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Mononuclear cell infiltration of the central nervous system and ganglioneuritis are characteristic histopathological findings of proventricular dilatation disease (PDD) caused by parrot bornavirus (PaBV) infection. The purpose of this study was to clarify the link between the degree of inflammatory lesions and the distribution of the virus antigen in naturally PaBV-infected parrots. Pathological examination was performed on 18 PaBV-infected birds identified by reverse transcriptase-PCR. Dilatation of the crop, proventriculus, and ventriculus was observed in all 18 (100%) birds, and dilation of the right ventricle of the heart was observed in 14/18 (78%) birds. Cases were classified based on the scores for the distribution and degree of histological lesions into neural type, with severe brain lesions, digestive type, with severe gastric lesions, or nervous/digestive type, with severe lesions in both the brain and ventriculus. The PaBV immunohistological score correlated with the inflammatory lesion scores. Ganglioneuritis, myocarditis, and myocardial degeneration were frequently observed in the heart. Interestingly, macroscopic and microscopic lesions and virus antigen were detected in the hearts of all three histological types. The present study showed that parrots naturally infected with PaBVs can be grouped into three types based on the lesion distribution, and heart failure is an important symptom in PaBV-infected parrots.

Background: Balloon aortic valvuloplasty (BAV) has gained renewed interest as a bridge to transcatheter aortic valve replacement (TAVR) for patients with aortic stenosis (AS). However, it is unclear whether they patients should undergo TAVR directly or receive a staged bridge to BAV before TAVR is unclear. We used a national database to examine the association between BAV and TAVR in patients with TAVR and its effect on in-hospital mortality., Methods: Using the nationwide inpatient database of the Japanese registry of all cardiac and vascular diseases and the combination of the diagnosis procedure combination, we retrospectively analyzed 27,600 patients with AS who underwent TAVR between October 2013 and March 2021. Outcomes of the direct TAVR group (n = 27,387) were compared with those of the BAV bridge to TAVR group (n = 213), which received BAV at least 1 day before TAVR., Results: The median age was 85 (interquartile range: 82-88) years, with 33.3% (n = 9188) being male. Unplanned/emergent admissions increased with TAVR, whereas the use of BAV bridge to TAVR decreased. The in-hospital mortality rate was 1.3% and decreased over time. However, the BAV bridge to TAVR had a significantly higher in-hospital mortality than direct TAVR (5.6% vs. 1.3%; p < .0001). Factors associated with in-hospital mortality included age, body mass index, chronic renal disease, percutaneous coronary intervention, and BAV bridge to TAVR., Conclusions: In unplanned/emergent and planned admission settings, the in-hospital mortality rate for BAV bridge to TAVR is worse than that for direct TAVR. Practical criteria for BAV bridge to TAVR should be proposed to improve outcomes., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST-segment elevation myocardial infarction (STEMI) even in cardiogenic shock and is now the standard of care in most of Japanese institutions. The Task Force on Primary PCI of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) proposed an expert consensus document for the management of acute myocardial infarction (AMI) focusing on procedural aspects of primary PCI in 2018 and updated in 2022. Recently, the European Society of Cardiology (ESC) published the guidelines for the management of acute coronary syndrome in 2023. Major new updates in the 2023 ESC guideline include: (1) intravascular imaging should be considered to guide PCI (Class IIa); (2) timing of complete revascularization; (3) antiplatelet therapy in patient with high-bleeding risk. Reflecting rapid advances in the field, the Task Force on Primary PCI of the CVIT group has now proposed an updated expert consensus document for the management of ACS focusing on procedural aspects of primary PCI in 2024 version., (© 2024. The Author(s).)

