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Few studies have reported about isolated contracture in the extensor hallucis longus (EHL) muscle, but none of the EHL muscle contracture after distal tibial physeal injury. Two such cases in 16- and 14-year-old boys who underwent surgeries for distal physeal injury of the tibia at a previous hospital are presented. Extension contracture of the hallux appeared 1-2 months post-surgery. Physical examinations revealed that the extension contracture of the first metatarsophalangeal joint was aggravated in plantar flexion of the ankle due to a tenodesis effect, and magnetic resonance imaging showed atrophy and signal changes in the anterior compartment muscles. This was diagnosed as EHL muscle contracture due to anterior compartment syndrome (ACS) after distal tibial physeal injury. The EHL tendon transfers were performed in both cases, with favorable short-term results. Therefore, the EHL tendon transfer might be preferable in case of the EHL muscle contracture due to partial ACS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Hallux valgus (HV) is an important risk factor for falls (in older people); however, the detailed relationship is less understood. We aimed to evaluate postural stability in bilateral HV patients., Methods: Two groups of 20 female patients-an HV group and a C (i.e., non-HV) group-participated in this study. Evaluations were made using the Timed Up and Go (TUG) test, the Berg Balance Scale (BBS), the Falls Efficacy Scale (FES), track length (LNG), velocity (VEL), enveloped area (ENV), and root mean square area (RMS)., Results: TUG and FES scores were significantly higher and BBS scores were lower in the HV group than in the C group. LNG was significantly longer, VEL was higher, and ENV and RMS were wider in the HV group than in the C group., Conclusions: The HV group exhibited impaired walking mobility, balance, and postural stability., (Copyright © 2020 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Since sexual function and testosterone levels after image-guided proton therapy (IGPT) have not yet been examined in detail, we prospectively evaluated changes before and after IGPT. Among patients treated with IGPT with or without combined androgen blockade (CAB) therapy between February 2013 and September 2014, patients who agreed to participate in the study and were followed up for >3 years after IGPT were evaluated. Serum testosterone levels were regularly measured together with prostate-specific antigen (PSA) levels before and after IGPT. The Erection Hardness Score (EHS) and the sexual domain summary, function subscale and bother subscale of the sexual domain in the Expanded Prostate Cancer Index Composite (EPIC) were assessed. There were 38 low-risk, 46 intermediate-risk and 43 high- or very-high-risk patients (NCCN classification). Although serum testosterone levels in low-risk patients did not decrease after IGPT, reductions were observed in the average EHS and the sexual domain summary score of the EPIC. In intermediate-, high- and very-high-risk patients, testosterone and PSA levels both increased following the termination of CAB after IGPT, and the average EHS increased. The sexual domain summary score gradually increased, but not above minimally important differences. In intermediate-risk patients, the function subscale increased from 4.4 to 14.8 (P < 0.05) 12 months after IGPT and reached a plateau after 60 months. The results of the present study would suggest the potential of IGPT, and further prospective studies to directly compare IGPT with other modalities are warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC)., Methods and Materials: The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m 2 ) on day 1 and S-1 (∼40 mg/m 2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented., Results: Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia., Conclusions: CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study retrospectively investigated the efficacy and safety of image-guided proton therapy (IGPT) for elderly (≥80 years old) hepatocellular carcinoma (HCC) patients. Proton therapy was performed using respiratory-gated and image-guided techniques. Seventy-one elderly HCC patients were treated using IGPT. The Child-Pugh score was A5 in 49 patients, A6 in 15, and B7-9 in 7. Forty-seven patients with a peripherally located tumor were administered 66 gray relative biological effectiveness (GyRBE) in 10 fractions, whereas 24 with a centrally located tumor received 72.6 GyRBE in 22 fractions. The median follow-up period of surviving patients was 33 months (range: 9-68). Two-year overall survival (OS) and local control (LC) rates estimated by the Kaplan-Meier method were 76% (95% confidence interval: 66-87%) and 88% (80-97%), respectively. According to the Common Terminology Criteria for Adverse Events version 4.0, no grade 2 or higher radiation-induced liver disease was observed, and only 1 patient developed grade 3 dermatitis. The quality of life score (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0, QLQ-HCC18, and SF-36) did not change after 1 year, except for the three-mental component summary (SF-36, improvement). IGPT is a safe and effective treatment for HCC in elderly patients.

UR-1102, a novel uricosuric agent for treating gout, has been confirmed to exhibit a pharmacological effect in patients. We clarified its metabolic pathway, estimated the contribution of each metabolic enzyme, and assessed the impact of genetic polymorphisms using human in vitro materials. Glucuronide, sulfate and oxidative metabolites of UR-1102 were detected in human hepatocytes. The intrinsic clearance by glucuronidation or oxidation in human liver microsomes was comparable, but sulfation in the cytosol was much lower, indicating that the rank order of contribution was glucuronidation ≥ oxidation > sulfation. Recombinant UGT1A1 and UGT1A3 showed high glucuronidation of UR-1102. We took advantage of a difference in the inhibitory sensitivity of atazanavir to the UGT isoforms and estimated the fraction metabolised ( fm ) with UGT1A1 to be 70%. Studies using recombinant CYPs and CYP isoform-specific inhibitors showed that oxidation was mediated exclusively by CYP2C9. The effect of UGT1A1 and CYP2C9 inhibitors on UR-1102 metabolism in hepatocytes did not differ markedly between the wild type and variants.

A radiophotoluminescent glass dosimeter (RGD) is widely used in postal audit system for photon beams in Japan. However, proton dosimetry in RGDs is scarcely used owing to a lack of clarity in their response to beam quality. In this study, we investigated RGD response to beam quality for establishing a suitable linear energy transfer (LET)-corrected dosimetry protocol in a therapeutic proton beam. The RGD response was compared with ionization chamber measurement for a 100-225 MeV passive proton beam. LET of the measurement points was calculated by the Monte Carlo method. An LET-correction factor, defined as a ratio between the non-corrected RGD dose and ionization chamber dose, of 1.226×(LET) -0.171 was derived for the RGD response. The magnitude of the LET-dependence of RGD increased with LET; for an LET of 8.2 keV/μm, the RGD under-response was up to 16%. The coefficient of determination, mean difference ± SD of non-corrected RGD dose, residual range-corrected RGD dose, and LET-corrected RGD dose to the ionization chamber are 0.923, 3.7 ± 4.2%, -2.4 ± 7.5%, and 0.04 ± 2.1%, respectively. The LET-corrected RGD dose was within 5% of the corresponding ionization chamber dose at all energies until 200 MeV, where it was 5.3% lower than the ionization chamber dose. A corrected LET-dependence of RGD using a correction factor based on a power function of LET and precise dosimetric verification close to the maximum LET were realized here. We further confirmed establishment of an accurate postal audit under various irradiation conditions., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: The present study investigated the biological effects of spot scanning and passive scattering proton therapies at the distal end region of the spread-out Bragg peak (SOBP) using single cell and multicell spheroids., Materials and Methods: The Geant4 Monte Carlo simulation was used to calculate linear energy transfer (LET) values in passive scattering and spot scanning beams. The biological doses of the two beam options at various points of the distal end region of SOBP were investigated using EMT6 single cells and 0.6-mm V79 spheroids irradiated with 6 and 15 Gy, respectively, by inserting the fractions surviving these doses onto dose-survival curves and reading the corresponding dose., Results: LET values in the entrance region of SOBP were similar between the two beam options and increased at the distal end region of SOBP, where the LET value of spot scanning beams was higher than that of passive scattering beams. Increases in biological effects at the distal end region were similarly observed in single cells and spheroids; biological doses at 2-10 mm behind the distal end were 4.5-57% and 5.7-86% higher than physical doses in passive scattering and spot scanning beams, respectively, with the biological doses of spot scanning beams being higher than those of passive scattering beams ( p  < .05)., Conclusions: In single cells and spheroids, the effects of proton irradiation were stronger than expected from measured physical doses at the distal end of SOBP and were correlated with LET increases.

