Current Status and Issues of Ethical Review for Surgical Research in Japanese University Hospitals.

INTRODUCTION: In clinical research, ethical review is required prior to conducting the research. A surgical procedure is a complex intervention with properties that make it more difficult to evaluate rigorously and monitor than drug treatments. This study aimed to clarify the current status and issues in the ethical review and monitoring of surgical research. METHODS: We developed a self-administered questionnaire on surgical ethical review. The questionnaire was distributed to university hospitals in Japan and collected from November 2018 to February 2019. The distributed questionnaire consisted of the reviewed items, items with difficulties, and important items on ethical review. Fisher's exact test or the chi-square test was used for analysis. RESULTS: The questionnaires from 39 medical university hospitals were completed with appropriate answers to all items. "Technical review" was conducted at a significantly lower proportion (n = 30/39, 76.9%, p = 0.002). "Evaluation of the progress and results" was also (n = 22/39, 56.4%, p < 0.001). University hospitals in which "technical aspects and ethical review" was regarded the most important and difficult were higher (n = 24/39, 61.5%; n = 26/39, 66.7%, respectively). Respondents considered not only items written in the study protocol but also those on monitoring or oversight of surgical research as difficult. CONCLUSIONS: Our findings suggest that it is necessary to improve the ethical review system and provide supports to conduct an appropriate review for surgical research, e.g., technical aspect review or study progress/result evaluation.

Characteristics of Asian 4 countries on cancer clinical trials registered in the International Clinical Trials Registry Platform between 2005 and 2018.

BACKGROUND: The characteristics and comparison of countries regarding clinical trials for cancer were unknown. The World Health Organization-International Clinical Trials Registry Platform (WHO-ICTRP) are providing data from various countries and releases them generally in a downloadable format. We aimed to examine and descriptively identify the number of cancer clinical trials registered in the world and the fundamental characteristics in Asian 4 countries of China, India, Japan and South Korea, focusing on study characteristics, e.g., phase or targeted size, using the WHO-ICTRP. METHODS: We extracted information on cancer clinical studies in the ICTRP database on September 20, 2019. Then, we performed a cross-sectional study on the annual number of registered studies and country, registered registry, phase, target sizes and sponsors. RESULTS: We identified 80,677 cancer clinical studies. The annual number of registered cancer clinical studies significantly increased between 2005 and 2018 (3,172 to 8,156, ß =382.2, 95% CI: 329.6, 434.8). Among the Asian 4 countries, the numbers of trials were significantly increasing in 2005-2018 (P<0.001). The characteristics on interventional studies for cancer differed in those 4 countries, e.g., the registered registries, phase and sponsors, compared with the US. CONCLUSIONS: This study descriptively clarified an increase and the characteristics of cancer clinical trials in Asian 4 countries. It suggests to take that characteristics into account and select a database or data source discreetly for analysis of clinical trials, according to the purpose of the research and the required data.

Cost-Effectiveness of Behavior Modification Intervention for Patients With Chronic Kidney Disease in the FROM-J Study.

OBJECTIVES: Chronic kidney disease (CKD) is a significant public health problem. An advanced, or innovative, CKD care system of clinical practice collaboration among general physicians (GPs), nephrologists, and other healthcare workers achieved behavior modification in patients with Stage 3 CKD in the Frontier of Renal Outcome Modifications in Japan (FROM-J) study. This behavior modification intervention consisted of educational sessions on nutrition and lifestyle, as well as encouragement of patients' regular visits. The intervention contributed to slowing CKD progression. This study aimed to evaluate the cost-effectiveness of the widespread diffusion of the behavior modification intervention proven effective by the FROM-J study. METHODS: A cost-effectiveness analysis was carried out to compare the behavior modification intervention with the current practice recommended by the latest CKD clinical guidelines for GPs. A Markov model with a societal perspective under Japan's health system was constructed. We assumed that the behavior modification intervention proven effective by the FROM-J study would be initiated by GPs for targeted patient cohorts-patients aged 40-74 years with Stage 3 CKD-as a part of the innovative CKD care system. RESULTS: The incremental cost-effectiveness ratio for the behavior modification intervention compared with current guideline-based practice was calculated as 145,593 Japanese yen (¥; $1,324 United States dollars [$]) per quality-adjusted life year (QALY). CONCLUSIONS: Using the suggested value of social willingness to pay for a one-QALY gain in Japan of ¥5 million (US$45,455) as the threshold to judge cost-effectiveness, the behavior modification intervention is cost-effective. Our results suggest that diffusing the behavior modification intervention proven effective by the FROM-J study could be justifiable as an efficient use of finite healthcare resources. GPs could be encouraged to initiate this intervention by revising the National Health Insurance fee schedule and strengthening clinical guidelines regarding behavior modification interventions.