Aim: The effectiveness of the coronavirus disease (COVID-19) vaccine in Japanese patients undergoing haemodialysis has previously not been evaluated on a large scale. We analyzed data from the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR), covering nearly all Japanese patients undergoing dialysis (~95% coverage), to examine the association between COVID-19 vaccination and infection or mortality., Methods: We used data from the JRDR end-of-year surveys conducted in 2020 and 2021, including information on the COVID-19 vaccination and infection months. COVID-19 infection incidence and its associated mortality rates based on vaccination status (time updated) and odds ratio (OR) (vaccinated vs. unvaccinated) were estimated monthly from April 2021, when vaccination commenced in Japan., Results: COVID-19 infection analysis included 228 865 patients (215 941 vaccinated and 12 924 unvaccinated patients at the end of 2021). The age- and sex-adjusted ORs (aORs) were significantly lower in August, September, October and November 2021, especially in September (aOR [95% confidence interval (CI)]: 0.25 [0.18-0.36]). Additional adjustments for past medical history and laboratory results rarely affected these results. Similarly, in the COVID-19-related mortality analysis with 228 731 patients, including 216 781 vaccinated and 11 950 unvaccinated at the end of 2021, COVID-19-related mortality risk was significantly lower in the vaccinated group in August, September, October and November (aOR [95% CI]: August, 0.32 [0.12-0.84], September, 0.04 [0.01-0.11]; October, 0.10 [0.01-0.81]; November, 0.05 [0.00-0.79])., Conclusion: In Japanese patients undergoing haemodialysis, the first or second COVID-19 vaccine dose was significantly associated with decreased COVID-19 infection and mortality rates, suggesting its effectiveness in this population., (© 2024 The Author(s). Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP)., Methods: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618)., Results: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD., Conclusions: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan., Methods: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR)., Results: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively., Discussion: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The aim of the study was to evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an IL2 variant, administered alone or with the PDL1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors., Patients and Methods: In this phase 1, open-label, dose-escalation study, patients received i.v. FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with i.v. atezolizumab. The primary objectives were identification of dose-limiting toxicities (DLT), recommended dose, and maximum tolerated dose, and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab., Results: All 11 patients experienced adverse events (AE) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients: one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with increased aspartate aminotransferase. No AE-related deaths occurred. One DLT (grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The recommended dose and maximum tolerated dose could not be determined. The pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued because of portfolio prioritization (not for efficacy/safety reasons)., Conclusions: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted because of early study termination., Significance: This phase I study assessed the safety/tolerability and PK of simlukafusp alfa alone or combined with atezolizumab in Japanese patients with advanced solid tumors. No notable differences in PK were noted with the combination versus simlukafusp alfa alone; however, high-dose simlukafusp alfa treatment was associated with recombinant IL2-related toxicity, despite the drug's FAP targeting and IL2Rβγ-biased IL2 variant design., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Since the introduction of the Exeter stem for clinical use in Japan in 1996, the number of stems used has continued to rise owing to its favorable results. We investigated the outcomes of patients who had previously undergone total hip arthroplasty with the Exeter stem in Japan with a 10-year + follow-up period., Methods: This retrospective cohort study used clinical and radiographic data of 682 cases of primary total hip arthroplasty performed using the Exeter stem., Results: The mean postoperative follow-up period was 13.3 years. Femoral-side revision was required in 14 hips, with no cases of aseptic stem loosening-associated revision observed. Kaplan-Meier survival analysis predicted 97.3% 15-year survival when revision for any reason was used as the endpoint., Conclusion: The obtained findings suggested the excellent long-term stability of the Exeter stem for primary total hip arthroplasty in Japan., (© 2024. The Author(s).)

Purpose: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT)., Materials and Methods: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention., Results: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05)., Conclusions: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes., Clinical Impact: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.K. has received a research grant and consulting fees from Terumo and has received lecture fees from Medicon, Otsuka Pharmaceutical, and Kowa Pharmaceutical. H.O. has received lecture fees from Bayer Pharmaceutical, Bristol-Meyers Squibb, Eisai, Novartis Pharma, Pfizer, Towa Pharmaceutical, and Toa Eiyo. S.Y. has received remuneration for lecture from Bristol-Meyers, Bayer, and Daiichi-Sankyo; has received trust research/joint research funds from Takeda, NEC, Daiichi-Sankyo, Bayer, and Abbott; and is affiliated with endowed department sponsored by Abbott, Terumo, Nihon-Kohden, Medtronic, Japan Lifeline, Otsuka, Ono, Boehringer Ingelheim, Takeda, Kowa, Zeon, Shionogi, Nippon-Shinyaku, Mochida, and Tesco. The remaining authors have nothing to disclose.

In this study, we evaluated the thermal environments of different tennis courts using wet-bulb globe temperature (WBGT) meters. WBGT meters were installed in an outdoor hard court, sand-filled artificial grass court, and clay court (a softball field), and measurements were taken hourly from 9:00 to 17:00 on weekdays from June 1 to September 21, 2022. The results were compared with data from different courts and the nearest Japan Meteorological Agency station (JMA WBGT) based on the Japan Sports Association's guidelines for exercise to prevent heat stroke. The median WBGT on each court was significantly higher for hard courts at the "Warning" (25 ≤ JMA WBGT < 28) level or above, sand-filled artificial grass courts at the "Severe Warning" (28 ≤ JMA WBGT < 31) level or above, and clay courts at the "Danger" (31 ≤ JMA WBGT) level than the JMA WBGT. Compared with the JMA WBGT, hard and sand-filled artificial grass courts are played on under particularly hot conditions. The results of this study could indicate to tournament organizers and coaches the importance of measuring the WBGT on each court surface from an early stage to prevent heat-related incidents., (© 2024. The Author(s).)