The purpose of the current study was to investigate the biological effects of protons and photons in combination with cisplatin in cultured cells and elucidate the mechanisms responsible for their combined effects. To evaluate the sensitizing effects of cisplatin against X-rays and proton beams in HSG, EMT6 and V79 cells, the combination index, a simple measure for quantifying synergism, was estimated from cell survival curves using software capable of performing the Monte Carlo calculation. Cell death and apoptosis were assessed using live cell fluorescence imaging. HeLa and HSG cells expressing the fluorescent ubiquitination-based cell cycle indicator system (Fucci) were irradiated with X-rays and protons with cisplatin. Red and green fluorescence in the G1 and S/G2/M phases, respectively, were evaluated and changes in the cell cycle were assessed. The sensitizing effects of ≥1.5 μM cisplatin were observed for both X-ray and proton irradiation (P < 0.05). In the three cell lines, the average combination index was 0.82-1.00 for X-rays and 0.73-0.89 for protons, indicating stronger effects for protons. In time-lapse imaging, apoptosis markedly increased in the groups receiving ≥1.5 μM cisplatin + protons. The percentage of green S/G2/M phase cells at that time was higher when cisplatin was combined with proton beams than with X-rays (P < 0.05), suggesting more significant G2 arrest. Proton therapy plus ≥1.5 μM cisplatin is considered to be very effective. When combined with cisplatin, proton therapy appeared to induce greater apoptotic cell death and G2 arrest, which may partly account for the difference observed in the combined effects., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: We recently obtained nearly the same depth profiles of luminescence images of water as dose for protons by subtracting the Cerenkov light component emitted by secondary electrons of prompt gamma photons. However, estimating the distribution of Cerenkov light with this correction method is time-consuming, depending on the irradiated energy of protons by Monte Carlo simulation. Therefore, we proposed a method of estimating dose distributions from the measured luminescence images of water using a deep convolutional neural network (DCNN)., Methods: In this study, we adopted the U-Net architectures as the DCNN. To prepare a large amount of image data for DCNN training, we calculated the training data pairs of two-dimensional (2D) dose distributions and luminescence images of water by Monte Carlo simulation for protons and carbon ions. After training the U-Net model for protons or carbon ions using these dose distributions and luminescence images calculated by Monte Carlo simulation, we predicted the dose distributions from the calculated and measured luminescence images of water using the trained U-Net model., Results: All of the U-Net model's predicted images were in good agreement with the MC-calculated dose distributions and showed lower values of the root mean square percentage error (RSMPE) and higher values in the structural similarity index (SSIM) in comparison with these values for calculated or measured luminescence images., Conclusion: We confirmed that the DCNN effectively predicts dose distributions in water from the measured as well as calculated luminescence images of water for particle therapy., (© 2020 American Association of Physicists in Medicine.)

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c ). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.

Objectives: Some forefoot shapes are ideal for pointe work in ballet. Egyptian-type, with the hallux being longest and the remaining toes decreasing in size, and Greek-type, with the second toe longer than the hallux, are considered less optimal for pointe work. Square-type, with the second toe the same length as the hallux, is considered optimal. This study compared postural stability in the bipedal stance, demi pointe, and en pointe between ballet dancers with the two toe types using a stabilometer., Methods: This study included 25 Japanese ballet academy dancers who had received ballet lessons for at least 6 years. Toes were categorized into Egyptian-type (n=14) and square-type (n=11). Bipedal stance, demi pointe, and en pointe were tested. Center of pressure (COP) parameters were calculated from ground-reaction forces using two force plates: total trajectory length (LNG), velocities of anterior-posterior (VAP) and medial-lateral directions (VML), and maximum range displacement in the anterior-posterior (MAXAP) and medial-lateral directions (MAXML). Mann-Whitney U-tests were used to examine differences in COP parameters., Results: There were no differences in parameters during bipedal stance or demi pointe. However, dancers with Egyptian-type toes had significantly greater LNG (p<0.01), VML (p=0.01), MAXML (p<0.01), and MAXAP (p=0.03) during en pointe., Conclusions: Ballet dancers with Egyptian-type toes demonstrated greater displacement in the medial-lateral and anterior-posterior directions during en pointe. Ballet dancers should be aware of toe types and sway character to optimize ballet training and balance., (Copyright© 2020 by the author(s). Open Access: licensed under CC BY-NC-ND 4.0 Int.)

Background and Purpose: In Japan, the first domestic clinical trial of proton beam therapy for the liver was initiated as the Japan Clinical Oncology Group trial (JCOG1315C: Non-randomized controlled study comparing proton beam therapy and hepatectomy for resectable hepatocellular carcinoma). Purposes of this study were to develop a new dosimetric verification system and to carry out a credentialing for the JCOG1315C clinical trial., Materials and Methods: Accuracy and differences in doses in proton treatment planning among participating institutions were surveyed and investigated. We designed and developed a suitable water tank-type liver phantom for a dosimetric verification of proton beam therapy for liver. In a visiting survey of five institutions participating in the clinical trial, we performed the dosimetric verification using the liver phantom and an air-filled ionization chamber., Results: The shape of the dose distributions calculated in proton treatment planning was characteristic and dependent on the manufacturers of the proton beam therapy system, the proton treatment planning system and the setup at the participating institutions. Widths of the lateral penumbra were 5.8-12.7 mm among participating institutions. The accuracy between the calculated and the measured doses in the proton irradiation was within 3% at five measurement points including both points on the isocenter and off the isocenter., Conclusions: These findings confirmed the accuracy of the delivery doses in the institutions participating in the clinical trial, and the clinical trial with integration of all institutions (five institutions) could be initiated., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To investigate optimal treatment planning using proton beams for non-squamous cell carcinoma of the head and neck (NSCHN), the dose distributions of plans involving pencil beam scanning (PBS) with or without a patient-specific aperture system (PSAS), passive-scattering proton therapy (PSPT) and X-ray intensity-modulated radiotherapy (IMRT) were compared. As clinical results, toxicities of PBS with PSAS, including changes in quality of life, were reported. Between April 2014 and August 2016, a total of 30 patients were treated using PBS with PSAS. In 20 patients selected at random, the dose distributions of PBS with or without the PSAS, PSPT and IMRT plans were compared. Neutron exposure by proton therapy was calculated using a Monte Carlo simulation. Toxicities were scored according to CTCAE ver. 4.0. Patients completed EORTC quality of life survey forms (QLQ-C30 and QLQ-HN35) before and 0-12 months after proton therapy. The 95% conformity number of PBS with the PSAS plan was the best, and significant differences were detected among the four plans (P < 0.05, Bonferroni tests). Neutron generation by PSAS was ~1.1-fold higher, but was within an acceptable level. No grade 3 or higher acute dermatitis was observed. Pain, appetite loss and increased weight loss were more likely at the end of treatment, but recovered by the 3 month follow-up and returned to the pretreatment level at the 12 month follow-up. PBS with PSAS reduced the penumbra and improved dose conformity in the planning target volume. PBS with PSAS was tolerated well for NSCHN., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Differentiation of stem cells to hepatocytes provides an unlimited supply of human hepatocytes and therefore has been vigorously studied. However, to date, the stem cell-derived hepatocytes were suggested to be of immature features. To obtain matured hepatocytes from stem cells, we tested the effect of culturing human-induced pluripotent stem (hiPS) cell-derived endoderm cells on collagen vitrigel membrane and compared with our previous reported nanofiber matrix. We cultured hiPS cell-derived endoderm cells on a collagen vitrigel membrane and examined the expression profiles, and tested the activity of metabolic enzymes. Gene expression profile analysis of hepatocytic differentiation markers revealed that upon culture on collagen vitrigel membrane, immature markers of AFP decreased, with a concomitant increase in the expression of mature hepatocyte transcription factors and mature hepatocyte markers such as ALB , ASGR1 Mature markers involved in liver functions, such as transporters, cytochrome P450 enzymes and phase II metabolic enzymes were also upregulated. We observed the upregulation of the liver markers for at least 2 weeks. Gene array profiling analysis revealed that hiPS cell-derived hepatocyte-like cells (hiPS-hep) resemble those of the primary hepatocytes. Functions of the CYP enzyme activities were tested in multi-institution and all revealed high CYP1A, CYP2C19, CYP2D6, CYP3A activity, which could be maintained for at least 2 weeks in culture. Taken together, the present approach identified that collagen vitrigel membrane provides a suitable environment for the generation of hepatocytes from hiPS cells that resemble many characteristics of primary human hepatocytes., Competing Interests: Competing interestsH.Y. and N.T. are employees in Kanto Chemical Co. Inc., which supplies collagen vitrigel membrane products., (© 2019. Published by The Company of Biologists Ltd.)

