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The efficacy of unrelated transplantation for patients with ALL who lack an HLA-matched sibling remains unclear. We performed a decision analysis to determine the efficacy of myeloablative transplantation from a genetically HLA-A, -B, -DRB1 allele-matched unrelated donor for patients with Ph chromosome-negative ALL aged 21-54 years. The transition probabilities were estimated from the Japan Adult Leukemia Study Group studies (ALL93; n=80, ALL97; n=82), and the Japan Marrow Donor Program database (transplantation in first CR (CR1): n=177). The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustment. Subgroup analyses were performed according to risk stratification based on the WBC count and cytogenetics, and according to age stratification. In all patients, unrelated transplantation in CR1 was shown to be superior in analyses both with and without QOL adjustment (40.8 vs 28.4% and 43.9 vs 29.0%, respectively). A similar tendency was observed in all subgroups. The decision model was sensitive to the probability of leukemia-free survival following chemotherapy and the probability of survival after transplantation in standard-risk and higher-aged patients. Unrelated transplantation in CR1 improves the long-term survival probability in patients who lack an HLA-matched sibling. However, recent improvements in treatment strategies may change this result. [ABSTRACT FROM AUTHOR]

Cell dose is one of the major factors that can be manipulated in unrelated BMT. However, regarding disease-stage-stratified effects of cell dose, data are limited. We analyzed the registry data from 3559 patients with acute leukemia, CML and myelodysplastic syndrome who received T-cell replete unrelated BMT through the Japan Marrow Donor Program. Adjusted effects of cell dose were evaluated for various outcomes separately according to disease stages and children or adults. Acute GVHD and nonrelapse mortality were not affected by cell dose. Among children, a cell dose lower than 3.0 × 108/kg was associated with lower engraftment rates in advanced-stage diseases. Among adults, a cell dose of 3.4 × 108/kg or higher was associated with lower relapse rates and better survival rates only in early-stage diseases, whereas cell dose below 2.3 × 108/kg was associated with lower engraftment rates in advanced-stage diseases. In conclusion, effects of cell dose may differ among disease stages. A cell dose of 3.4 × 108/kg or higher is recommended only for adults with early-stage diseases. With the number of patients available for analysis in this study, we could not show any significant benefits associated with 4.6 × 108/kg or higher in children. [ABSTRACT FROM AUTHOR]

Pegylated interferon and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C (CHC). Some groups have reported a relation between lipid values and response while others have reported that microsomal triglyceride transfer protein, a key enzyme in the assembly and secretion of lipoproteins, was related to hepatitis C virus (HCV). The aim of this study was to investigate the association between the lipoprotein profiles, classified according to size, and hepatitis C treatment and the usefulness for predicting the outcome of treatment. Forty-four patients with CHC (27 men and 17 women) were included in the study. The serum cholesterol and triglyceride (TG) levels in the lipoprotein subclasses were determined using high-performance liquid chromatography with gel permeation columns, which classified lipoproteins into 20 subfractions based on particle size. According to a univariate analysis, those who achieved an sustained viral response (SVR) had a significantly higher serum total cholesterol level, higher cholesterol levels in the low-density lipoprotein subfraction (25.5 nm in diameter) and the very low-density lipoprotein (VLDL) subfraction (44.5 and 36.8 nm), and a higher serum TG level in the VLDL subfraction (44.5 nm), compared with the corresponding values in the non-SVR group. Higher serum cholesterol and TG concentrations in the lipoprotein subfractions were predictive of an SVR to therapy for HCV infection with genotype 1b prior to the start of interferon treatment. [ABSTRACT FROM AUTHOR]

Purpose: To determine the prevalence and progression of Barrett's epithelium and associated risk factors in Japan.Methods: The study population comprised 869 cases. Endoscopic Barrett's epithelium was diagnosed based on the Prague C & M Criteria. The correlations of clinical factors with the prevalence and progression of endoscopic Barrett's epithelium were examined.Results: Endoscopic Barrett's epithelium was diagnosed in 374 cases (43%), in the majority of which the diagnosis was short-segment Barrett's esophagus. The progression of Barrett's epithelium was identified in 47 cases. In univariate and multiple logistic regression analyses, aging, smoking habit, and erosive esophagitis were significantly associated with the prevalence of Barrett's epithelium, whereas aging and erosive esophagitis, especially severe erosive esophagitis, were significant contributing factors to the progression of Barrett's epithelium.Conclusions: Forty-three percent of the total study population was diagnosed as having endoscopic Barrett's epithelium. During the follow-up period, 12.6% of the cases with Barrett's epithelium exhibited progression which was associated with aging and severe erosive esophagitis. [ABSTRACT FROM AUTHOR]

Seasonal changes in resource investment into individual offspring are well documented, but no attention has been paid to the allocation of the invested resource among the body parts of the offspring. In the present study, seasonal changes in the absolute and relative sizes in a spiderling of the wolf spider Pardosa pseudoannulata Boes. et Str. are investigated, and the relationship between spiderling body size and the ability to moult during a food shortage is clarified. Spiderlings that emerge in November have a significantly larger cephalothorax and abdomen than those that emerge in June. In addition, the abdomen–cephalothorax size ratio is significantly greater in November than in June offspring. Under limited food availability conditions, only 40% of spiderlings moult. Nymphs that do moult have a significantly larger cephalothorax, abdomen and abdomen–cephalothorax size ratio than nymphs that do not moult. Thus, both the quantity of resources invested in the cephalothorax and abdomen of a spiderling and the proportional allocation of resources between the two body parts change seasonally in Pa. pseudoannulata; alteration of the resource allocation occurs in late autumn. Larger spiderlings of Pa. pseudoannulata that emerge in late autumn would be able to develop into advanced instars even during food shortage, and therefore may have better overwintering survival rates. [ABSTRACT FROM AUTHOR]

Summary:To evaluate the incidence, risk factors and prognosis for solid tumors after hematopoietic stem cell transplantation (HSCT) in Japan, 809 patients who had received HSCT between 1981 and 2000 were retrospectively analyzed. In all, 19 newly diagnosed secondary cancers were observed. The risk for cancer development was 2.8 times as high as that for expected cases. The cumulative incidence ratios at 5 and 10 years were 1.9 and 4.2%, respectively. The risk was significantly elevated for buccal cavity cancer (standard incidental ratio (SIR), 44.42: 95% confidence interval (CI) 17.86–91.51), esophageal cancer (SIR, 22.36: 95% CI 6.09–57.25), and cervical cancer (SIR, 8.58: 95% CI 1.04–31.01). Of 15 patients who developed solid cancers following allografting, 12 had chronic graft-versus-host disease (GVHD), and all 10 patients with squamous cell carcinoma of the buccal cavity or esophagus had chronic GVHD. On multivariate analysis, extensive chronic GVHD and age over 45 years at the time of transplantation were associated with a higher risk for solid cancers. In all, 17 patients received therapy for secondary cancers, nine of whom are still alive and the 5-year probability of survival from the diagnosis is 42.8%. Our data suggest that early detection of secondary cancers is very important in prolonging overall survival.Bone Marrow Transplantation (2005) 36, 115–121. doi:10.1038/sj.bmt.1705020 Published online 23 May 2005 [ABSTRACT FROM AUTHOR]