Purpose: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926)., Methods: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity., Results: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: C max 217 μg/mL; C min 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t 1/2 , 17.6 days. Best overall response was stable disease in two patients., Conclusion: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials., Trial Registration Number: jRCT2080224926., (© 2024. The Author(s).)

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated., (© 2024 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Background: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity., Methods: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group., Results: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1β, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group., Conclusions: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: Acute mesenteric ischemia is rare, and few large-scale trials have evaluated endovascular therapy (EVT) and open surgical revascularization (OS). This study aimed to assess clinical outcomes after EVT or OS for acute superior mesenteric artery occlusion and identify predictors of mortality and bowel resection., Methods and Results: Data from the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) database from April 2012 to March 2020 were retrospectively analyzed. Overall, 746 patients with acute superior mesenteric artery occlusion who underwent revascularization were classified into 2 groups: EVT (n=475) or OS (n=271). The primary clinical outcome was in-hospital mortality. The secondary outcomes were bowel resection, bleeding complications (transfusion or endoscopic hemostasis), major adverse cardiovascular events, hospitalization duration, and cost. The in-hospital death or bowel resection rate was ≈30%. In-hospital mortality (22.5% versus 21.4%, P =0.72), bowel resection (8.2% versus 8.5%, P =0.90), and major adverse cardiovascular events (11.6% versus 9.2%, P =0.32) were comparable between the EVT and OS groups. Hospitalization duration in the EVT group was 6 days shorter than that in the OS group, and total hospitalization cost was 0.88 million yen lower. Interaction analyses revealed that EVT and OS had no significant difference in terms of in-hospital death in patients with thromboembolic and atherothrombotic characteristics. Advanced age, decreased activities of daily living, chronic kidney disease, and old myocardial infarction were significant predictive factors for in-hospital mortality. Diabetes was a predictor of bowel resection after revascularization., Conclusions: EVT was comparable to OS in terms of clinical outcomes in patients with acute superior mesenteric artery occlusion. Some predictive factors for mortality or bowel resection were obtained., Registration: URL: www.umin.ac.jp/ctr/; Unique Identifier: UMIN000045240.

Background: Water is one of the most essential nutrients for life. The water turnover (WT), total body water (TBW), and total energy expenditure (TEE) can be measured using the doubly labeled water (DLW) method. WT and TBW are lower in older adults than in young adults, and the former are susceptible to dehydration, necessitating to identify predictors of the WT in older adults., Objectives: The current study aimed to examine the association between WT and physical activity, physical function, and body composition in Japanese adults aged ≥65 y and identify predictors for WT in this population., Methods: This study enrolled 133 older adults (women, n = 61; men, n = 72) aged 65-88 y. WT, TBW, TEE, fat-free mass (FFM), and percent body fat (%Fat) were determined using the DLW method. The fitness age score (FAS) was obtained from 5 physical fitness tests. Physical activity and the step count were assessed using a previously validated triaxial accelerometer. Multiple regression analyses were performed with WT as the dependent variable., Results: WT was positively associated with weight, physical activity level (PAL), moderate-vigorous physical activity, and TEE, and negatively associated with sedentary behavior. We examined potential predictors for WT using age, sex, height, weight, FFM, %Fat, TEE, PAL, and FAS in older Japanese adults., Conclusions: Our results confirmed that age, sex, weight, FFM, TEE, and PAL are the potential predictors of WT in older Japanese adults aged ≥65 y., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dialyzers are classified into five types based on their β 2 -microglobulin clearance rate and albumin sieving coefficient: Ia, Ib, IIa, and IIb. In addition, a new classification system introduced a type S dialyzer. However, limited information is available regarding the impact of dialyzer type on patient outcomes. A cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry database. Total 181,804 patients on hemodialysis (HD) were included in the study, categorized into four groups (type Ia, IIa, IIb, and S). The associations between each group and two-year all-cause mortality were assessed using Cox proportional hazard models. Furthermore, propensity score-matching analysis was performed. By the end of 2019, 34,185 patients on dialysis had died. After adjusting for all confounders, the risk for all-cause mortality was significantly lower in the type IIa, and S groups than in the type Ia group. These significant findings were consistent after propensity score matching. In conclusion, our findings suggest that super high-flux dialyzers, with a β 2 -microglobulin clearance of ≥ 70 mL/min, may be beneficial for patients on HD, regardless of their albumin sieving coefficient. In addition, type S dialyzers may be beneficial for elderly and malnourished patients on dialysis.Trial registration number: UMIN000018641., (© 2024. The Author(s).)