Background: Operative treatment is indicated for patients who have symptomatic hallux valgus (HV) with moderate to severe metatarsus adductus (MA). However, there is limited information available on the operative procedures and outcomes for the treatment of HV with MA. We aimed to investigate the average 10-year follow-up clinical and radiologic outcomes., Methods: Seventeen patients (21 feet, average age: 60.1 years) with symptomatic HV with moderate to severe MA were operatively treated. Mean postoperative follow-up duration was 114.4 (24-246) months. All feet had metatarsus adductus angle ≥20 degrees on dorsoplantar weight-bearing radiograph. The procedure included a proximal crescentic osteotomy of the first metatarsal and abduction osteotomy of the proximal third of the second and third metatarsals., Results: The mean American Orthopaedic Foot & Ankle Society scale score improved significantly postoperatively ( P < .001). The mean postoperative visual analog scale score (17 feet) was 2.0 (0-6). Preoperative metatarsalgia was severe in 2 feet, moderate in 17, and mild in 2. At the most recent follow-up evaluation, 11 feet had no pain, 9 had mild pain, and 1 had moderate pain. The mean hallux valgus angle, intermetatarsal angle, and metatarsus adductus angle significantly decreased postoperatively ( P < .001 for all). Recurrence of HV (HV angle ≥ 20 degrees) was observed in 4 feet., Conclusion: The clinical and radiologic results indicated that our novel operative treatment for HV with moderate to severe MA can achieve significant correction of HV with MA deformities and significant improvement in pain and function., Level of Evidence: Level IV, retrospective case series.

Background: Proximal crescentic osteotomy (PCO) in patients with moderate-to-severe hallux valgus (HV) is a well-established and effective procedure for correcting the deformity. However, there are no published studies comparing plantar pressure in postoperative HV feet with healthy feet. This study aimed to compare the plantar pressure distribution in postoperative HV feet with healthy feet., Methods: Twenty-six patients were included in the HV group, and 24 healthy participants were included in the control (C) group. All patients in the HV group underwent unilateral PCO. After undergoing PCO, this group was defined as the OP group. All subjects were women with no significant differences in age, height, weight, and body mass index. There were no significant differences in demographic characteristics between patients in each group. We divided the subjects' feet into 8 regions and measured the peak pressure (Peak-P), maximum force (Max-F), contact time, contact area, and the force-time integral in each region., Results: All parameters of the great toe were significantly higher in the OP group than in the HV group. All forefoot parameters were not significantly different between the 2 groups. No parameter of the great toe was significantly different between the OP and C groups. However, mean Peak-P and Max-F of the central forefoot were significantly higher in the OP group than in the C group., Conclusion: PCO can improve the plantar pressure of the great toe in patients with moderate-to-severe HV to a level similar to that in healthy subjects., Level of Evidence: Level III, comparative study.

The purpose of this study was to propose a verification method and results of intensity-modulated proton therapy (IMPT), using a commercially available heterogeneous phantom. We used a simple simulated head and neck and prostate phantom. An ionization chamber and radiochromic film were used for measurements of absolute dose and relative dose distribution. The measured doses were compared with calculated doses using a treatment planning system. We defined the uncertainty of the measurement point of the ionization chamber due to the effective point of the chamber and mechanical setup error as 2 mm and estimated the dose variation base on a 2 mm error. We prepared a HU-relative stopping power conversion table and fluence correction factor that were specific to the heterogeneous phantom. The fluence correction factor was determined as a function of depth and was obtained from the ratio of the doses in water and in the phantom at the same effective depths. In the simulated prostate plan, composite doses of measurements and calculations agreed within ±1.3% and the maximum local dose differences of each field were 10.0%. Composite doses in the simulated head and neck plan agreed within 4.0% and the maximum local dose difference for each field was 12.0%. The dose difference for each field came within 2% when taking the measurement uncertainty into consideration. In the composite plan, the maximum dose uncertainty was estimated as 4.0% in the simulated prostate plan and 5.8% in the simulated head and neck plan. Film measurements showed good agreement, with more than 92.5% of points passing a gamma value (3%/3 mm). From these results, the heterogeneous phantom should be useful for verification of IMPT by using a phantom-specific HU-relative stopping power conversion, fluence correction factor, and dose error estimation due to the effective point of the chamber., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

The purpose of this study was to provide periodic quality assurance (QA) methods for respiratory-gated proton beam with a range modulation wheel (RMW) and to clarify the characteristics and long-term stability of the respiratory-gated proton beam. A two-dimensional detector array and a solid water phantom were used to measure absolute dose, spread-out Bragg peak (SOBP) width and proton range for monthly QA. SOBP width and proton range were measured using an oblique incidence beam to the lateral side of a solid water phantom and compared between with and without a gating proton beam. To measure the delay time of beam-on/off for annual QA, we collected the beam-on/off signals and the dose monitor-detected pulse. We analyzed the results of monthly QA over a 15-month period and investigated the delay time by machine signal analysis. The dose deviations at proximal, SOBP center and distal points were -0.083 ± 0.25%, 0.026 ± 0.20%, and -0.083 ± 0.35%, respectively. The maximum dose deviation between with and without respiratory gating was -0.95% at the distal point and other deviations were within ±0.5%. Proximal and SOBP center doses showed the same trend over a 15-month period. Delay times of beam-on/off for 200 MeV/SOBP 16 cm were 140.5 ± 0.8 ms and 22.3 ± 13.0 ms, respectively. Delay times for 160 MeV/SOBP 10 cm were 167.5 ± 15.1 ms and 19.1 ± 9.8 ms. Our beam delivery system with the RMW showed sufficient stability for respiratory-gated proton therapy and the system did not show dependency on the energy and the respiratory wave form. The delay times of beam-on/off were within expectations. The proposed QA methods will be useful for managing the quality of respiratory-gated proton beams and other beam delivery systems., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Two prospective phase II trials were designed to assess the efficacy and safety of image-guided proton therapy (IGPT) for either medically inoperable or operable stage I non-small cell lung cancer (NSCLC). The present study reports the interim results of these trials., Methods: Fifty-five patients with histologically confirmed stage I NSCLC (IA in 33 patients and IB in 22 patients; inoperable in 21 patients and operable in 34 patients) who received IGPT between July 2013 and February 2017 were analyzed. The median patient age was 71 years (range: 48-88 years). IGPT with fiducial metallic marker matching was performed for suitable patients, and a respiratory gating method for motion management was used for all treatments. Peripherally located tumors were treated with 66 Gy relative biological effectiveness equivalents (Gy(RBE)) in 10 fractions (n = 49) and centrally located tumors were treated with 72.6 Gy(RBE) in 22 fractions (n = 6). Treatment associated toxicities were evaluated using Common Toxicity Criteria for Adverse Events (v.4.0)., Results: Median follow-up was 35 months (range: 12-54 months) for survivors. For all patients, the 3-year overall survival, progression-free survival, and local control rates were 87% (95% confidence interval: 73-94%), 74% (58-85%), and 96% (83-99%), respectively. Fiducial marker matching was used in 39 patients (71%). Grade 2 toxicities observed were radiation pneumonitis in 5 patients (9%), rib fracture in 2 (4%), and chest wall pain in 5 (9%). There were no grade 3 or higher acute or late toxicities., Conclusions: IGPT appears to be effective and well tolerated for all patients with stage I NSCLC., Trial Registration: Lung-001, 13-02-09 (9), registered 11 June 2013 and Lung-002, 13-02-10 (10), registered 11 June 2013.