We found that river water is acidified not only in the first stage but also in the later stage of the snowmelt season in Japan, which differs from the so called acid shock occurring in the first stage of the snowmelt in the northern Europe. The acid shocks depend on the regional characteristics of the melt-refreeze processes forming the internal distribution of acid materials within snow crystals under the warm metamorphism. In a warm climatic region like the central Japan, there are possibilities to have the complicated distribution structure of acid materials within granular-snow crystals due to the repeated melt-refreeze processes even in midwinter. Consequently, the pH value of meltwater does not always increase as the snowmelt proceeds. Then, we showed the possibility by using the X-ray computed tomography that the domains with the acid materials exist in the inner parts of snow crystals. So, the acidification of the river water may occur even in the later stage of the snowmelt. [ABSTRACT FROM AUTHOR]

Aim: Advanced glycation end-products (AGEs) are irreversibly and heterogeneously formed compounds during the non-enzymatic modification of macromolecules, such as proteins. Aging and lifestyle habits, such as high-fat and high-protein diets, and smoking, promote AGEs accumulation. This study aimed to investigate the relationship between fall risk and AGEs in community-dwelling older adults., Methods: This cross-sectional study included patients from the 2022 Yakumo Study who were evaluated for fall risk index 5-items version, locomotive syndrome stage and AGEs. AGEs were evaluated using Skin autofluorescence (SAF) measured by the AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). We divided the participants into two groups according to the presence or absence of fall risk (fall risk index 5-items version ≥6 or not), and investigated the factors associated with fall risk., Results: The fall risk group had a higher age and SAF, and a higher proportion of locomotive syndrome stage >2 than the without fall risk group in patients aged ≥65 years (P < 0.01). The multivariate logistic regression analysis after adjustment of age, sex and body mass index showed that locomotive syndrome stage ≥2 and SAF were independent associators of fall risk in older adults (odds ratio 3.26, P < 0.01, odds ratio 2.96, P < 0.05, respectively). The optimal cutoff value of the SAF for fall risk was 2.4 (area under the curve 0.631; 95% CI 0.53-0.733; sensitivity 0.415; specificity 0.814; P < 0.05)., Conclusion: The accumulation of AGEs in skin tissues can be used to screen for fall risk comprehensively. Geriatr Gerontol Int 2024; 24: 517-522., (© 2024 Japan Geriatrics Society.)

Background: To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan., Methods: The EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications., Results: A total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients., Conclusion: This is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior., (© 2024. The Author(s).)

Advanced glycation end products (AGEs) have been reported to be associated with osteoporosis, aging, sarcopenia, and frailty. This study aimed to investigate the association AGEs with locomotive syndrome (LS). Participants were Japanese individuals aged 39 years or older who participated in the Yakumo Study (n=230). AGEs were measured by skin autofluorescence (SAF) using an AGE reader. We investigated SAF values for each locomotive stage. Multivariate logistic regression models were used to calculate the odds ratios of LS-associated factors. The relationships between SAF and physical performance and bone mineral density (BMD) were investigated. A receiver operating characteristic (ROC) curves were generated to determine the optimal cut-off value of SAF for predicting LS. SAF values tended to increase correspondingly with LS severity. SAF was an independently explanatory factor for LS (odds ratio 2.70; 95% confidence interval [CI] 1.040-6.990). SAF was positively correlated with the 10-m walking speed, The Timed Up and Go test results, and was negatively correlated with BMD. ROC curve represented by SAF for the presence or absence of LS risk had an area under the curve of 0.648 (95% CI: 0.571-0.726). High SAF values were identified as an independent risk factor for LS. AGEs could be a potential screening tool for people for LS., Competing Interests: There are no conflicts of interest among the authors.