Background: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors., Methods: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients., Results: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy., Conclusion: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Chicken chaphamaparvovirus causes diarrheal symptoms and can be detected in fecal samples. This study reports the detection of chicken chapparvovirus 2 in debilitated chickens with hemorrhagic hepatitis at a broiler farm in Japan. After euthanasia and necropsy, liver hemorrhage was observed. Nuclear inclusion bodies in the hepatocytes were identified using histological analysis. High-throughput sequencing analysis using RNA from livers of three affected chickens revealed infection by chicken chapparvovirus 2 and chicken anemia virus. Polymerase chain reaction analysis showed that all three chickens were positive for chicken chapparvovirus 2, and only one was positive for both chicken chapparvovirus 2 and chicken anemia virus. In conclusion, chicken chapparvovirus 2 causes infection in chickens in Japan and might be involved in hemorrhagic hepatitis.

Objectives: This study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity., Design: Retrospective observational study of a nationwide database., Setting: The Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint., Participants: This study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018., Main Outcome Measure: The primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis., Results: The median time to surgery was 9 months (IQR 4-22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p<0.001, respectively), in early stage ONFH with no or mild joint destruction (stages II and III, p<0.001), and with joint preserving surgery (p<0.001). The proportion without surgery was 75.8% at 3 months, 59.6% at 6 months, 48.2% at 9 months, 40.5% at 1 year, 22.2% at 2 years and 8.3% at 5 years., Conclusion: ONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of the patients within 9 months from diagnosis suggests severe disease with a significant clinical impact., Trial Registration Number: Chiba University ID1049., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To revise the 2017 clinical practice guidelines (CPG) for the management of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) to reflect advancements in the field., Methods: Similar to the 2017 CPG, the Grading of Recommendations, Assessment, Development, and Evaluation system was adopted for this revision. The intended users of this CPG include patients diagnosed with MPA or GPA in Japan and their families and healthcare professionals, including specialists and non-specialists. Based on a scoping review, four clinical questions (CQs) of the 2017 guidelines were modified, and six new CQs were added., Results: We suggest a combination of glucocorticoid and cyclophosphamide or rituximab for remission induction therapy. In cases where cyclophosphamide or rituximab is used, we suggest the use of avacopan over high-dose glucocorticoid. Furthermore, we suggest against the use of plasma exchange in addition to the standard treatment in severe cases of MPA/GPA. Finally, we suggest the use of glucocorticoid and rituximab over glucocorticoid and azathioprine for remission maintenance therapy., Conclusions: The recommendations have been updated based on patient preference, certainty of evidence, benefit and risk balance, and cost., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Skeletal-related events (SREs), including the pathological fracture, surgical treatment or radiation of bone lesions, malignant spinal cord compression, hypercalcemia, are important considerations when managing metastatic bone tumors; however, owing to their rarity, the incidence of SREs in patients with Ewing sarcoma remains unknown., Methods: We retrospectively reviewed the clinical data from 146 patients with Ewing sarcoma treated at a single institution from 2005 to 2019. The median age at diagnosis was 22.7 years. Fifty patients (34.2%) had metastatic disease at diagnosis. The primary outcome was the SRE-free rate among patients with Ewing sarcoma. Moreover, we identified the risk factors for SREs using univariate or multivariate analyses., Results: During the observational period (median, 2.6 years), SREs occurred in 23 patients. Radiation to the bone, malignant spinal cord compression, and hypercalcemia were documented as the initial SREs in 12 patients (52.2%), 10 patients (43.5%), and one patient (4.3%), respectively. The SRE-free rate was 94.2 ± 2.0, 87.3 ± 3.0, and 79.6 ± 3.8% at 1, 2, and 3 years after the initial visit, respectively. Multivariate analysis revealed bone metastasis at diagnosis (hazard ratio [HR] = 4.41, p = 0.007), bone marrow invasion (HR = 34.08, p < 0.001), and local progression or recurrence after definitive treatment (HR = 3.98, p = 0.012) as independent risk factors for SREs., Conclusions: SREs are non-rare events that can occur during the treatment course for Ewing sarcoma, with an especially high incidence of malignant spinal cord compression. Patients with metastatic disease at diagnosis, especially in the bone or bone marrow, or with local progression or recurrence after definitive treatment, should be carefully monitored for the occurrence of SREs. The most effective methods to monitor the occurrence of SREs and new preventative therapies for SREs should be investigated in the future., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors., Materials and Methods: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle., Results: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease., Conclusions: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown., Trial Registration: ClinicalTrials.gov, NCT04462952., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S Kondo has received research funding from AstraZeneca, Chugai, Astellas, AbbVie, Eisai, and Incyte. Y Katsuya has no conflicts of interest to disclose. K Yonemori has received honoraria from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma, MSD, Boehringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, and Sanofi; and research funding from MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe. N Yamamoto has a leadership/advisory role in Healios; has received honoraria from Chugai; and has received research funding from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, and Rakuten Medical. K Komuro, M Sugeno, T Kawata, D Ghiorghiu, and D Meulendijks are employees of AstraZeneca and may own stock in AstraZeneca., (Copyright © 2024. Published by Elsevier Ltd.)