During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC 20 of 3.0 μM and EC 50 of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.

Although luminescence of water lower in energy than the Cerenkov-light threshold during proton and carbon-ion irradiation has been found, the phenomenon has not yet been implemented for Monte Carlo simulations. The results provided by the simulations lead to misunderstandings of the physical phenomenon in optical imaging of water during proton and carbon-ion irradiation. To solve the problems, as well as to clarify the light production of the luminescence of water, we modified a Monte Carlo simulation code to include the light production from the luminescence of water and compared them with the experimental results of luminescence imaging of water. We used GEANT4 for the simulation of emitted light from water during proton and carbon-ion irradiation. We used the light production from the luminescence of water using the scintillation process in GEANT4 while those of Cerenkov light from the secondary electrons and prompt gamma photons in water were also included in the simulation. The modified simulation results showed similar depth profiles to those of the measured data for both proton and carbon-ion. When the light production of 0.1 photons/MeV was used for the luminescence of water in the simulation, the simulated depth profiles showed the best match to those of the measured results for both the proton and carbon-ion compared with those used for smaller and larger numbers of photons/MeV. We could successively obtain the simulated depth profiles that were basically the same as the experimental data by using GEANT4 when we assumed the light production by the luminescence of water. Our results confirmed that the inclusion of the luminescence of water in Monte Carlo simulation is indispensable to calculate the precise light distribution in water during irradiation of proton and carbon-ion.

1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated. 2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b. 3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major. 4. In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug-drug interactions.

Luminescence was found during pencil-beam proton irradiation to water phantom and range could be estimated from the luminescence images. However, it is not yet clear whether the luminescence imaging is applied to the uniform fields made of spot-scanning proton-beam irradiations. For this purpose, imaging was conducted for the uniform fields having spread out Bragg peak (SOBP) made by spot scanning proton beams. We designed six types of the uniform fields with different ranges, SOBP widths and irradiation fields. One of the designed fields was irradiated to water phantom and a cooled charge coupled device camera was used to measure the luminescence image during irradiations. We estimated the ranges, field widths, and luminescence intensities from the luminescence images and compared those with the dose distribution calculated by a treatment planning system. For all types of uniform fields, we could obtain clear images of the luminescence showing the SOBPs. The ranges and field widths evaluated from the luminescence were consistent with those of the dose distribution calculated by a treatment planning system within the differences of  -4 mm and  -11 mm, respectively. Luminescence intensities were almost proportional to the SOBP widths perpendicular to the beam direction. The luminescence imaging could be applied to uniform fields made of spot scanning proton beam irradiations. Ranges and widths of the uniform fields with SOBP could be estimated from the images. The luminescence imaging is promising for the range and field width estimations in proton therapy.

Background: Hypofractionated proton therapy (HFPT) is expected to become an effective treatment approach for localized prostate cancer (PCa). The purpose of this study was to evaluate differences in acute toxicity among patients with localized PCa treated with either conventional fractionated proton therapy (CFPT) or HFPT., Methods: A total of 526 eligible patients treated with proton therapy between February 2013 and May 2016 in three phase II trials were analyzed. We prescribed 74 gray relative biological effectiveness equivalents [Gy (RBE)]/37 fractions for low-risk patients and 78 Gy (RBE)/39 fractions for intermediate- and high-risk patients in the CFPT group (n = 254) and 60 Gy (RBE)/20 fractions for low-risk and 63 Gy (RBE)/21 fractions for intermediate- and high-risk patients in the HFPT group (n = 272). Patients were evaluated for acute toxicity with the Common Terminology Criteria for Adverse Events, version 4.0, and urinary quality-of-life change using the International Prostate Symptom Score (IPSS)., Results: No grade ≥3 acute toxicity was observed in either group. Among acute genitourinary toxicities, grade 2 rates were 15% (n = 38) in CFPT and 5.9% (n = 16) in HFPT (P ≤ 0.001). The median baseline IPSSs of the CFPT and HFPT groups were 7 (0-29) and 6 (0-31), respectively (P = 0.70). One-month post-treatment scores were 9 (0-32) and 11 (0-32), respectively (P = 0.036), and 6-month post-treatment scores were 7 (0-30) and 7 (0-33), respectively (P = 0.88). There were no significant differences in acute gastrointestinal toxicity between the two groups., Conclusion: Our results demonstrated the safety of HFPT for localized PCa patients in terms of acute toxicity.

Although the luminescence images of water during proton-beam irradiation using a cooled charge-coupled device camera showed almost the same ranges of proton beams as those measured by an ionization chamber, the depth profiles showed lower Bragg peak intensities than those measured by an ionization chamber. In addition, a broad optical baseline signal was observed in depths that exceed the depth of the Bragg peak. We hypothesize that this broad baseline signal originates from the interaction of proton-induced prompt gamma photons with water. These prompt gamma photons interact with water to form high-energy Compton electrons, which may cause luminescence or Cherenkov emission from depths exceeding the location of the Bragg peak. To clarify this idea, we measured the luminescence images of water during the irradiations of protons in water with minimized parallax errors, and also simulated the produced light by the interactions of prompt gamma photons with water. We corrected the measured depth profiles of the luminescence images by subtracting the simulated distributions of the produced light by the interactions of prompt gamma photons in water. Corrections were also conducted using the estimated depth profiles of the light of the prompt gamma photons, as obtained from the off-beam areas of the luminescence images of water. With these corrections, we successfully obtained depth profiles that have almost identical distributions as the simulated dose distributions for protons. The percentage relative height of the Bragg peak with corrections to that of the simulation data increased to 94% from 80% without correction. Also, the percentage relative offset heights of the deeper part of the Bragg peak with corrections decreased to 0.2%-0.4% from 4% without correction. These results indicate that the luminescence imaging of water has potential for the dose distribution measurements for proton therapy dosimetry.

Monitoring the in vivo dose distribution in proton therapy is desirable for the accurate irradiation of a tumor. Although positron emission tomography (PET) is widely used for confirmation, the obtained distribution of positron emitters produced by the protons does not trace the dose distribution due to the different physical processes. To estimate the accurate dose from the PET image, the cross sections of nuclear reactions that produce positron emitters are important yet far from being sufficient. In this study, we measured the cross sections of 16 O(p,x) 15 O, 16 O(p,x) 13 N, and 16 O(p,x) 11 C with a wide-energy range (approximately 5-70 MeV) by observing the temporal evolution of the Cherenkov radiation emitted from positrons generated via β + decay along the proton path. Furthermore, we implemented the new cross sectional data into a conventional Monte Carlo (MC) simulation, so that a direct comparison was possible with the PET measurement. We confirmed that our MC results showed good agreement with the experimental data, both in terms of the spatial distributions and temporal evolutions. Although this is the first attempt at using the Cherenkov radiation in the measurements of nuclear cross sections, the obtained results suggest the method is convenient and widely applicable for high precision proton therapy.

