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A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.
Okonogi, N, Murata, K, Yamada, S, Habu, Y, Hori, M, Kurokawa, T, Inaba, Y, Fujiwara, T, Fujii, Y, Hanawa, M, et al
International journal of molecular sciences. 2023;(13)
Abstract
We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.
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A Randomized, Double-Blind, Controlled Trial Assessing If Medium-Chain Triglycerides in Combination with Moderate-Intensity Exercise Increase Muscle Strength in Healthy Middle-Aged and Older Adults.
Kojima, K, Ishikawa, H, Watanabe, S, Nosaka, N, Mutoh, T
Nutrients. 2023;(14)
Abstract
An adequate nutritional intake is recommended for the prevention of physical frailty and sarcopenia. In particular, medium-chain fatty acids (MCFAs) are reportedly important for muscle strength in nursing home residents. However, the effects of MCFAs on healthy adults at risk for frailty remain unknown. Hence, a randomized, placebo-controlled study was conducted to investigate the effects of 12 weeks of medium-chain triglycerides (MCTs) intake and walking on muscle mass and function in healthy, sedentary, middle-aged and older adults with a low body mass index. Three MCT intake groups with different amounts of octanoic and decanoic acid intake were compared with a control group. After 12 weeks, knee extension strength increased in all groups, with the increases in all MCT intake groups being significantly higher than those in the control group (p < 0.05). Grip strength significantly increased from baseline in the MCT 6 g/day intake group (p < 0.05). The combination of aerobic exercise and MCT intake may be effective in preventing decline in muscle strength and promoting increase in muscle strength as they can improve muscle energy production, thereby contributing to the maintenance of good health for middle-aged and older adults at high risk for frailty and sarcopenia.
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A Japanese registry study and systematic review of particle therapy for renal cell carcinoma.
Ishikawa, H, Arimura, T, Maruo, K, Kawamura, H, Toyama, S, Ogino, T, Okimoto, T, Murakami, M, Sato, Y, Nishioka, K, et al
Journal of radiation research. 2023;(Supplement_1):i41-i48
Abstract
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.
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Effect of medium-chain triglycerides supplements and walking on health-related quality of life in sedentary, healthy middle-aged, and older adults with low BMIs: a randomized, double-blind, placebo-controlled, parallel-group trial.
Ishikawa, H, Kojima, K, Watanabe, S, Nosaka, N, Mutoh, T
Frontiers in nutrition. 2023;:1296896
Abstract
INTRODUCTION To extend individuals' healthy life expectancies, the improvement of subjective health and quality of life (QOL) has been increasingly prioritized, alongside the improvement of their physical functioning. Reports have indicated that intake of medium-chain triglycerides (MCTs) benefits the physical health of older individuals requiring nursing care, and athletes, and healthy individuals. But there are few studies investigating the effects of MCTs on subjective health and QOL. The present study sought to evaluate the combined effects of 12-week MCTs supplements and moderate-intensity walking exercise on the subjective health and QOL of middle-aged and older adults aged 60-74 with low BMIs (< 24 kg/m2) and who had no exercise habits. METHODS A placebo-controlled, double-blind, parallel-group trial was conducted. Three MCTs supplement groups with different doses and fatty acid compositions were compared with a control group. The study used the SF-36v2 questionnaire to assess subjective health and health-related QOL (HRQOL). RESULTS The result showed significant improvements in the scores on subscales of the physical QOL, such as Physical functioning and General health, and summary scores on the mental QOL, compared to the control. CONCLUSION It is estimated that the combination of continuous intake of MCTs and walking exercise may affect HRQOL and improve subjective physical and mental health in sedentary, healthy, middle-aged and older adults. CLINICAL TRIAL REGISTRATION https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000046861, UMIN000046861.
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Proton beam therapy for muscle-invasive bladder cancer: A systematic review and analysis with Proton-Net, a multicenter prospective patient registry database.
Araya, M, Ishikawa, H, Nishioka, K, Maruo, K, Asakura, H, Iizumi, T, Takagi, M, Murakami, M, Azuma, H, Obara, W, et al
Journal of radiation research. 2023;(Supplement_1):i49-i58
Abstract
To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40-41.4 Gy (relative biological effectiveness (RBE) delivered in 20-23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8-36.3 Gy (RBE) delivered in 10-14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57-84.8% in OS, 39-78% in PFS and 51-68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC.
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Efficacy of active hexose correlated compound on survival of patients with resectable/borderline resectable pancreatic cancer: a study protocol for a double-blind randomized phase II study.