The Japanese version of high bleeding risk (J-HBR) criteria was domestically proposed to identify patients at HBR after percutaneous coronary intervention (PCI). The applicability of J-HBR on bleeding events has been validated, while whether J-HBR predicts ischemic events is uncertain. This bi-center registry included 904 patients with acute myocardial infarction (MI) undergoing primary PCI. Patients were stratified by the J-HBR major (1 point) and minor (0.5 point) criteria. Patients with J-HBR ≥ 1 point were diagnosed as having HBR. The primary endpoint was major adverse cardiovascular events (MACE), a composite of cardiovascular death, recurrent MI, and ischemic stroke, after discharge. Of the 904 patients, 451 (49.9%) had the J-HBR. The primary endpoint more frequently occurred in patients with J-HBR than in those without (10.9% vs. 4.9%, p < 0.001) during the median follow-up period of 522 days. Probability of MACE was progressively increased with the increase in the number of J-HBR major and minor criteria, in which severe anemia, severe chronic kidney disease, prior heart failure, peripheral artery disease, and prior ischemic stroke were identified as significant factors associated with MACE. In patients with acute MI undergoing PCI, the J-HBR criteria were predictive for ischemic outcomes after discharge, suggesting that the J-HBR criteria may be useful to identify patients at high bleeding and ischemic risks., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Background and Objectives : The Wakayama prefecture is endemic for two types of tick-borne rickettsioses: Japanese spotted fever (JFS) and scrub typhus (ST). Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne hemorrhagic viral disease with a high mortality rate and is often difficult to differentiate from such rickettsioses. SFTS cases have recently increased in Wakayama prefecture. For early diagnosis, this study aimed to evaluate the clinical characterization of such tick-borne infections in the co-endemic area. Materials and Methods : The study included 64 febrile patients diagnosed with tick-borne infection in Wakayama prefecture between January 2013 and May 2022. Medical records of 19 patients with SFTS and 45 with rickettsiosis (JSF, n = 26; ST, n = 19) were retrospectively examined. The receiver operating curve (ROC) and area under the curve (AUC) were calculated to evaluate potential factors for differentiating SFTS from rickettsiosis. Results : Adults aged ≥70 years were most vulnerable to tick-borne infections (median, 75.5 years; interquartile range, 68.5-84 years). SFTS and rickettsiosis occurred mostly between summer and autumn. However, no significant between-group differences were found in age, sex, and comorbidities; 17 (89%) patients with SFTS, but none of those with rickettsiosis, experienced gastrointestinal symptoms such as vomiting, abdominal pain, and diarrhea. Meanwhile, 43 (96%) patients with rickettsiosis, but none of those with SFTS, developed a skin rash. The AUCs of white blood cells (0.97) and C-reactive protein (CRP) levels (0.98) were very high. Furthermore, the differential diagnosis of SFTS was significantly associated with the presence of gastrointestinal symptoms (AUC 0.95), the absence of a skin rash (AUC 0.98), leukopenia <3.7 × 10 9 /L (AUC 0.95), and low CRP levels < 1.66 mg/dL (AUC 0.98) ( p < 0.001 for each factor). Conclusions : Clinical characteristics and standard laboratory parameters can verify the early diagnosis of SFTS in areas where tick-borne infections are endemic.