In this study, we evaluate dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy (IMPT) for head and neck tumors at the shallow depth. We used four types of patient-specific aperture system (PSAS) to irradiate shallow regions less than 4 g/cm 2 with a sharp lateral penumbra. Ten head and neck IMPT plans with or without aperture were optimized separately with the same 95% prescription dose and same dose constraint for organs at risk (OARs). The plans were compared using dose volume histograms (DVHs), dose distributions, and some dose indexes such as volume receiving 50% of the prescribed dose (V 50 ), mean or maximum dose (D mean and D max ) to the OARs. All examples verified in this study had decreased V 50 and OAR doses. Average, maximum, and minimum relative reductions of V 50 were 15.4%, 38.9%, and 1.0%, respectively. D max and D mean of OARs were decreased by 0.3% to 25.7% and by 1.0% to 46.3%, respectively. The plans with the aperture over more than half of the field showed decreased V 50 or OAR dose by more than 10%. The dosimetric advantage of patient-specific apertures with IMPT was clarified in many cases. The PSAS has some dosimetric advantages for clinical use, and in some cases, it enables to fulfill dose constraints., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Detailed information regarding differences in plantar pressure distribution between hallux valgus and healthy feet is unavailable. The purposes of the present study were to clarify the characteristics of the plantar pressure distribution in patients with hallux valgus compared with healthy matched controls and to determine whether hallux valgus leads to dysfunction of the great toe during walking., Methods: The study consisted of 25 patients with symptomatic moderate-to-severe hallux valgus (HV group) and 13 healthy matched volunteers (C group) without hallux valgus. All patients and volunteers were women. The HV and C groups did not differ significantly in age, height, weight, and body mass index. Plantar pressure during walking was measured using F-scan. The plantar aspect of the foot was divided into eight regions. The peak pressure (Peak-P), maximum force (Max-F), contact time (Con-T), contact area (Con-A), and force time integral (FTI) were measured in each region., Results: The Peak-P of the great toe did not differ significantly between the HV and C groups. However, all other parameters: Max-F, Con-T, Con-A, and FTI of the great toe in the HV group were significantly lower than in the C group. In the central forefoot, the Peak-P and Max-F in the HV group were significantly higher than in the C group., Conclusion: The present study demonstrated that a moderate-to-severe hallux valgus deformity leads to dysfunction of the great toe during walking and may increase mechanical loading on the central forefoot., (Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [ 14 C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

Background: Objective data on chronic injuries of the medial collateral ligament (MCL) of the ankle are scarce. Chronic MCL injuries are frequently associated with lateral collateral ligament (LCL) injuries. For patients with chronic combined MCL and LCL injuries, the authors have performed simultaneous surgery of the 2 ligaments., Hypothesis: Simultaneous surgery of the 2 ligaments may be effectively used to treat chronic combined MCL and LCL injuries., Study Design: Case series; Level of evidence, 4., Methods: Surgical outcomes were evaluated in 29 consecutive patients presenting with chronic MCL and LCL injuries (30 ankles; 15 men and 14 women; mean age, 31 years; 13 competitive and 10 recreational athletes). Preoperative and postoperative clinical outcomes were measured with the Karlsson score and the Japanese Society for Surgery of the Foot (JSSF) ankle-hindfoot scale score. The patients underwent preoperative and postoperative functional measurements and a radiological examination. In addition, preoperative magnetic resonance imaging (MRI) results, arthroscopic findings, and histology of the MCL were evaluated., Results: Preoperatively, the deep fibers of the MCL did not appear striated in 29 ankles, and high-intensity signal changes were observed in 23 ankles on T2-weighted or gradient echo MRI. MCL ruptures were confirmed with arthroscopic surgery. Medial impingement lesions and focal chondral lesions were confirmed in 10 and 21 ankles, respectively. Histology of the reconstructed MCL showed dense collagen fibers with vessels. The mean postoperative follow-up period was 30 months (range, 24-52 months). There was a significant change between preoperative and postoperative Karlsson scores (69.0 vs 96.1 points, respectively; P < .0001) and JSSF scores (69.8 vs 94.5 points, respectively; P < .0001). On varus and valgus stress radiography, the postoperative talar tilt angle was significantly lower than the preoperative angle. Postoperative anterior displacement on stress radiography was significantly lower than preoperative anterior displacement. Postoperatively, all 23 athletes returned to their preinjury level of sports participation., Conclusion: MCL insufficiency resulted from medial ankle instability and medial impingement lesions. Outcomes in the patients indicated that MCL reconstruction or resection of medial impingement lesions, performed in addition to LCL reconstruction, is effective for treating chronic combined MCL and LCL injuries of the ankle.

Imaging of secondary electron bremsstrahlung x-ray emitted during proton irradiation is a possible method for measurement of the proton beam distribution in phantom. However, it is not clear that the method is used for range estimation of protons. For this purpose, we developed a low-energy x-ray camera and conducted imaging of the bremsstrahlung x-ray produced during irradiation of proton beams. We used a 20 mm  ×  20 mm  ×  1 mm finely grooved GAGG scintillator that was optically coupled to a one-inch square high quantum efficiency (HQE)-type position-sensitive photomultiplier tube to form an imaging detector. The imaging detector was encased in a 2 cm-thick tungsten container, and a pinhole collimator was attached to its camera head. After performance of the camera was evaluated, secondary electron bremsstrahlung x-ray imaging was conducted during irradiation of the proton beams for three different proton energies, and the results were compared with Monte Carlo simulation as well as calculated value. The system spatial resolution and sensitivity of the developed x-ray camera with 1.5 mm-diameter pinhole collimator were estimated to be 32 mm FWHM and 5.2  ×  10 -7 for ~35 keV x-ray photons at 100 cm from the collimator surface, respectively. We could image the proton beam tracks by measuring the secondary electron bremsstrahlung x-ray during irradiation of the proton beams, and the ranges for different proton energies could be estimated from the images. The measured ranges from the images were well matched with the Monte Carlo simulation, and slightly smaller than the calculated values. We confirmed that the imaging of the secondary electron bremsstrahlung x-ray emitted during proton irradiation with the developed x-ray camera has the potential to be a new tool for proton range estimations.

Objective: The aim of the present study was to evaluate the effects of PRP on Achilles tendon healing in rabbits during the inflammatory, proliferative, and remodeling phases by histological examination and quantitative assessments., Methods: Fifty mature male Japanese albino rabbits with severed Achilles tendons were divided into two equal groups and treated with platelet-rich plasma (PRP) or left untreated. Tendon tissue was harvested at 1, 2, 3, 4, and 6 weeks after treatment, and sections were stained with hematoxylin-eosin and monoclonal antibodies against CD31 and type I collagen., Results: Collagen fibers proliferated more densely early after severance, and subsequent remodeling of the collagen fibers and approximation of normal tendinous tissue occurred earlier in the PRP group than in the control group. The fibroblast number was significantly higher in the PRP group than in the control group at 1 and 2 weeks. Similarly, the area ratio of CD31-positive cells was significantly higher in the PRP group than in the control group at 1 and 2 weeks. Positive staining for type I collagen was more intense in the PRP group than in the control group after 3 weeks, indicating tendon maturation., Conclusion: Administration of PRP shortened the inflammatory phase and promoted tendon healing during the proliferative phase., (Copyright © 2016 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

The purpose of this paper is to describe an outline of a proton therapy system in Nagoya Proton Therapy Center (NPTC). The NPTC has a synchrotron with a linac injector and three treatment rooms: two rooms are equipped with a gantry and the other one is equipped with a fixed horizontal beamline. One gantry treatment room has a pencil beam scanning treatment delivery nozzle. The other two treatment rooms have a passive scattering treatment delivery nozzle. In the scanning treatment delivery nozzle, an energy absorber and an aperture system to treat head and neck cancer have been equipped. In the passive treatment delivery nozzle, a multi-leaf collimator is equipped. We employ respiratory gating to treat lung and liver cancers for passive irradiation. The proton therapy system passed all acceptance tests. The first patient was treated on February 25, 2013, using passive scattering fixed beams. Respiratory gating is commonly used to treat lung and liver cancers in the passive scattering system. The MLCs are our first choice to limit the irradiation field. The use of the aperture for scanning irradiation reduced the lateral fall off by half or less. The energy absorber and aperture system in scanning delivery is beneficial to treat head and neck cancer.