Supervision of new surgical procedures in Japan: Current practice and supervision issues at university hospitals in Japan.

BACKGROUND: Sometimes the development of new surgical procedures takes place during patient treatment in clinical practice but can result in undesirable outcomes and social concerns. This study aims to reveal how university hospitals in Japan supervise the implementation of new surgical procedures and what difficulties they confront. METHODS: Self-administered questionnaire surveys were conducted, targeting all university-affiliated hospitals in Japan. RESULTS: It was found that most university hospitals in Japan supervised new surgical procedures internally, but they considered it difficult and burdensome to review and monitor them, both technically and practically, owing to several factors. CONCLUSION: It is advisable to set up more effective and efficient organizational collaborations and implement standard processes of supervision, in both domestic and international clinical settings.

Optimization of therapeutic strategy for p16-positive oropharyngeal squamous cell carcinoma: Multi-institutional observational study based on the national Head and Neck Cancer Registry of Japan.

BACKGROUND: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date. METHODS: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality. RESULTS: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m2 ; 17 patients). CONCLUSIONS: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m2 .

Effect of Neoadjuvant Nab-Paclitaxel plus Gemcitabine Therapy on Overall Survival in Patients with Borderline Resectable Pancreatic Cancer: A Prospective Multicenter Phase II Trial (NAC-GA Trial).

We conducted a prospective multicenter phase II trial of patients with borderline resectable pancreatic carcinoma to investigate the efficacy of neoadjuvant nab-paclitaxel plus gemcitabine therapy on overall survival (OS). The clinical trial primarily evaluated OS time from the first day of protocol therapy as a primary endpoint. The secondary endpoints were recurrence-free survival from the first day of protocol therapy, safety of the protocol therapy (adverse effect), morbidity based on the Clavien Dindo classification of more than III, response rate, preoperative/postoperative tumor marker (CA 19-9, CEA), rate of normalization, reduction rate of the maximum standardized uptake value on positron emission tomography-computed tomography (limited to institutions where positron emission tomography-computed tomography was available), chemotherapeutic effect grade based on Evans' classification, resection rate, R0 resection rate, surgical data (operative time, blood loss, transfusion, postoperative hospital day), overall morbidity rates (reoperation, rate of readmission, mortality), patient rate in postoperative adjuvant therapy (entry rate, completion rate), dose intensity, quality of life regarding fatigue and malaise assessed by the questionnaire of FACIT-F (Japanese version), and peripheral sensory neuropathy assessed by the questionnaire of the FACT/GOG-NTX subscale (version 4; Japanese version). Sixty patients were included in the study, and 18 leading Japanese institutions and hospitals (all high-volume centers in pancreatic surgery) participated in this trial.

Evaluation of the Validity of a Novel CKD Assessment Checklist Used in the Frontier of Renal Outcome Modifications in Japan Study.

OBJECTIVE: This study aimed to assess the validity of a novel chronic kidney disease (CKD) evaluation checklist method used in the Frontier of Renal Outcome Modifications in Japan study. METHODS: Nineteen patients with CKD were recruited, and each patient was assessed by 2 dietitians using the checklist and provided with lifestyle modification instructions based on their assessment. We evaluated the concordance between dietitians, and we assessed the accuracy of the protein and salt intake estimates made by dietitians who only had access to patients' food diaries and verbal reports through comparison with assessments made by an independent dietitian who additionally had access to patients' meal photographs and urine collections. RESULTS: The most frequently given instructions concerned blood pressure control (46%), followed by body mass index control (28%), and potassium control (9%). The instructions provided to patients corresponded between dietitians at rates of 94% for patients' 1st evaluation and 74% for their 2nd evaluation. The evaluated items showed good agreement between dietitians except for their estimates of salt and protein intakes. The dietitians categorized salt and protein intakes into 3 groups each (<6, 6-12, and >12 g and <0.8, 0.8-1.2, and >1.2 g/kg, respectively). The concordance rates between dietitians were 77.1% and 80.8%, and Cohen's κ coefficients were 0.633 and 0.613 for salt and protein intakes, respectively. The concordance rates between the dietitians' estimates and the independent dietitian's objective assessment were 78.5% and 45.1%, and Cohen's κ coefficients were 0.616 and 0.311 for salt and protein intakes, respectively. The estimates and objective assessments were strongly correlated for salt intake, but weakly correlated for protein intake. CONCLUSION: We concluded that the checklist method was appropriate for the evaluation of CKD patients except for protein intake estimation. We hope it will be useful for the instruction of CKD patients widely in the future.