Background: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD., Methods: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020., Results: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001)., Conclusions: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation., Methods: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020., Results: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p < .001). Disease-free survival (DFS), overall survival (OS), and post-recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p < .001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥ .577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K-adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates., Conclusions: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Hip fracture is among the most common injuries in elderly people. We aimed to investigate the decennial trends in hip fractures in patients ≥65 years of age., Methods: A questionnaire was distributed to all hospitals with a Department of Orthopaedic Surgery in Yamagata Prefecture to collect data on hip fractures occurring in 1996, 2006 and 2016., Results: The response rate was 100%. The total numbers of hip fractures in 1996, 2006 and 2016 were 665, 1169 and 1,728, respectively (crude incidence: 258, 373 and 494 per 100,000 person-year, respectively). Injuries frequently occurred in the early morning and daytime morning in 1996. In contrast, they frequently occurred in activity times (e.g., morning and afternoon) in 2006 and 2016. Among the patients, 80-90% were injured by simple falls, and 70-80% were injured indoors. The incidence of trochanteric fractures was approximately 1.8-1.9 times greater than incidence of neck fractures in all years. Especially, trochanteric fractures in females of ≥90 years of age markedly increased. The rate of surgical treatment was the same in 1996 and 2006, but was lower in 2016. In 1996, the percentage of independent walkers at discharge and 1 year later was almost the same. In 2006 and 2016, the rate of independent walkers was low at discharge, but increased 1 year later. The rate of discharge to home decreased gradually. The combined percentage of patients discharged to home and to rehabilitation institutions in 2006 and the percentage of patients who entered the regional referral clinical pathway in 2016 were both approximately 70%, with no marked changes observed., Conclusions: Hip fractures, especially trochanteric fractures in super-aged females, increased. Discharge to home decreased, and the use of the regional referral clinical pathway was widespread. Ambulation ability was reduced at discharge, but improved after 1 year., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest in association with the present study., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: This study compared the outcomes of dialysis patients who received SARS-CoV-2 vaccine with those who did not use data from the Japanese COVID-19 registry., Methods: A total of 1260 dialysis patients with confirmed positive SARS-CoV-2 infection was included in this study. Patients were divided into two groups: patients who experienced breakthrough infection and those who were unvaccinated. The need of oxygen supplementation and mortality risks were compared using multivariate logistic regression analysis., Results: The mortality rate was 24.2% in unvaccinated patients and 8.6% in breakthrough patients. The odds ratio of need of oxygen supplementation in the breakthrough patients relative to unvaccinated patients was 0.197. The hazard ratio of mortality in the breakthrough patients relative to unvaccinated patients was 0.464., Conclusion: Our prospective observational study showed that SRAS-CoV-2 vaccination in hemodialysis patients is vital for reducing need of oxygen supplementation and mortality risk., (© 2022 International Society for Apheresis and Japanese Society for Apheresis.)

Introduction: Vascular access usage varies widely across countries. Previous studies have evaluated the association of clinical outcomes with the three types of vascular access, namely, arteriovenous fistula (AVF), arteriovenous graft (AVG), and tunneled and cuffed central venous catheter (TC-CVC). However, little is known regarding the association between arterial superficialization (AS) and the mortality of patients., Methods: A nationwide cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry (2006-2007). We included patients aged ≥20 years undergoing hemodialysis with a dialysis vintage ≥6 months. The exposures of interest were the four types of vascular access: AVF, AVG, AS, and TC-CVC. Cox proportional hazard models were used to evaluate the associations of vascular access types with 1-year all-cause and cause-specific mortality., Results: A total of 183,490 maintenance hemodialysis patients were included: 90.7% with AVF, 6.9% with AVG, 2.0% with AS, and 0.4% with TC-CVC. During the 1-year follow-up period, 13,798 patients died. Compared to patients with AVF, those with AVG, AS, and TC-CVC had a significantly higher risk of all-cause mortality after adjustment for confounding factors: adjusted hazard ratios (95% confidence intervals) - 1.30 (1.20-1.41), 1.56 (1.39-1.76), and 2.15 (1.77-2.61), respectively. Similar results were obtained for infection-related and cardiovascular mortality., Conclusion: This nationwide cohort study conducted in Japan suggested that AVF usage may have the lowest risk of all-cause mortality. The study also suggested that the usage of AS may be associated with better survival rates compared to those of TC-CVC in patients who are not suitable for AVF or AVG., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors., Methods: Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed., Results: Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3-77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1., Conclusions: This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified., Trial Registration: Clinical Trials.gov number: NCT03006887., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Talazoparib, a poly(ADP-ribose) polymerase enzyme inhibitor, is approved for the treatment of patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative advanced breast cancer. This two-part study, a recently published dose-escalation part followed by the dose-expansion part reported here, evaluated the efficacy and safety of talazoparib in Japanese patients with gBRCA1/2-mutated advanced breast cancer., Methods: In this open-label, multicenter phase 1 study (NCT03343054), the primary endpoint of the dose-expansion part was confirmed objective response rate (ORR), determined by investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Patients received the recommended phase 2 dose (1 mg/day; 0.75 mg/day moderate renal impairment)., Results: Nineteen Japanese patients with gBRCA1/2-mutated locally advanced or metastatic breast cancer were enrolled. Confirmed ORR was 57.9% (11/19; 90% confidence interval [CI] 36.8-77.0). Stable disease was observed in 36.8% (7/19) of patients. Per investigator assessment, median PFS was 7.2 months (95% CI 4.1-not estimable) and 12-month OS rate was 84.7% (90% CI 57.5-95.1). Median OS was not reached; 17/19 patients were alive and censored at 12 months. All patients experienced treatment-related adverse events (AEs); the majority were hematologic. The most common treatment-related AE was anemia (68.4%; [13/19]). Grade 3/4 treatment-related AEs were observed in 52.6% (10/19) of patients. During the safety period, there were no grade 5 treatment-emergent AEs, treatment-related serious AEs, or deaths., Conclusions: In Japanese patients with gBRCA mutations and locally advanced or metastatic breast cancer, talazoparib monotherapy was generally well tolerated and resulted in clinically meaningful ORRs., Gov Identifier: NCT03343054., (© 2022. The Author(s).)