The aim of this study was to compare the dosimetric parameters of whole-pelvic radiotherapy (WPRT) for cervical cancer among plans involving 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), or spot-scanning proton therapy (SSPT). The dose distributions of 3D-CRT-, IMRT-, and SSPT-based WPRT plans were compared in 10 patients with cervical cancer. All of the patients were treated with a prescribed dose of 50.4 Gy in 1.8-Gy daily fractions, and all of the plans involved the same planning target volume (PTV) constrictions. A 3D-CRT plan involving a four-field box, an IMRT plan involving seven coplanar fields, and an SSPT plan involving four fields were created. The median PTV D95% did not differ between the 3D-CRT, IMRT and SSPT plans. The median conformity index 95% and homogeneity index of the IMRT and SSPT were better than those of the 3D-CRT. The homogeneity index of the SSPT was better than that of the IMRT. SSPT resulted in lower median V20 values for the bladder wall, small intestine, colon, bilateral femoral heads, skin, and pelvic bone than IMRT. Comparing the Dmean values, SSPT spared the small intestine, colon, bilateral femoral heads, skin and pelvic bone to a greater extent than the other modalities. SSPT can reduce the irradiated volume of the organs at risk compared with 3D-CRT and IMRT, while maintaining excellent PTV coverage. Further investigations of SSPT are warranted to assess its role in the treatment of cervical cancer., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Several surgical procedures for chronically ruptured Achilles tendons have been reported. Resection of the interposed scar tissue located between the tendon stumps and reconstruction using normal autologous tissue have been well described. We developed a direct repair procedure that uses scar tissue, which obviates the need to use normal autologous tissue., Methods: Thirty consecutive patients with Achilles tendon ruptures with a delay in diagnosis of >4 weeks underwent removal of a section of scar and healing tissue with direct primary suture of the ends of the tendon without the use of allograft or autograft. Patients were followed for a mean time of 33 months. Preoperative and postoperative clinical outcomes were measured with the Achilles Tendon Total Rupture Score (ATRS) and the American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score. In addition, the patients underwent preoperative and postoperative functional measurements and magnetic resonance imaging. Lastly, we evaluated the histology of the interposed healing tissue., Results: The mean AOFAS scores were 82.8 points preoperatively and 98.1 points postoperatively. The mean postoperative ATRS was 92.0 points. At the time of the latest follow-up, none of the patients had experienced tendon reruptures or difficulties in walking or climbing stairs, and all except 2 patients could perform a single-limb heel rise. All athletes had returned to their pre-injury level of sports participation. Preoperative T2-weighted magnetic resonance imaging showed that 22 Achilles tendons were thickened with diffuse intratendinous high-signal alterations, and 8 Achilles tendons were thinned. Postoperative T2-weighted magnetic resonance imaging findings included fusiform-shaped tendon thickening and homogeneous low-signal alterations of the tendons in all patients. Histologically, the interposed scar tissue consisted of dense collagen fibers., Conclusions: Shortening of the tissue between the 2 tendon ends that included healing scar and direct repair of healing tendon without allograft or autograft can be effective for treatment-delayed or neglected Achilles tendon rupture., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.)

Purpose: The authors previously reported successful luminescence imaging of water during proton irradiation and its application to range estimation. However, since the feasibility of this approach for carbon-ion irradiation remained unclear, the authors conducted luminescence imaging during carbon-ion irradiation and estimated the ranges., Methods: The authors placed a pure-water phantom on the patient couch of a carbon-ion therapy system and measured the luminescence images with a high-sensitivity, cooled charge-coupled device camera during carbon-ion irradiation. The authors also carried out imaging of three types of phantoms (tap-water, an acrylic block, and a plastic scintillator) and compared their intensities and distributions with those of a phantom containing pure-water., Results: The luminescence images of pure-water phantoms during carbon-ion irradiation showed clear Bragg peaks, and the measured carbon-ion ranges from the images were almost the same as those obtained by simulation. The image of the tap-water phantom showed almost the same distribution as that of the pure-water phantom. The acrylic block phantom's luminescence image produced seven times higher luminescence and had a 13% shorter range than that of the water phantoms; the range with the acrylic phantom generally matched the calculated value. The plastic scintillator showed ∼15 000 times higher light than that of water., Conclusions: Luminescence imaging during carbon-ion irradiation of water is not only possible but also a promising method for range estimation in carbon-ion therapy.

Purpose: To determine the relative biological effectiveness (RBE), oxygen enhancement ratio (OER), and contribution of the indirect effect of spot scanning proton beams, passive scattering proton beams, or both in cultured cells in comparison with clinically used photons., Methods and Materials: The RBE of passive scattering proton beams at the center of the spread-out Bragg peak (SOBP) was determined from dose-survival curves in 4 cell lines using 6-MV X rays as controls. Survival of 2 cell lines after spot scanning and passive scattering proton irradiation was then compared. Biological effects at the distal end region of the SOBP were also investigated. The OER of passive scattering proton beams and 6 MX X rays were investigated in 2 cell lines. The RBE and OER values were estimated at a 10% cell survival level. The maximum degree of protection of radiation effects by dimethyl sulfoxide was determined to estimate the contribution of the indirect effect against DNA damage. All experiments comparing protons and X rays were made under the same biological conditions., Results: The RBE values of passive scattering proton beams in the 4 cell lines examined were 1.01 to 1.22 (average, 1.14) and were almost identical to those of spot scanning beams. Biological effects increased at the distal end of the SOBP. In the 2 cell lines examined, the OER was 2.74 (95% confidence interval, 2.56-2.80) and 3.08 (2.84-3.11), respectively, for X rays, and 2.39 (2.38-2.43) and 2.72 (2.69-2.75), respectively, for protons (P<.05 for both cells between X rays and protons). The maximum degree of protection was significantly higher for X rays than for proton beams (P<.05)., Conclusions: The RBE values of spot scanning and passive scattering proton beams were almost identical. The OER was lower for protons than for X rays. The lower contribution of the indirect effect may partly account for the lower OER of protons., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: The main purpose in this study was to present the results of beam modeling and how the authors systematically investigated the influence of double and triple Gaussian proton kernel models on the accuracy of dose calculations for spot scanning technique., Methods: The accuracy of calculations was important for treatment planning software (TPS) because the energy, spot position, and absolute dose had to be determined by TPS for the spot scanning technique. The dose distribution was calculated by convolving in-air fluence with the dose kernel. The dose kernel was the in-water 3D dose distribution of an infinitesimal pencil beam and consisted of an integral depth dose (IDD) and a lateral distribution. Accurate modeling of the low-dose region was important for spot scanning technique because the dose distribution was formed by cumulating hundreds or thousands of delivered beams. The authors employed a double Gaussian function as the in-air fluence model of an individual beam. Double and triple Gaussian kernel models were also prepared for comparison. The parameters of the kernel lateral model were derived by fitting a simulated in-water lateral dose profile induced by an infinitesimal proton beam, whose emittance was zero, at various depths using Monte Carlo (MC) simulation. The fitted parameters were interpolated as a function of depth in water and stored as a separate look-up table. These stored parameters for each energy and depth in water were acquired from the look-up table when incorporating them into the TPS. The modeling process for the in-air fluence and IDD was based on the method proposed in the literature. These were derived using MC simulation and measured data. The authors compared the measured and calculated absolute doses at the center of the spread-out Bragg peak (SOBP) under various volumetric irradiation conditions to systematically investigate the influence of the two types of kernel models on the dose calculations., Results: The authors investigated the difference between double and triple Gaussian kernel models. The authors found that the difference between the two studied kernel models appeared at mid-depths and the accuracy of predicting the double Gaussian model deteriorated at the low-dose bump that appeared at mid-depths. When the authors employed the double Gaussian kernel model, the accuracy of calculations for the absolute dose at the center of the SOBP varied with irradiation conditions and the maximum difference was 3.4%. In contrast, the results obtained from calculations with the triple Gaussian kernel model indicated good agreement with the measurements within ±1.1%, regardless of the irradiation conditions., Conclusions: The difference between the results obtained with the two types of studied kernel models was distinct in the high energy region. The accuracy of calculations with the double Gaussian kernel model varied with the field size and SOBP width because the accuracy of prediction with the double Gaussian model was insufficient at the low-dose bump. The evaluation was only qualitative under limited volumetric irradiation conditions. Further accumulation of measured data would be needed to quantitatively comprehend what influence the double and triple Gaussian kernel models had on the accuracy of dose calculations.