The Speckle Tracking Imaging for the Assessment of Cardiac Resynchronization Therapy (START) study.

BACKGROUND: We sought to identify the feasibility of speckle tracking echocardiography (STE) to predict cardiac resynchronization therapy (CRT) responders in a prospective multicenter study. METHODS AND RESULTS: Patients who were newly implanted with a CRT device were enrolled. Time (T) from QRS to maximum peak radial and circumferential strain (CS) in 6 segments on the left ventricular (LV) short-axis plane, and to the maximum peak of longitudinal strain in 18 segments on 3 apical LV planes was measured (Tmax). In segments with multiple peaks on the time-strain curves, time to the first peak (Tfirst) was also assessed. Difference in T between the earliest and latest segment and standard deviation (SD) of T in each strain component were assessed. CRT responders were defined as having LV end-systolic volume reduction >15% at 6 months after CRT. Clinical outcomes were assessed with a composite endpoint of death from cardiac causes or unplanned hospitalization for heart failure. Among 180 patients, 109 patients were identified as responders. Tfirst-SD of CS >116 ms was selected as the best independent predictor of CRT responders (P<0.001, hazard ratio=9.83, 95% confidence interval 3.78-25.6). In addition, Tfirst-SD of CS was associated with the clinical endpoints. CONCLUSIONS: This prospective multicenter study revealed the high feasibility of dyssynchrony assessment by STE, which may improve the ability to predict CRT responders.

Arsenic exposure affects plasma insulin-like growth factor 1 (IGF-1) in children in rural Bangladesh.

BACKGROUND: Exposure to inorganic arsenic (As) through drinking water during pregnancy is associated with lower birth size and child growth. The aim of the study was to assess the effects of As exposure on child growth parameters to evaluate causal associations. METHODOLOGY/FINDINGS: Children born in a longitudinal mother-child cohort in rural Bangladesh were studied at 4.5 years (n=640) as well as at birth (n=134). Exposure to arsenic was assessed by concurrent and prenatal (maternal) urinary concentrations of arsenic metabolites (U-As). Associations with plasma concentrations of insulin-like growth factor 1 (IGF-1), calcium (Ca), vitamin D (Vit-D), bone-specific alkaline phosphatase (B-ALP), intact parathyroid hormone (iPTH), and phosphate (PO4) were evaluated by linear regression analysis, adjusted for socioeconomic factor, parity and child sex. Child U-As (per 10 µg/L) was significantly inversely associated with concurrent plasma IGF-1 (ß=-0.27; 95% confidence interval: -0.50, -0.0042) at 4.5 years. The effect was more obvious in girls (ß=-0.29; -0.59, 0.021) than in boys, and particularly in girls with adequate height (ß=-0.491; -0.97, -0.02) or weight (ß=-0.47; 0.97, 0.01). Maternal U-As was inversely associated with child IGF-1 at birth (r=-0.254, P=0.003), but not at 4.5 years. There was a tendency of positive association between U-As and plasma PO4 in stunted boys (ß=0.27; 0.089, 0.46). When stratified by % monomethylarsonic acid (MMA, arsenic metabolite) (median split at 9.7%), a much stronger inverse association between U-As and IGF-1 in the girls (ß=-0.41; -0.77, -0.03) was obtained above the median split. CONCLUSION: The results suggest that As-related growth impairment in children is mediated, at least partly, through suppressed IGF-1 levels.

Association between calcium in cord blood and newborn size in Bangladesh.