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m 2  + cisplatin 50 mg/m 2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (C max ). The overall response rate (ORR) was 11.4% (n = 4) and disease control rate (DCR) was 34.3% (n = 12). Consistent with that observed in other envafolimab Phase 1 trials and approved PD-1/PD-L1 inhibitors, the safety profile of SC envafolimab in Japanese patients with advanced solid tumors was well tolerated with efficacy comparable to IV administered treatments. Pharmacokinetics data and preliminary anti-tumor response support dose regimens with longer dosing intervals (Q2W or Q4W). As such, envafolimab offers patients a more convenient treatment option than currently available intravenously administered PD-1/PD-L1 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT03248843(August 14, 2017)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m 2 Q3W or paclitaxel 80 mg/m 2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow-up, 11.8 [range, 1.1-26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63-1.73) in patients with pMMR and 0.81 (0.50-1.31) in all-comers. Hazard ratios for OS were 0.74 (0.41-1.34) with pMMR and 0.59 (0.33-1.04) for all-comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE-775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum-based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Relative age effect is defined as a phenomenon where children born early generally perform better than children born later in the same cohort. Physical activity is an important factor that might be influenced by the relative age effect. Socioeconomic factors (e.g., parent's income, education level) are also associated with the adolescent's physical activity. However, no existing study has examined whether socioeconomic factors moderate the relative age effect on the adolescent's physical activity. This study aims to clarify whether and how birth month and socioeconomic factors relate to organized sports and physical activity among adolescents in Japan., Methods: We conducted a questionnaire survey targeting 21,491 adolescents who live in a widespread neighborhood. We included 8102 adolescents (4087 males and 4015 females: mean age 13.1 ± 1.4) in the analysis. Based on the participants' birth months, we divided them into four groups (April to June, July to September, October to December, January to March). We asked participants to report their organized sports participation. Using the International Physical Activity Questionnaire for Japanese Early Adolescents, we identified their moderate to vigorous physical activity (MVPA). Neighborhood-level socioeconomic factors (areal deprivation, average annual income, education level) were analyzed based on national surveys, such as the population census. We performed multilevel logistic and linear regression analysis for organized sports participation and MVPA, respectively. Moreover, a simple slope analysis was implemented if the interaction between birth month and socioeconomic factor was significant in the multilevel linear regression analysis., Results: Among males, relatively younger adolescents (adolescents who were born later in the same grade) were less likely to participate in organized sports activites (OR=0.90, 95% CI 0.82-0.97, p<0.05), while both males and females engaged in less MVPA (b=-0.54, b=-0.25, p< 0.01, respectively). We observed an interaction between birth month and socioeconomic factors. Among males in low-income neighborhoods, and females in more deprived neighborhoods, relatively younger adolescents engaged in less MVPA., Conclusions: Socioeconomic factors moderate the relative age effect on adolescents' physical activity. The relative age effect on adolescents' physical activity might be more likely to appear among adolescents from socioeconomically disadvantaged neighborhoods., (© 2022. The Author(s).)