Purpose: In the authors' proton therapy system, the patient-specific aperture can be attached to the nozzle of spot scanning beams to shape an irradiation field and reduce lateral fall-off. The authors herein verified this system for clinical application., Methods: The authors prepared four types of patient-specific aperture systems equipped with an energy absorber to irradiate shallow regions less than 4 g/cm(2). The aperture was made of 3-cm-thick brass and the maximum water equivalent penetration to be used with this system was estimated to be 15 g/cm(2). The authors measured in-air lateral profiles at the isocenter plane and integral depth doses with the energy absorber. All input data were obtained by the Monte Carlo calculation, and its parameters were tuned to reproduce measurements. The fluence of single spots in water was modeled as a triple Gaussian function and the dose distribution was calculated using a fluence dose model. The authors compared in-air and in-water lateral profiles and depth doses between calculations and measurements for various apertures of square, half, and U-shaped fields. The absolute doses and dose distributions with the aperture were then validated by patient-specific quality assurance. Measured data were obtained by various chambers and a 2D ion chamber detector array., Results: The patient-specific aperture reduced the penumbra from 30% to 70%, for example, from 34.0 to 23.6 mm and 18.8 to 5.6 mm. The calculated field width for square-shaped apertures agreed with measurements within 1 mm. Regarding patient-specific aperture plans, calculated and measured doses agreed within -0.06% ± 0.63% (mean ± SD) and 97.1% points passed the 2%-dose/2 mm-distance criteria of the γ-index on average., Conclusions: The patient-specific aperture system improved dose distributions, particularly in shallow-region plans.

Purpose: Proton therapy has the ability to selectively deliver a dose to the target tumor, so the dose distribution should be accurately measured by a precise and efficient method. The authors found that luminescence was emitted from water during proton irradiation and conjectured that this phenomenon could be used for estimating the dose distribution., Methods: To achieve more accurate dose distribution, the authors set water phantoms on a table with a spot scanning proton therapy system and measured the luminescence images of these phantoms with a high-sensitivity, cooled charge coupled device camera during proton-beam irradiation. The authors imaged the phantoms of pure water, fluorescein solution, and an acrylic block., Results: The luminescence images of water phantoms taken during proton-beam irradiation showed clear Bragg peaks, and the measured proton ranges from the images were almost the same as those obtained with an ionization chamber. Furthermore, the image of the pure-water phantom showed almost the same distribution as the tap-water phantom, indicating that the luminescence image was not related to impurities in the water. The luminescence image of the fluorescein solution had ∼3 times higher intensity than water, with the same proton range as that of water. The luminescence image of the acrylic phantom had a 14.5% shorter proton range than that of water; the proton range in the acrylic phantom generally matched the calculated value. The luminescence images of the tap-water phantom during proton irradiation could be obtained in less than 2 s., Conclusions: Luminescence imaging during proton-beam irradiation is promising as an effective method for range estimation in proton therapy.

Background: Hallux valgus (HV) is occasionally associated with chronic dislocation of the lesser metatarsophalangeal (MTP) joints. We have developed a novel surgical procedure to treat dislocation of the lesser MTP joints. This study aimed to describe our procedure and investigate the outcomes of surgical intervention in the treatment of HV with dislocation of the lesser MTP joints., Methods: Twenty-three patients (27 feet, average age: 63.6 years, average follow-up: 49.5 months; a minimum follow-up of 24 months) underwent surgical intervention for HV and dislocation of the lesser MTP joints. Twenty-three feet had dislocation (10 feet) or subluxation (13 feet) of the second MTP joint, whereas 4 feet had dislocation of the second and third MTP joints. The surgical procedure included a distal soft-tissue procedure combined with proximal osteotomy for correction of the HV, and reconstruction of the collateral ligaments (CL) following open reduction with complete release of the capsule and the CL at the metatarsal head for dislocation of the lesser MTP joints. Outcomes were assessed using the Japanese Society for Surgery of the Foot (JSSF) scale and radiological examinations., Results: The JSSF score improved significantly from an average of 49.7 points preoperatively to 93.1 points postoperatively. The average HV angle and intermetatarsal angle decreased significantly from 44.6° and 18.1° preoperatively to 7.9° and 6.0° postoperatively, respectively. The average extension and flexion of the second MTP joint was 53.1° and 13.8° at the most recent follow-up, respectively. Postoperatively, no feet had dislocation of the second or third MTP joint, three had subluxation of the second MTP joint, and one had subluxation of the third MTP joint. Osteoarthritis of the lesser MTP joint had developed in two feet (7.4 %) at the time of the most recent follow-up., Conclusion: Our surgical procedure achieved significant correction of HV, a low rate of postoperative re-dislocation of the lesser MTP joints, and significant improvement of pain and function for symptomatic moderate-to-severe HV with dislocation of the lesser MTP joints., Level of Evidence: Level IV, retrospective case series.

We developed a prototype positron emission tomography (PET) system based on a new concept called Open-close PET, which has two modes: open and close-modes. In the open-mode, the detector ring is separated into two halved rings and subject is imaged with the open space and projection image is formed. In the close-mode, the detector ring is closed to be a regular circular ring, and the subject can be imaged without an open space, and so reconstructed images can be made without artifacts. The block detector of the Open-close PET system consists of two scintillator blocks that use two types of gadolinium orthosilicate (GSO) scintillators with different decay times, angled optical fiber-based image guides, and a flat panel photomultiplier tube. The GSO pixel size was 1.6 × 2.4 × 7 mm and 8 mm for fast (35 ns) and slow (60 ns) GSOs, respectively. These GSOs were arranged into an 11 × 15 matrix and optically coupled in the depth direction to form a depth-of-interaction detector. The angled optical fiber-based image guides were used to arrange the two scintillator blocks at 22.5° so that they can be arranged in a hexadecagonal shape with eight block detectors to simplify the reconstruction algorithm. The detector ring was divided into two halves to realize the open-mode and set on a mechanical stand with which the distance between the two parts can be manually changed. The spatial resolution in the close-mode was 2.4-mm FWHM, and the sensitivity was 1.7% at the center of the field-of-view. In both the close- and open-modes, we made sagittal (y-z plane) projection images between the two halved detector rings. We obtained reconstructed and projection images of (18)F-NaF rat studies and proton-irradiated phantom images. These results indicate that our developed Open-close PET is useful for some applications such as proton therapy as well as other applications such as molecular imaging.