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study., (© 2024 Daiichi Sankyo Co., Ltd. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Patients with locomotive syndrome (LS) are poor ambulatory status and a high risk of requiring nursing care. The purpose of this study is to investigate the relationship between LS and fall risk among community-dwelling elderly individuals., Methods: The subjects were Japanese elderly individuals aged 65 and over who participated in Yakumo study 2019 (N = 189). We defined the fall risk index 5 items version (FRI-5) ≥6 points as the fall risk group. LS was evaluated by stand-up test, two-step test, and 25-Geriatric Locomotive Function Scale (GLFS-25). We divided the subjects into two groups according to the presence or absence of fall risk, and investigated factors associated with fall risk., Results: The fall risk group (30 patients, 15.9%) had higher GLSF-25 (P = 0.001). The results of logistic regression analysis adjusted for age, sex, BMI, and knee osteoarthritis revealed that GLFS-25 (OR: 1.052; 95%CI: 1.009-1.097) was independent factor associated with fall risk. In the ROC analysis, the optimal cut-off value of the GLFS-25 to predict fall risk was 12, which is equivalent to LS stage 1 (AUC 0.688; 95% CI: 0.588-0.787; sensitivity: 0.467, specificity: 0.836)., Conclusions: GLFS-25 was associated with fall risk among community-dwelling elderly individuals aged 65 and over., Competing Interests: Conflict of interest statement Hiroki Iida, Taisuke Seki, Yasuhiko Takegami, Yusuke Osawa, Kato Daisaku, Genta Takemoto, Kei Ando, Shinya Ishizuka, Yukiharu Hasegawa, and Shiro Imagama declare that they have no conflict of interest., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Spiritual care for patients' quality of life (QOL) and hope should be included in home medical care for patients with limited life expectancy. This study aimed to analyze the associations between estimated life expectancy, QOL, and hope among patients receiving home medical care in Japan. This multicenter cross-sectional study involved 29 home medical care facilities in Japan. Patients were categorized by estimated life expectancy, as assessed by home medical care physicians. The outcomes were QOL measured via the Quality-of-Life Scale for Elderly Patients Receiving Professional Home Care (QOL-HC: higher score indicates better QOL), the domain scores of health-related hope ("health," "role and connectedness," and "something to live for"; higher scores indicate higher levels of hope), and life functioning measured using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0; higher score indicates worse functioning and disability). QOL-HC scores were significantly higher in patients with shorter life expectancy (< 6 m vs. ≥ 1 y, adjusted mean differences: 0.7 points [95%CI 0.1 to 1.3]). Regarding health-related hope, "something to live for" scores were associated with shorter life expectancy (< 6 m vs. ≥ 1 y, -17.7 points [-34.2 to -1.2]), whereas "role and connectedness" scores did not change remarkably with shorter life expectancy (< 6 m vs. ≥ 1 y, -3.3 points [-16.4 to 9.8]). Furthermore, shorter life expectancy was associated with higher WHODAS 2.0 scores (< 6 m vs. ≥ 1 y, 19.6 points [4.3 to 34.8]). Home medical care physicians who engage in spiritual care should facilitate thoughtful dialogue with their patients by recognizing declines in life functions and hope for fulfilment, which are associated with short life expectancy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yasunaka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Radionuclides released and deposited because of the 2011 Fukushima Dai-ichi Nuclear Power Plant accident caused an increase in air dose rates in Fukushima Prefecture forests. Although an increase in air dose rates during rainfall was previously reported, the air dose rates in the Fukushima forests decreased during rainfall. This study aimed to develop a method to estimate rainfall-related changes in air dose rates, even in the absence of soil moisture data, in Namie-Town and Kawauchi-Village, Futaba-gun, Fukushima Prefecture. Moreover, we examined the relationship between preceding rainfall (Rw) and soil moisture content. The air dose rate was estimated by calculating the Rw in Namie-Town from May to July 2020. We found that the air dose rates decreased with increasing soil moisture content. The soil moisture content was estimated from Rw by combining short-term and long-term effective rainfall using half-live values of 2 h and 7 d and considering the hysteresis of water absorption and drainage processes. Furthermore, the soil moisture content and air dose rate estimations showed a good agreement with coefficient of determination (R 2 ) scores >0.70 and >0.65, respectively. The same method was tested to estimate the air dose rates in Kawauchi-Village from May to July 2019. At the Kawauchi site, variation in estimated value is relatively large due to the presence of water repellency in dry conditions, and the amount of 137 Cs inventory was low, so estimating air dose from rainfall remained a challenge. In conclusion, rainfall data were successfully used to estimate soil moisture and air dose rates in areas with high 137 Cs inventories. This leads to the possibility of removing the influence of rainfall on measured air dose rate data and could contribute to the improvement of methods currently used to estimate the external air dose rates for humans, animals, and terrestrial forest plants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yuichi Onda reports financial support was provided by University of Tsukuba., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Although several guidelines recommend monotherapy with antipsychotics for the treatment of schizophrenia, patients who receive long-acting injectable antipsychotics (LAIs) are frequently treated with oral antipsychotics (OAPs). In the present study, we investigated the detailed use of psychotropic medications among patients throughout Japan with schizophrenia who received LAIs or OAPs., Methods: The present study used data from the project for the Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment from 94 facilities in Japan. The LAI group included patients who received any LAI, and the non-LAI group included patients who took only OAP medications at discharge. The participants of this study were 2518 schizophrenia patients (263 in the LAI group and 2255 in the non-LAI group) who received inpatient treatment and had prescription information at discharge between 2016 and 2020., Results: This study revealed significantly higher rates of polypharmacy antipsychotics, number of antipsychotics, and chlorpromazine equivalents in the LAI group than in the non-LAI group. In contrast, the LAI group showed lower rate of concomitant use of hypnotic and/or antianxiety medication than the non-LAI group., Conclusions: Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan., Methods: Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1-28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1-10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed., Results: Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61-84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome., Conclusions: The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events., (© The Author(s) 2023. Published by Oxford University Press.)

Background: There is a growing need to realize high-quality end-of-life care at home that respects the patient's wishes., Objective: To examine the association between the quality of primary care and advance care planning (ACP) participation among patients receiving home-based medical care., Methods: In this multicentre, cross-sectional study, 29 home medical care clinics in Japan were included. Adult Japanese patients receiving home medical care were surveyed to assess their consideration of ACP. The quality of primary care, which reflects patient-centredness, was assessed with the Japanese version of the Primary Care Assessment Tool-Short Form (JPCAT-SF). Information on the clinical conditions that require home medical care was collected from physicians., Results: Of the 194 patients surveyed from 29 home medical services, 62 patients (32%) showed signs of ACP participation. Lack of opportunities was the most common reason for not participating in the ACP. In a multivariable-adjusted generalized estimating equation, primary care quality was associated with ACP participation (per 10-point increase, adjusted odds ratio: 1.96, 95% confidence interval: 1.51-2.56). In addition, all domains of the JPCAT-SF were associated with ACP participation., Conclusions: Patient-centredness in home medical care facilitates the initiation of ACP participation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Treatment guidelines are designed to assist patients and health care providers and are used as tools for making treatment decisions in clinical situations. The treatment guidelines of the Japanese Society of Mood Disorders establish treatment recommendations for each severity of depression. The individual fitness score (IFS) was developed as a simple and objective indicator to assess whether individual patients are practicing treatment by the recommendations of the depression treatment guidelines of the Japanese Society of Mood Disorders., Methods: The EGUIDE project members determined the IFS through the modified Delphi method. In this article, the IFS was calculated based on the treatment of depressed patients treated and discharged between 2016 and 2020 at facilities participating in the EGUIDE project. In addition, we compared scores at admission and discharge., Results: The study included 428 depressed patients (mild n = 22, moderate/severe n = 331, psychotic n = 75) at 57 facilities. The mean IFS scores by severity were statistically significantly higher at discharge than at admission with moderate/severe depression (mild 36.1 ± 34.2 vs. 41.6 ± 36.9, p = 0.49; moderate/severe 50.2 ± 33.6 vs. 55.7 ± 32.6, p = 2.1 × 10-3; psychotic 47.4 ± 32.9 versus 52.9 ± 36.0, p = 0.23)., Conclusion: We developed the IFS based on the depression treatment guideline, which enables us to objectively determine how close the treatment is to the guideline at the time of evaluation in individual cases. Therefore, the IFS may influence guideline-oriented treatment behavior and lead to the equalization of depression treatment in Japan, including pharmacotherapy., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m 2 Bor administered subcutaneously on days 1 and 8, 25 mg Len administered on days 1-14, and 20 mg Dex on days 1-2 and 8-9 of a 3 week cycle for 8 cycles, followed by a 4 week cycle of Dex (40 mg weekly). Among the 30 patients enrolled, 60.0% (95% CI 40.6-77.3) had a very good partial response or better, and the best overall response rate was 96.7% (95% CI 82.8-99.9). Eight patients (26.7%) achieved a complete response. Grade 3 or higher PN was not observed and hematological toxicity was the most common adverse event. The modified BLd regimen showed favorable efficacy with a manageable safety profile, which suggests it could be a treatment option for transplant-ineligible NDMM., (© 2022. Japanese Society of Hematology.)