Hashimoto, D, Satoi, S, Ishikawa, H, Kodera, Y, Kamei, K, Hirano, S, Fujii, T, Uemura, K, Tsuchida, A, Yamada, S, et al
Trials. 2022;(1):135
Abstract
BACKGROUND The prognosis of pancreatic ductal adenocarcinoma remains very poor. One possible reason for the short survival of patients with this disease is malnutrition, which can be present at the initial diagnosis, and continue after pancreatectomy. Then, it is important to improve nutritional status and to decrease adverse events during neoadjuvant and adjuvant chemotherapy. Active hexose correlated compound (AHCC) is a standardized extract of cultured Lentinula edodes mycelia, and is considered a potent biological response modifier in the treatment of cancer. To evaluate the survival impact of AHCC on the patients with pancreatic ductal adenocarcinoma, we plan to perform this trial. METHODS This is a prospective multicenter phase II trial in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma to investigate the efficacy of AHCC regarding survival. Patients will begin taking AHCC or placebo on the first day of neoadjuvant therapy. AHCC or placebo will be continued until 2 years after surgery. The primary endpoint will be 2-year disease-free survival. The secondary endpoints are the completion rate, dose intensity, and adverse event profile of preoperative chemotherapy; response rate to preoperative chemotherapy; rate of decrease in tumor marker (carbohydrate antigen 19-9, carcinoembryonic antigen) concentrations during preoperative chemotherapy; entry rate, completion rate, dose intensity, and adverse event profile of adjuvant chemotherapy; safety of the protocol therapy (adverse effect of AHCC); 2-year overall survival rate; and nutrition score before and after preoperative chemotherapy, and before and after adjuvant chemotherapy. We will enroll 230 patients, and the study involves eight leading Japanese institutions that are all high-volume centers in pancreatic surgery. DISCUSSION AHCC is expected to function as a supportive food in patients with pancreatic ductal adenocarcinoma, to reduce the proportion of severe adverse events related to neoadjuvant chemotherapy, and to increase the completion proportion of multimodal treatments, resulting in improved survival. TRIAL REGISTRATION The trial protocol has been registered in the protocol registration system at the Japan Registry of Clinical Trials (Trial ID: jRCTs051200029 ). At the time of the submission of this paper (October 2020), the protocol version is 2.0. The completion date is estimated to be November 2024.
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Carbon-ion radiotherapy for urological cancers.
Ishikawa, H, Hiroshima, Y, Kanematsu, N, Inaniwa, T, Shirai, T, Imai, R, Suzuki, H, Akakura, K, Wakatsuki, M, Ichikawa, T, et al
International journal of urology : official journal of the Japanese Urological Association. 2022;(10):1109-1119
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Abstract
Carbon-ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon-ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell-cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon-ion radiotherapy as a standard cancer therapy, the Japan Carbon-ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi-institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon-ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon-ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon-ion radiotherapy and our efforts to disseminate the use of this new technology worldwide.
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Effects of polymorphic cytochrome P450 2A6 genotypes on chemoprevention against colorectal tumors in single Japanese cohort using daily low-dose aspirin: insights into future personalized treatments.
Yamazaki, H, Shimizu, M, Otani, T, Mizugaki, A, Mure, K, Suzuki, S, Ishikawa, H
Journal of pharmaceutical health care and sciences. 2021;(1):26
Abstract
BACKGROUND A chemopreventive effect of low-dose aspirin against colorectal tumors was previously found in participants of two Japanese multicenter, double-blind, randomized, placebo-controlled clinical trials investigating the effects of daily aspirin (100 mg/day) for 0.7-2 years on tumor recurrence in colorectal cancer patients whose tumors were excised endoscopically. METHODS In the current study, chemopreventive data from single-center subsets having daily aspirin (100 mg/day) were reanalyzed with respect to variations in polymorphic cytochrome P450 2A6 (CYP2A6). From the J-CAPP study, 56 of 311 participants (47 men, 9 women; excluding patients with familial adenomatous polyposis) were genotyped for CYP2A6*1, *4 (whole-gene deletion), *7 (amino acid substitution), and *9 (upstream mutation), and from the J-FAPP IV study, 81 of 102 participants (43 men, 38 women; including patients with familial adenomatous polyposis) were also genotyped. RESULTS The chemopreventive effects of daily aspirin were found to be inversely dependent on the predicted enzyme activity of the CYP2A6 phenotype [based on normal genotypes (CYP2A6*1/*1,*7,*9) and impaired genotypes (CYP2A6*4,*7,*9/*4,*7,*9 and CYP2A6*1/*4)] among a nonsmoker Japanese cohort without familial adenomatous polyposis. CONCLUSIONS The CYP2A6 wild-type allele could be a candidate biomarker for reduced chemopreventive effects of daily aspirin in a population with wide-ranging CYP2A6 phenotypes with a high frequency of impaired activities resulting from variations and whole-gene deletions. The CYP2A6 genotypes could be applicable to future personalized treatments for colorectal tumor chemoprevention with daily aspirin.
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Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.
Yamada, S, Fujii, T, Yamamoto, T, Takami, H, Yoshioka, I, Yamaki, S, Sonohara, F, Shibuya, K, Motoi, F, Hirano, S, et al
The British journal of surgery. 2020;(13):1811-1817
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BACKGROUND Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.
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Real-world management of treatment-naïve diabetic macular oedema: 2-year visual outcome focusing on the starting year of intervention from STREAT-DMO study.
Shimura, M, Kitano, S, Muramatsu, D, Fukushima, H, Takamura, Y, Matsumoto, M, Kokado, M, Kogo, J, Sasaki, M, Morizane, Y, et al
The British journal of ophthalmology. 2020;(12):1755-1761
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BACKGROUND/AIMS: To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). METHODS Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. RESULTS Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. CONCLUSION For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.