Background: Risk factors for hallux valgus recurrence include postoperative round-shaped lateral edge of the first metatarsal head and postoperative incomplete reduction of the sesamoids. To prevent the occurrence of such conditions, we developed a proximal supination osteotomy of the first metatarsal. Our aim was to describe this novel technique and report the outcomes in this report., Methods: Sixty-six patients (83 feet) underwent a distal soft tissue procedure combined with a proximal supination osteotomy. After the proximal crescentic osteotomy, the proximal fragment was pushed medially, and the distal fragment was abducted, and then the distal fragment of the first metatarsal was manually supinated. Outcomes were assessed using the American Orthopaedic Foot & Ankle Society (AOFAS) score and radiographic examinations. The average follow-up duration was 34 (range, 25 to 52) months., Results: The mean AOFAS score improved significantly from 58.0 points preoperatively to 93.8 points postoperatively (P < .0001). The mean hallux valgus and intermetatarsal angle decreased significantly from 38.6 and 18.0 degrees preoperatively to 11.0 and 7.9 degrees postoperatively, respectively (both, P < .0001). Sixty-nine feet (69/83, 83%) had a positive round sign preoperatively, and 66 feet (66/83, 80%) had a negative round sign postoperatively. According to the Hardy's classification of position of the sesamoids, all feet were classified as grade V or greater preoperatively, and 49 feet (49/83, 59%) were classified as grade IV or less postoperatively. Three feet (3/83, 4%) had recurrence of hallux valgus, defined as a hallux valgus angle ≥ 25 degrees., Conclusion: The rates of occurrence of a positive round sign and incomplete reduction of the sesamoids significantly decreased postoperatively, which may have contributed to the low hallux valgus recurrence rates. We conclude that a proximal supination osteotomy was an effective procedure for correction of hallux valgus and can achieve a low rate of hallux valgus recurrence., Level of Evidence: Level IV, retrospective case series., (© The Author(s) 2015.)

Purpose: In proton therapy, imaging of proton-induced positrons is a useful method to monitor the proton beam distribution after therapy. Usually, a positron emission tomography (PET) system installed in or near the proton beam treatment room is used for this purpose. However, a PET system is sometimes too large and expensive for this purpose. We developed a small field-of-view (FOV) gamma camera for high-energy gamma photons and used it for monitoring the proton-induced positron distribution., Methods: The gamma camera used 0.85 mm × 0.85 mm × 10 mm Ce:Gd3Al2Ga3O12 (GAGG) pixels arranged in 20 × 20 matrix to form a scintillator block, which was optically coupled to a 1-inch-square position-sensitive photomultiplier tube (PSPMT). The GAGG detector was encased in a 20-mm thick container and a pinhole collimator was mounted on its front. The gamma camera was set 1.2 m from the 35 cm × 35 cm × 5 cm plastic phantom in the proton therapy treatment room, and proton beams were irradiated to the phantom with two proton energies., Results: The gamma camera had spatial resolution of ~6.7 cm and sensitivity of 3.2 × 10(-7) at 1 m from the collimator surface. For both proton energies, positron distribution in the phantom could be imaged by the gamma camera with 10-min acquisition. The lengths of the range of protons measured from the images were almost identical to the simulation results., Conclusions: These results indicate that the developed high-energy gamma camera is useful for imaging positron distributions in proton therapy.

Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH5137291 is expected to offer a novel therapeutic approach against major types of castration-resistant prostate cancers.

Purpose: In proton therapy, imaging of the positron distribution produced by fragmentation during or soon after proton irradiation is a useful method to monitor the proton range. Although positron emission tomography (PET) is typically used for this imaging, its spatial resolution is limited. Cerenkov light imaging is a new molecular imaging technology that detects the visible photons that are produced from high-speed electrons using a high sensitivity optical camera. Because its inherent spatial resolution is much higher than PET, the authors can measure more precise information of the proton-induced positron distribution with Cerenkov light imaging technology. For this purpose, they conducted Cerenkov light imaging of induced positron distribution in proton therapy., Methods: First, the authors evaluated the spatial resolution of our Cerenkov light imaging system with a (22)Na point source for the actual imaging setup. Then the transparent acrylic phantoms (100 × 100 × 100 mm(3)) were irradiated with two different proton energies using a spot scanning proton therapy system. Cerenkov light imaging of each phantom was conducted using a high sensitivity electron multiplied charge coupled device (EM-CCD) camera., Results: The Cerenkov light's spatial resolution for the setup was 0.76 ± 0.6 mm FWHM. They obtained high resolution Cerenkov light images of the positron distributions in the phantoms for two different proton energies and made fused images of the reference images and the Cerenkov light images. The depths of the positron distribution in the phantoms from the Cerenkov light images were almost identical to the simulation results. The decay curves derived from the region-of-interests (ROIs) set on the Cerenkov light images revealed that Cerenkov light images can be used for estimating the half-life of the radionuclide components of positrons., Conclusions: High resolution Cerenkov light imaging of proton-induced positron distribution was possible. The authors conclude that Cerenkov light imaging of proton-induced positron is promising for proton therapy.

Background: Surgical treatment of adolescent hallux valgus has been a challenging intervention because of high rates of postoperative recurrence. The purposes of this study were to describe a proximal abduction-supination osteotomy of the first metatarsal and prospectively review preliminary results of this procedure for correction of adolescent hallux valgus., Methods: Eleven patients (12 feet) who had had a proximal abduction-supination osteotomy of the first metatarsal combined with a distal soft-tissue procedure to correct an adolescent hallux valgus deformity were prospectively reviewed clinically and radiologically. The average duration of follow-up was 22 months. The average age at the time of surgery was 17 years., Results: The mean score on the Japanese Society for Surgery of the Foot standard rating system for hallux improved significantly, from 62.0 points preoperatively to 99.2 points postoperatively (p = 0.002). All patients were satisfied and would choose to have the same procedure again. The mean hallux valgus angle decreased significantly, from 32.3° preoperatively to 12.2° postoperatively (p = 0.002); mean intermetatarsal angle decreased significantly from 14.0° preoperatively to 6.2° postoperatively (p = 0.002). No feet had postoperative recurrence of hallux valgus (a hallux valgus angle ≥20°). There were no occurrences of nonunion or transfer lesions., Conclusions: The clinical and radiological results of this study demonstrate that a proximal abduction-supination osteotomy with a distal soft-tissue procedure, which described in this study, achieved significant correction of an adolescent hallux valgus deformity, significant improvement in pain and function, and reduction in rate of recurrence.

We investigated the applicability of the repairable-conditionally repairable (RCR) model and the multi-target (MT) model to dose conversion in high-dose-per-fraction radiotherapy in comparison with the linear-quadratic (LQ) model. Cell survival data of V79 and EMT6 single cells receiving single doses of 2-12 Gy or 2 or 3 fractions of 4 or 5 Gy each, and that of V79 spheroids receiving single doses of 5-26 Gy or 2-5 fractions of 5-12 Gy, were analyzed. Single and fractionated doses to actually reduce cell survival to the same level were determined by a colony assay. Single doses used in the experiments and surviving fractions at the doses were substituted into equations of the RCR, MT and LQ models in the calculation software Mathematica, and each parameter coefficient was computed. Thereafter, using the coefficients and the three models, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually-determined equivalent single doses for the hypofractionated doses. The equivalent single doses calculated using the RCR, MT and LQ models tended to be lower than the actually determined equivalent single doses. The LQ model seemed to fit relatively well at doses of 5 Gy or less. At 6 Gy or higher doses, the RCR and MT models seemed to be more reliable than the LQ model. In hypofractionated stereotactic radiotherapy, the LQ model should not be used, and conversion models incorporating the concept of the RCR or MT models, such as the generalized linear-quadratic models, appear to be more suitable.