This study aimed to investigate the effects of physical therapists' exercise instructions in Japanese patients with type 2 diabetes. Thirty-six participants were recruited from the outpatient clinic at Matsushita Memorial Hospital, Osaka, Japan from June 2020 to September 2020 and were randomly assigned to either the non-intervention or intervention group. The intervention group received exercise instructions from physical therapists for 30 min at baseline (week 0) and at week 4 by referring to ambulatory accelerometer records. Laboratory parameters, physical activity, body composition, motor skill, and transtheoretical model were assessed in both the groups at baseline (week 0) and week 8. In week 8, patients in the intervention group had a statistically significant reduction in HbA1c levels compared with those in the non-intervention group (7.3% [6.8-%-7.9%] vs. 7.4% [7.3%-7.7%], P = 0.04). The number of steps per day (P = 0.001), energy expenditure (P = 0.01), lower extremity muscle strength (P = 0.002), and 6-min walk test results (P = 0.04) were significantly increased in the intervention group compared with those in the non-intervention group in week 8. The transtheoretical model varied between baseline (week 0) and week 8 only in the intervention group (P < 0.001). Thus, outpatient exercise instructions from physical therapists could improve glycemic control owing to physical activity by improving motor skills and changing the transtheoretical model in Japanese patients with type 2 diabetes., Competing Interests: HO received personal fees from MSD K.K., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk Pharma Ltd., Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K, Kyowa Hakko Kirin Company Ltd, Ltd, Kowa Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd. and Sanofi K.K. MF received grants from Ono Pharma Co. Ltd., Oishi Kenko inc., Yamada Bee Farm, Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co. Ltd., MSD K.K., Kissei Pharma Co. Ltd., Daiichi Sankyo Co. Ltd., Sanwa Kagagu Kenkyusho Co., Ltd., Sanofi K.K., Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Terumo Corp., Tejin Pharma Ltd., Novo Nordisk Pharma Ltd., Eli Lilly, Japan, K.K., Taisho Pharma Co., Ltd., Abbott Japan Co. Ltd., Nippon Chemiphar Co., Ltd., Kowa Pharma Co. Ltd. and Johnson & Johnson K.K. Medical Co. and received personal fees from Abbott Japan Co. Ltd., Kissei Pharma Co., Ltd., Sumitomo Dainippon Pharma Co. Ltd., Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co. Ltd., Sanofi K.K., Astellas Pharma Inc., MSD K.K., Kyowa Kirin Co. Ltd., Taisho Pharma Co., Ltd., Kowa Pharma Co. Ltd., Mochida Pharma Co. Ltd., Novo Nordisk Pharma Ltd., Ono Pharma Co. Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., Eli Lilly Japan K.K., Bayer Yakuhin, Ltd., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Teijin Pharma Ltd., Medtronic Japan Co. Ltd., Arkray Inc. and Nipro Corp. outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matsushita, Okada, Okada, Sekiyama, Iida, Shindo, Murata and Fukui.)

Aims/introduction: Diabetes mellitus is reported as a risk factor for increased coronavirus disease 2019 (COVID-19) severity and mortality, but there have been few reports from Japan. Associations between diabetes mellitus and COVID-19 severity and mortality were investigated in a single Japanese hospital., Materials and Methods: Patients aged ≥20 years admitted to Osaka City General Hospital for COVID-19 treatment between April 2020 and March 2021 were included in this retrospective, observational study. Multivariable logistic regression analysis was carried out to examine whether diabetes mellitus contributes to COVID-19-related death and severity., Results: Of the 262 patients included, 108 (41.2%) required invasive ventilation, and 34 (13.0%) died in hospital. The diabetes group (n = 92) was significantly older, more obese, had longer hospital stays, more severe illness and higher mortality than the non-diabetes group (n = 170). On multivariable logistic regression analysis, age (odds ratio [OR] 1.054, 95% confidence interval [CI] 1.023-1.086), body mass index (OR 1.111, 95% CI 1.028-1.201), history of diabetes mellitus (OR 2.429, 95% CI 1.152-5.123), neutrophil count (OR 1.222, 95% CI 1.077-1.385), C-reactive protein (OR 1.096, 95% CI 1.030-1.166) and Krebs von den Lungen-6 (OR 1.002, 95% CI 1.000-1.003) were predictors for COVID-19 severity (R 2  = 0.468). Meanwhile, age (OR 1.104, 95% CI 1.037-1.175) and Krebs von den Lungen-6 (OR 1.003, 95% CI 1.001-1.005) were predictors for COVID-19-related death (R 2  = 0.475)., Conclusions: Diabetes mellitus was a definite risk factor for COVID-19 severity in a single Japanese hospital treating moderately-to-severely ill patients., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients., (© 2022. Japanese Society of Hematology.)

Introduction: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL)., Materials and Methods: Globally recommended blinatumomab doses were administered to adult (9-28 μg/day) and pediatric (5-15 μg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs., Results: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response., Conclusion: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL., (© 2022 S. Karger AG, Basel.)

Background: Until recently, no effective targeted therapies for FLT3-mutated (FLT3 mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3 mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001)., Methods: We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC., Results: Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%)., Conclusion: Findings in Japanese patients are consistent with those of the overall ADMIRAL study population., (© 2021. The Author(s).)

Background: In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27)., Methods: VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1-28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1-10). The primary endpoint was median overall survival., Results: In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each)., Conclusions: Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Since the 1990s, insurance has been the primary field focused on the social disadvantages of using genetic test results because of the concerns related to adverse selection. Although life insurance is popular in Japan, Japan does not currently have any regulations on the use of genetic information and insurers have largely kept silent for decades. To reveal insurers' attitudes on the topic, we conducted an anonymous questionnaire survey with 100 insurance company employees and recruited nine interviewees from the survey respondents. We found that genetic discrimination is not generally considered as a topic of human rights. We also found that insurers have uncertain fears and concerns about adverse selection in terms of actuarial fairness but not regarding profits. When it comes to preparing guidelines on the use of genetic information by Japanese insurers, we believe that public dialog and consultation are necessary to gain understanding of the people.