Ca status in the uterus during pregnancy has been suggested to affect fetal growth and size at birth. In Bangladesh, low Ca levels in pregnant women and low birth weight in infants are common. The present study explored the association between Ca levels in cord blood and newborn size at birth (birth weight and birth length) in Bangladesh. Samples and data included 223 women with live-born singleton deliveries in rural Bangladesh. Newborn weight and length were measured at birth. From cord blood obtained at delivery, Ca, 25-hydroxy vitamin D, bone-specific alkaline phosphatase and intact parathyroid hormone levels were determined. An association between size at birth and Ca levels in cord blood was found (birth weight, P = 0.022; birth length, P = 0.001). Associations between Ca and newborn size were further analysed using multivariate regression analyses. After adjusting for several covariates of characteristics in mothers and newborns (gestational weeks at birth, sex of newborn, socio-economic status, maternal height, BMI, age and season at birth), birth length still exhibited a significant relationship with Ca levels in cord blood (birth length, P = 0.030). The present study indicates that Ca status in cord blood might be associated with the birth length of newborns. Ca levels during gestation may affect fetal growth.

Measurement of health-related quality of life in patients with chronic kidney disease in Japan with EuroQol (EQ-5D).

BACKGROUND: Chronic kidney disease (CKD) is a health-related quality-of-life (HRQOL) deteriorating disease which is not only a public health but also a socioeconomic problem. Interest in developing cost-effective interventions to control CKD has increased. The aim of this study was to measure HRQOL in terms of quality-adjustment weights for cost-effectiveness analysis using EQ-5D in patients with CKD. The relationships between the measured HRQOL and clinical indices/complications were also analyzed. METHODS: EQ-5D, a generic preference-based instrument, was administered to 569 CKD outpatients at Tsukuba University Hospital between November and December 2008. The response rate was 94.4% (537/569). Data on sex, age, creatinine, hemoglobin, serum albumin and eGFR were obtained from the patients' records. Data on the presence of complications such as hypertension, diabetes, and history of cardiovascular disease (CVD) were also retrieved. RESULTS: Measured quality-adjustment weights by the CKD stage were 0.940 (95% CI 0.915-0.965), 0.918 (0.896-0.940), 0.883 (0.857-0.909), 0.839 (0.794-0.884), and 0.798 (0.757-0.839) for stages 1-5, respectively. The decrease in weight was significant by ANOVA (P < 0.0001), and the weight for all stages was 0.885 (0.871-0.898). There was a positive relationship between hemoglobin/serum albumin and the weight. The presence of hypertension lowered the weight from 0.910 (0.885-0.936) to 0.874 (0.858-0.891), diabetes from 0.901 (0.886-0.917) to 0.840 (0.811-0.869), and CVD from 0.892 (0.878-0.906) to 0.783 (0.718-0.848). CONCLUSIONS: HRQOL decreases with progression of CKD stage and/or presence of anemia, undernutrition, hypertension, diabetes, or history of CVD.

Beneficial effects of a new 20-hydroxyeicosatetraenoic acid synthesis inhibitor, TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], on hemorrhagic and ischemic stroke.

The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 microM. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.

Increased excretion of urinary 20-HETE in rats with cyclosporine-induced nephrotoxicity.

The present study examined the contribution of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in cyclosporine A (CsA)-induced renal nephrotoxicity. Treatment of rats with CsA (50 mg/kg) for 9 days induced renal damage as indicated by marked increase in urine flow (from 9.0 +/- 0.3 ml/day to 46.6 +/- 7.1 ml/day) and a 3 - 5-fold rise in blood urea nitrogen (BUN) levels. The urinary excretion of 20-HETE increased from 164 +/- 5 ng/day (N = 5) to 2432 +/- 290 ng/day (N = 5, P<0.01) after 9 days of CsA treatment. The increase in the urinary excretion of 20-HETE in the CsA treated rats was highly correlated with the increase in BUN levels (r = 0.819, P<0.001) and urine volume (r = 0.832, P<0.001). Immunohistochemical examination of kidney revealed that expression of cytochrome P450 4A (CYP4A) protein was markedly enhanced in the proximal tubules of CsA-treated rats. These results indicate that CsA-induced nephrotoxicity in rats is associated with a marked elevation in the renal production of 20-HETE and that 20-HETE may contribute to the pathophysiological condition of CsA-induced nephrotoxicity.