (12%) in group A who experienced problems in the region covered with Airwall switched to standard skin care after peeling the film off. CONCLUSIONS: Film dressing using Airwall reduced the severity of ARD without delaying the response time of the skin to proton beam irradiation compared with standard skin management. Hence, film dressing is considered a promising measure for preventing ARD secondary to PBT.