Objective In Japan, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), and cyclosporine A (CsA) is the standard of care in patients with aplastic anemia (AA) who are not indicated for stem-cell transplantation, although some patients may experience relapse. This study assessed the efficacy and safety of eltrombopag in combination with rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan. Methods In this non-randomized, open-label, single-arm, phase II study, rabbit-ATG/CsA and eltrombopag were initiated on Days 1 and 15 (±3 days), respectively, and continued for ≥26 weeks; rabbit-ATG was given for 5 days (Days 1 to 5). The primary endpoint was the overall response rate (ORR) at Week 26. Patients Patients with AA who were IST-naïve and ≤70 years old or between 71 and 75 years old based on the recommendation of the investigator were enrolled in Japan. Results Of the 11 enrolled patients, 10 started treatment with eltrombopag. The ORRs at Weeks 26 and 52 were 70.0% and 60.0%, respectively. The ORR at Week 26 was 100% (all 3 patients) in patients with non-severe AA and 57.1% (4/7) in patients with severe AA. Among transfusion-dependent patients, 66.7% (4/6) and 62.5% (5/8) became red blood cell- and platelet-transfusion independent, respectively. The most common adverse events were nausea and headache. No deaths or hematologic malignancies were reported. A cytogenetic abnormality was reported in one patient. Conclusion This study confirmed the clinical benefit of eltrombopag plus rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan.

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n  = 100) and angioimmunoblastic T-cell lymphoma (AITL, n  = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20-30 mg/m 2 /day × 5 days), etoposide (50-100 mg/m 2 /day × 5 days), and cyclophosphamide (200-440 mg/m 2 /day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m 2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.

Background: Double-lumen endobronchial tubes (DLTs) are used for one-lung ventilation (OLV) during thoracic surgery. Overinflation into the bronchial cuff causes damage to the tracheobronchial mucosa, whereas underinflation leads to an incomplete collapse of the nonventilated lung or incomplete ventilation of the ventilated lung. However, how to determine the appropriate bronchial cuff volume and pressure during OLV is unclear. The objective of this study is to compare the required bronchial cuff volume for lung separation obtained by 2 different cuff inflation methods under closed- and open-chest conditions., Methods: A total of 64 patients scheduled to undergo elective thoracic surgery requiring OLV were recruited. Left DLTs were used for both right- and left-sided surgery. The patients were randomly assigned to 1 of 2 inflation-type groups to estimate the bronchial cuff volume. In the capnogram waveform-guided bronchial cuff inflation group (capno group, n = 27), the bronchial cuff was inflated until a capnometer sampling gas containing CO2 from the nonventilated lung displayed a flat line. The corresponding bronchial cuff volume and pressure were then recorded. In the pressure-guided bronchial cuff inflation group (pressure group, n = 29), the bronchial cuff was inflated by a cuff inflator to a pressure of 20 cm H2O. Lung separation was confirmed when a flat line of a capnometer was observed after gas sampling from the nonventilated lung., Results: Under closed-chest conditions, the bronchial cuff sealing volume for the capno group was significantly lower than that for the pressure group (mean [standard deviation {SD}], 1.00 [0.65] mL vs 1.44 [0.59] mL, mean difference, -0.44; 97.5% confidence interval [CI], -0.78 to -0.11; P = .010). Under open-chest conditions, the bronchial cuff sealing volume for the capno group was also significantly lower than that for the pressure group (mean [SD], 0.65 [0.66] mL vs 1.22 [0.45] mL, mean difference, -0.58; 97.5% CI, -0.88 to -0.27; P < .001)., Conclusions: The lowest cuff volume providing an air-tight bronchial seal was obtained by the capnogram waveform-guided bronchial cuff inflation method. Since the cuff volume required to achieve an air-tight seal decreases after opening the chest, readjustment of the bronchial cuff volume to prevent bronchial cuff damage to the tracheobronchial mucosa after opening the chest may be advisable., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Aim: This study aimed to examine the validity of the care-needs levels classified in Japan's long-term care insurance system (LTCI-CNLs) when compared with patients' self-perceived functioning, disability and physical performance among patients receiving home medical care., Methods: This was a multicenter cross-sectional study in Japan. Patients who were receiving continuous home medical care and who could respond to the questionnaire were enrolled in this study. In addition to the LTCI-CNLs, the 12-item version of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) and the SARC-F were used to measure functioning, disability and physical performance (sarcopenia). In addition, correlations and associations of the LTCI-CNLs with the WHODAS 2.0 and SARC-F were analyzed using Spearman correlations and linear mixed models., Results: Data from 181 patients were included in the analyses. The LTCI-CNLs varied, ranging from support level 1 (5.5%) to care-needs level 5 (10.5%), with care-needs level 2 being the most prevalent (24.9%). Moderate correlations of the LTCI-CNLs with the WHODAS 2.0 and SARC-F were found (ρ = 0.58 and 0.44, respectively). Although WHODAS 2.0 and SARC-F scores varied within each LTCI-CNL, predicted WHODAS 2.0 and SARC-F scores increased as LTCI-CNL increased. Dementia was not associated with WHODAS 2.0 or SARC-F., Conclusions: The LTCI-CNLs was associated with self-reported functioning, disability and physical performance among home medical care patients. Future studies can use the LTCI-CNLs as an outcome variable for specific care approaches or as a proxy covariate for casemix status. Geriatr Gerontol Int 2021; 21: 229-237., (© 2021 Japan Geriatrics Society.)

Background: Glucocorticoids (GCs) are expected to inhibit the synthesis and release of proinflammatory cytokines, which induces local pain. Serious side effects or complications are considered rare with single-dose GC use. However, the amount of systemic absorption and the side effects induced by local GC injections are not well understood., Objectives: We measured the changes in glucose levels after single-does dexamethasone injection with nerve blockade using a continuous glucose monitoring system (CGMS) in non-diabetes mellitus (DM) patients and investigated the risk factors for hyperglycemia., Study Design: This is a cohort study., Setting: This study was conducted at Gifu University Hospital in Japan., Methods: Forty-six non-DM patients who underwent elective lumbar or sacral nerve root pulsed radiofrequency or lumbar medial branch of the posterior primary rami conventional radiofrequency with dexamethasone (0.1 mg/kg) were analyzed. The patients underwent monitoring of their interstitial glucose using a CGMS. Hyperglycemia was defined as a blood glucose level >= 200 mg/dL. The area under the curve (AUC) where the blood glucose level was over 200 mg/dL was calculated and analyzed. The risk factors of hyperglycemia were determined using an applied ordinal regression model analysis with the AUC as the objective variable and 4 factors (age, body mass index, glucose level just before GC injection, and glycosylated hemoglobin) as explanatory variables. The blood glucose levels were predicted by a nonlinear regression model., Results: The AUC and maximum glucose level were higher on the first day than after the second day. None of the 4 factors were predictors of hyperglycemia. The glucose level before the procedure was associated with the predicted blood glucose level on the first day (P = 0.042). However, the 95% upper confidence limit of the maximum predicted blood glucose level was less than the safety margin. The predicted blood glucose levels returned to the usual level after the second day., Limitations: First, GCs are metabolized by cytochrome p450 3A4, and it is possible that the inhibition of this pathway decreases the clearance of GCs. Some of our patients were taking medications that influence this cytochrome pathway. Second, we cannot eliminate the possibility of stress-induced hyperglycemia. Finally, we were unable to record the exact meal timing and calories the patients had consumed., Conclusions: The blood glucose levels were higher than usual on the first day following a local dexamethasone injection, but the levels were not critical in most cases. Because we cannot predict which patients will develop hyperglycemia, we must determine whether or not GCs can be safely administered and inform patients about potential complications.

Active pharmaceutical ingredients (APIs) have become a public concern owing to their possible adverse effects on aquatic organisms. Ministry of Health, Labor and Welfare in Japan (MHLW) issued "Guidance on the Environmental Risk Assessment (ERA) in new pharmaceutical development" in 2016. To evaluate the validity of phase 1 in the MHLW's ERA guidance, we monitored the measured environmental concentrations (MECs) of approved APIs in urban rivers and sewage treatment plants (STPs) in Japan and compared these MECs with the predicted environmental concentration (PEC). We collected water samples from urban seven rivers and three STPs during each season. Fifty-one APIs for human and veterinary use and the artificial sweetener sucralose were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Forty-four APIs were observed in the rivers and 42 were found in the influent and effluent of STPs, with levels ranging from nanograms to micrograms per liter. The action limit in phase I of the MHLW's guidance was set to 10 ng/L, and there was no API except for ketoprofen, for which PEC of the MHLW's guidance (PECjapan) was lower than 10 ng/L and the maximum MEC (MECmax) was 10 ng/L or greater. Almost all APIs also had median MECs that were lower than those of the respective PECjapan. These results indicate that the PECjapan values in phase I of the MHLW's guidance were appropriate. However, some APIs had MECmax values that were greater than those of the respective PECjapan due to overestimation of the dilution factor of river water and/or underestimation of API production.

Cytomegalovirus (CMV) infection is a major infectious complication following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent large-scale retrospective studies reported that CMV reactivation is an independent risk factor for poor post-transplant outcomes, although the development of CMV end-organ disease is suppressed by the CMV antiviral preemptive therapy, which has been mainly analyzed for hematopoietic malignancies, such as acute leukemia. However, it remains unclear whether CMV reactivation also has a negative effect on post-transplant outcomes in aplastic anemia (AA). Therefore, we evaluated the clinical relevance of CMV reactivation in patients with AA using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Adult patients with AA who underwent their first allo-HSCT between 2005 and 2017 and who survived with neutrophil engraftment until 100 days post-transplantation were analyzed (n = 672). Patients were monitored using pp65 antigenemia since the time of engraftment, and CMV reactivation in the analysis of this study was defined as the beginning of CMV preemptive or definitive therapy within 100 days post-transplantation. CMV reactivation occurred in 372 (55%) patients, including 19 with CMV end-organ disease. In time-dependent multivariate analysis, patients aged ≥40 years (hazard ratio [HR], 1.89; P = .003) who underwent transplantation from HLA-matched related peripheral blood stem cells (HR, 2.85; P = .008), HLA-matched unrelated bone marrow (BM) (HR, 2.01; P = .036), and other stem cell sources (HR, 2.32; P = .007) compared to HLA-matched related BM, CMV reactivation (HR 1.65; P = .042), grade II to IV acute graft-versus-host disease (HR 1.73; P = .013), and secondary graft failure (HR 7.09; P < .001) had independent risk factors that significantly decreased overall survival, indicating that CMV reactivation, one of the early events at post-transplantation, had a significant negative impact on the long-term prognosis at post-transplantation. This effect was more pronounced in patients aged ≥40 years who received a graft from other than HLA-matched related BM. Comparing the causes of death with and without CMV reactivation, no significant difference in the frequency of each cause of death was observed between the 2 groups (P = .453). Improvement of post-transplant CMV management that effectively suppresses CMV reactivation in the early stage at post-transplantation will be required to improve post-transplant outcomes, especially in high-risk patients., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Peritoneal metastasis of hepatocellular carcinoma (HCC) is rare. We investigated patients who underwent peritoneal metastasectomy in a multicenter study in Japan., Methods: The study included 92 patients with HCC who underwent resection for peritoneal metastasis between January 2007 and December 2013. We investigated background and operative factors, as well as overall and recurrence-free survival rates. Patients were classified according to the extent of peritoneal metastasis using the peritoneal cancer index (PCI) and the completeness of cytoreduction (CC) scores to examine whether peritoneal metastasectomy contributed to survival., Results: The mean maximum tumor size was 4.1 cm. Forty patients (43.5%) had multiple peritoneal metastases. Peritoneal metastasectomy and hepatectomy were performed simultaneously in 48 patients (52.2%). Overall, the 5-year survival rate after resection was 36.0%, and the recurrence-free survival rate was 13.0%. Multivariate analysis revealed that PCI scores of ≤6 + CC scores of 0 were an independent prognostic factor. The 5-year survival rate when these criteria were met was 43%, which was significantly better than that in those who did not meet these criteria (P < .001)., Conclusions: Peritoneal metastasectomy of HCC appears to contribute to improved survival of patients with a PCI scores of ≤6, without remnant tumors., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Clozapine is an effective antipsychotic medication for treatment resistant schizophrenia and is widely used in Asian countries. This study investigated clozapine prescription patterns and their associated factors in Asian countries and territories based on the database of the Research on Asian Psychotropic prescription study (REAP) conducted in 2016. Demographic and clinical information of 3744 schizophrenia patients in 15 Asian countries and territories was collected with a standardized data collection form. In total, 18.4% of the sample received clozapine, ranging from 2.6% in Japan to 32.3% in Hong Kong. Binary logistic regression analysis revealed that higher antipsychotic dose (OR = 1.002, P < 0.001), less frequent first admission in the sample (OR = 0.6, P < 0.001), more severe negative symptoms (OR = 1.4, P = 0.001) and less first generation antipsychotics (FGAs) (OR = 0.2, P < 0.001) were independently and significantly associated with clozapine prescription. Clozapine is frequently and increasingly prescribed for schizophrenia in Asia, with large variation across countries and territories. Given the diverse prescription patterns of clozapine found in Asian countries/territories, the clinical rationale of clozapine prescription needs careful consideration in Asia with more local input., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Excessive salt intake is widely known to be a cause of hypertension, cardiovascular events, and so on. However, simple tools for screening excessive salt intake are lacking., Objective: We aimed to develop a simple screening tool to identify community-dwelling adults with excessive salt intake., Methods: The present study involved participants who received health check-ups in Fukushima, Japan, in 2016 and 2017. We defined data from the 2016 check-up as the derivation set, and data from those who received check-ups in 2017 but not 2016 as the validation set. The outcome measure was excessive salt intake, defined as the estimated daily salt intake of 1 SD or more. Candidate predictors associated with the outcome were extracted using the Delphi method by an expert panel and narrowed down with clinical expertise and stepwise backward selection. The screening tool was developed using a coefficient-based multivariable scoring method and externally validated., Results: A total of 1101 participants were included in the derivation set and 249 in the validation set. At the conclusion of the deviation process, 8 predictors were selected and scored. The areas under the receiver operating characteristic curve for derivation and external validation were 0.70 (95% CI: 0.67, 0.74) and 0.71 (95% CI: 0.62, 0.80), respectively. The calibration slope and intercept for external validation were 1.16 and -0.03, respectively., Conclusion: We developed a screening tool to identify adults with excessive salt intake. By extracting groups with excessive salt intake, target populations needing intervention for salt reduction can be highlighted efficiently., (Copyright © The Author(s) 2020.)

Mixed chimerism (MC) and/or secondary graft failure (SGF) with recipient- or donor-type chimerism is a major obstacle in allogeneic transplantation for aplastic anemia (AA). From a registry database in Japan, patients with AA age >15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation between 2000 and 2014 and achieved engraftment were included in this study. MC that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support (group 1), MC (not SGF) that required G-CSF and/or transfusion support (group 2), SGF with MC or complete recipient-type chimerism (group 3), and SGF with complete donor-type chimerism (group 4) developed in 26, 16, 19, and 17 patients, respectively. The overall median duration of follow-up for survivors was 1727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In multivariate analyses, the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism, and the use of Flu in conditioning was associated with SGF with complete donor-type chimerism. In conclusion, the use of Flu may affect the occurrence of SGF with both recipient-type and donor-type chimerism., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The frequency of liver resection in elderly patients has been increasing. However, data are limited regarding the safety of laparoscopic liver resection (LLR) compared with that of open liver resection (OLR) for hepatocellular carcinoma (HCC) in elderly patients. The present study aimed to compare short-term outcomes between LLR and OLR in elderly patients with HCC using propensity score matching., Methods: The study included 630 patients (age, ≥ 75 years) who underwent liver resection for HCC at nine liver centres between April 2010 and December 2017. Patients were divided into LLR and OLR groups, and perioperative outcomes were compared between the groups. In addition, subgroup analysis was performed according to age (75-79 and ≥ 80 years)., Results: Of the 630 patients, 221 and 409 were included in the LLR and OLR groups, respectively. After propensity score matching, 155 patients were included in each group. Intraoperative blood loss and the transfusion, post-operative overall complication and major complication rates were lower in the matched LLR than the matched OLR group (P < 0.001, P = 0.004, P < 0.001 and P < 0.001, respectively). Moreover, post-operative pulmonary and cardiovascular complications were less frequent in the matched LLR group (P = 0.008 and P = 0.014, respectively). In subgroup analysis, among octogenarians, the post-operative major complication rate was lower and hospital stay was shorter in the matched LLR than the matched OLR group (P < 0.001 and P < 0.001, respectively)., Conclusion: LLR for HCC is associated with good short-term outcomes in patients aged ≥ 75 years compared with OLR. LLR is safe and feasible in selected octogenarians with HCC.

Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study.Trial registration ClinicalTrials.gov identifier NCT02675478.

Eltrombopag, an oral thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA) and has higher exposure in patients of East Asian origin. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with AA refractory or intolerant to immunosuppressive therapy (IST). Twenty-one patients (15 with non-severe AA, six with severe AA) with platelet counts < 30,000/µL received eltrombopag in a dose-escalation fashion (25, 50, 75, or 100 mg once daily) depending on individual platelet responses; the responders continued eltrombopag treatment beyond 6 months. The primary endpoint was hematologic response at 6 months, defined as improvements in blood counts or transfusion requirements. Ten (48%) patients achieved hematologic responses in at least one lineage at 6 months. Six patients achieved tri- and/or bi-lineage responses with continuation of eltrombopag treatment, with two patients no longer requiring eltrombopag treatment. The most common adverse events were nasopharyngitis and abnormal hepatic function, with the majority being grade 1 or 2. Cytogenetic abnormalities were observed in three patients; however, no progression to myelodysplastic syndrome/other malignancy was observed. Eltrombopag can safely restore multi-lineage hematopoiesis in Japanese patients with AA refractory or intolerant to IST.Clinical Trial registration NCT02148133.

Pyrethroid-resistance in onion thrips, Thrips tabaci, has been reported in many countries including Japan. Identifying factors of the resistance is important to correctly monitoring the resistance in field populations. To identify pyrethroid-resistance related genes in T. tabaci in Japan, we performed RNA-Seq analysis of seven T. tabaci strains including two pyrethroid-resistant and five pyrethroid-susceptible strains. We identified a pair of single point mutations, T929I and K1774N, introducing two amino acid mutations, in the voltage-gated sodium channel gene, a pyrethroid target gene, in the two resistant strains. The K1774N is a newly identified mutation located in the fourth repeat domain of the sodium channel. Genotyping analysis of field-collected populations showed that most of the T. tabaci individuals in resistant populations carried the mutation pair, indicating that the mutation pair is closely associated with pyrethroid-resistance in Japan. Another resistance-related mutation, M918L, was also identified in part of the resistant populations. Most of the individuals with the mutation pair were arrhenotokous while all individuals with the M918L single mutation were thelytokous. The result of differentially expressed gene analysis revealed a small number of up-regulated detoxification genes in each resistant strain which might be involved in resistance to pyrethroid. However, no up-regulated detoxification genes common to the two resistant strains were detected. Our results indicate that the mutation pair in the sodium channel gene is the most important target for monitoring pyrethroid-resistance in T. tabaci, and that pyrethroid-resistant arrhenotokous individuals with the mutation pair are likely to be widely distributed in Japan., (Copyright © 2019 Elsevier Inc. All rights reserved.)

As few epidemiological studies have investigated the effect of lifestyle factors on hypertension in the very elderly population, we conducted a cross-sectional study to examine the association of estimated salt intake and body weight with blood pressure in the very elderly population. We enrolled 288 participants aged 75 years or older who were residents of Sukagawa City, Fukushima Prefecture, Japan, who attended the health checkup conducted in 2015. Salt intake was estimated from spot urine samples using the Tanaka method. The mean values for age, estimated salt intake, and body weight of all participants were 79.7 years, 9.1 g/d (standard deviation 2.4 g), and 54.3 kg (standard deviation 10.2 kg), respectively. General linear models showed that salt intake and body weight were associated with higher systolic blood pressure (SBP) levels (per standard deviation higher level, adjusted difference 4.13 mm Hg [95% confidence interval 1.69-6.57] and 5.34 mm Hg [95% confidence interval 2.12-8.56], respectively). Body weight was associated with higher diastolic blood pressure (DBP) levels (per standard deviation higher level, 2.74 mm Hg [95% confidence interval 0.58-4.90]). However, salt intake was not associated with higher diastolic blood pressure levels (per standard deviation higher level, 1.15 mm Hg [95% confidence interval -0.49 to 2.79]). Our findings suggest that higher SBP is associated with both salt intake and body weight and that higher DBP is associated with body weight in the very elderly population. This study provides a rationale for lifestyle modifications to prevent hypertension as a population approach., (©2019 Wiley Periodicals, Inc.)

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n  =  24) or rhTM (n  =  41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

Aim: To assess for any additive value of hydroxychloroquine (HCQ) in Japanese patients with systemic lupus erythematosus (SLE) depending on calcineurin inhibitors (CNIs)., Methods: We retrospectively evaluated patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20 mg/d and one immunosuppressant (IS). Patients were divided into two groups depending on HCQ use and the groups were compared for changes in SLE Disease Activity Index (SLEDAI), prednisolone (PSL) dose, and cumulative flare rate between patients who were treated and not treated with CNI., Results: Among the 103 patients evaluated, 19 (18.4%) were treated with HCQ. On analysis of all patients, SLEDAI, PSL doses, and cumulative flare rate were significantly reduced in patients who received HCQ compared to those who did not (P = 0.04, P = 0.01, and P = 0.03, respectively). Regarding IS use, we found less additive therapeutic effect in CNI users than in users of other ISs in terms of reduction in SLEDAI and PSL dose (P = 0.05 and P < 0.01, respectively)., Conclusions: The addition of HCQ reduced disease activity, PSL dose, and flares in Japanese SLE patients but conferred less additive clinical efficacy when added to CNIs., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.

Objective: To evaluate the clinical outcomes after total knee arthroplasty (TKA) using the Genesis II posterior stabilized prosthesis with a high-flex insert during the mid-term follow-up and to assess its effect on the Japanese lifestyle., Materials and Methods: Fifty-three consecutive patients (8 men and 45 women) underwent primary TKA. The mean follow-up time was 76 months (5-9 years). Clinical results were assessed with the Japanese Orthopedic Association osteoarthritis knee rating score (JOA knee score), range of motion, and lifestyle changes., Results: The postoperative JOA knee score improved significantly compared to the preoperative JOA knee score. The mean preoperative flexion range improved from 112° to 123° postoperatively (p < 0.05). Additionally, our findings showed that 39% of patients enjoyed a floor-sitting life preoperatively, but only 30% of patients enjoyed floor-sitting life postoperatively., Conclusion: The postoperative range of knee motion and JOA knee score improved after TKA using the Genesis II posterior stabilized prosthesis with a high-flex insert, but the number of patients who enjoyed floor-sitting life decreased from 39% to 30% because of feelings of fear and discomfort., Level of Evidence: Level IV, Therapeutic study., (Copyright © 2016 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is one of the ultimately invasive procedures for managing a noncompressive torso injury. Since it is less invasive than resuscitative open aortic cross-clamping, its clinical application is expected., Methods: We retrospectively evaluated the safety and clinical feasibility of REBOA (intra-aortic occlusion balloon, MERA, Tokyo, Japan) using the Seldinger technique to control severe hemorrhage. Of 5,230 patients admitted to our trauma center in Japan from 2007 to 2013, we included 24 who underwent REBOA primarily. The indications for REBOA were a pelvic ring fracture or hemoperitoneum with hemodynamically instability and impending cardiac arrest. Emergency hemostasis was performed during REBOA in all patients., Results: All 24 patients had a blunt injury, the median age was 59 (interquartile range, 41-71 years), the median Injury Severity Score (ISS) was 47 (interquartile range, 37-52), the 30-day survival rate was 29.2% (n = 7), and the median probability survival rate was 12.5%. Indications for REBOA were hemoperitoneum and pelvic ring fracture in 15 cases and overlap in 8 cases. In 10 cases of death, the balloon could not be deflated in 5 cases. In 19 cases in which the balloon was deflated, the median duration of aortic occlusion was shorter in survivors than in deaths (21 minutes vs. 35 minutes, p = 0.05). The mean systolic blood pressure was significantly increased by REBOA (from 53.1 [21] mm Hg to 98.0 [26.6] mm Hg, p < 0.01). There were three cases with complications (12.5%), one external iliac artery injury and two lower limb ischemias in which lower limb amputation was necessary in all cases. Acute kidney injury developed in all three cases, but failure was not persistent., Conclusion: REBOA seems to be feasible for trauma resuscitation and may improve survivorship. However, the serious complication of lower limb ischemia warrants more research on its safety., Level of Evidence: Therapeutic/care management, level V.

Background: Aberrant signaling mediated by the mammalian target of rapamycin (mTOR) occurs at high frequency in hepatocellular carcinoma (HCC), indicating that mTOR is a candidate for targeted therapy. mTOR forms two complexes called mTORC1 (mTOR complexed with raptor) and mTORC2 (mTOR complexed with rictor). There are minor studies of the expression kinetics of mTORC1 and mTORC2 in HCC., Methods: We studied 62 patients with HCC who underwent curative resection. We used univariate and multivariate analyses to identify factors that potentially influence disease and overall survival after hepatectomy. The mRNA and protein levels of mTOR, rictor and raptor in cancer and non-cancer tissues were analyzed using quantitative RT-PCR, immunohistochemistry and Western blotting., Results/conclusion: High ratio of the levels of rictor and raptor mRNAs in tumors was identified as independent prognostic indicators for disease-free survival. Low and high levels of preoperative serum albumin and mTOR mRNA in the tumor, respectively, were identified as independent indicators of overall survival. HCC is likely to recur early after hepatic resection in patients with high levels of mTOR and rictor mRNAs and high rictor/raptor ratios in cancer tissues. We conclude that analysis of mTOR expression in cancer tissues represents an essential strategy to predict HCC recurrence after curative treatment.