Background: There are currently two species within the small enigmatic genus Atherospio Mackie & Duff, 1986, which belongs to the Pygospiopsis - Atherospio group in the family Spionidae Grube, 1850. The taxonomic relationship of the genus Atherospio with other spionid or spioniform genera is currently not well understood due to its unusual morphological characteristics., Methods: Here, we describe a new Atherospio species, Atherospio aestuarii , based on materials collected from three localities in Japan: Hirota Bay (Iwate Prefecture), Ago Bay (Mie Prefecture), and Yakushima Island (Kagoshima Prefecture). We have also evaluated the possible systematic position of this new species by conducting molecular phylogenetic analyses using the nuclear 18S, 28S, and mitochondrial 16S rRNA gene sequences.sp. nov. , based on materials collected from three localities in Japan: Hirota Bay (Iwate Prefecture), Ago Bay (Mie Prefecture), and Yakushima Island (Kagoshima Prefecture). We have also evaluated the possible systematic position of this new species by conducting molecular phylogenetic analyses using the nuclear 18S, 28S, and mitochondrial 16S rRNA gene sequences., Results: The morphology of A . aestuarii sp. nov. resembles that of A. disticha Mackie & Duff, 1986 and A . guillei (Laubier & Ramos, 1974) in having branchiae fused to the notopodial lamellae on a restricted number of segments from chaetiger 7, modified neurochaetae on chaetiger 5, and at least some bidentate neuropodial hooks with the secondary tooth below the main fang. The form and arrangement of the modified aristate neurochaetae in double vertical rows closely resemble those found on chaetigers 4 and 5 of A. disticha . The new species lacks the occipital antenna present in A . disticha . In this respect it resembles A . guillei , however, that species differs in having robust neuropodial spines on chaetiger 5 and peristomial papillae, and a preponderance of unidentate neurochaetae. Both A. guillei and the new species have slender needle-like notochaetae in their posteriormost chaetigers. Atherospio aestuarii sp. nov. is distinguished from both congeneric species by its branchial and neuropodial hook distributions. The new species is also unique in that it was recorded at relatively shallow depths, which included intertidal zones. The results of our molecular phylogenetic analysis indicate that the new species was included in a clade that included the genera of the Polydora complex, Pygospio Claparède, 1863, Glandulospio Meißner, Bick, Guggolz, Götting, 2014, Spio Fabricius, 1785, Microspio Mesnil, 1896, Marenzelleria Mesnil, 1896, Rhynchospio Hartman, 1936, Scolelepis Blainville, 1828, Dispio Hartman, 1951, and Malacoceros Quatrefages, 1843 with robust statistical support. The new species formed a clade with Dispio and Scolelepis , however, statistical support for the node was not significant., Competing Interests: The authors declare that they have no competing interests., (© 2022 Abe and Kan.)

Purpose: We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy., Patients and Methods: Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective., Results: Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4-41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased., Conclusions: E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background and Aim: Clinical manifestations and genetic backgrounds of Japanese patients with sitosterolemia have been unclear., Materials and Methods: We searched PubMed for studies using the keywords "sitosterolemia" or "phytosterolemia" and "Japan". Moreover, we added information from the members of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare (MHLW) of Japan., Results: We identified 36 patients with sitosterolemia caused by biallelic pathogenic mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or ATP-binding cassette subfamily G member 8 (ABCG8) from 31 families in Japan. The diagnosed age ranged from 0 to 64 years (median 13 years). The median sitosterol and LDL cholesterol levels were 100 μg/ml (IQR: 50-183), and 193 mg/dl (IQR: 108-295), respectively. All the patients exhibited cutaneous and/or tendon xanthomas, up to 9 (25%) patients exhibited premature coronary artery disease, 5 (16%) patients exhibited arthritis, and 8 (22%) patients exhibited blood abnormalities. Ezetimibe was administered to all the patients, including infantile cases, while statins, colestimide, evolocumab, probucol, and LDL apheresis were also used., Conclusion: We are providing a demographic overview of the clinical and genetic backgrounds of Japanese patients with sitosterolemia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Adenoviruses have been reported to infect a variety of birds. Here, we isolated a novel adenovirus from the liver of a dead owl chick (Bengal eagle owl; Bubo bengalensis) at a raptor-breeding facility in Japan and determined the complete genome sequence of the virus. We performed necropsies on the dead owl chicks and found that they had enlarged livers, pericardial edema, and focal necrosis of the liver tissue. Transmission electron microscopy of the liver tissue revealed a virus-like structure, appearing as paracrystalline arrays in the nucleus, and immunohistochemical staining with anti-adenovirus antibodies showed positive reactions in hepatocytes and other cells. Attempts to isolate the virus from homogenized liver tissue of a dead owl chick showed a cytopathic effect on chicken-derived cultured cells after multiple blind passages. Further, we determined the complete genome sequence of this virus and performed phylogenetic analysis, revealing that this adenovirus belongs to the genus Aviadenovirus, forming a cluster with fowl and turkey aviadenoviruses. The amino acid sequence divergence between the DNA polymerase of this virus and its closest known adenovirus relative is approximately 29%, implying that this virus can be assigned to a new species in the genus Aviadenovirus. Based on our data, this novel owl adenovirus is a likely cause of fatal infections in owls, which may threaten wild and captive owl populations. Further, this virus is unique among raptor adenoviruses in that it infects chicken-derived cultured cells, raising the importance of further investigations to evaluate interspecies transmission of this virus., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes., Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients., Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients., Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers., Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621., (© 2021. The Author(s).)

Objective: To examine whether there is an association between prehospital transfer distance and surgical mortality in emergency thoracic aortic surgery., Methods: A retrospective cohort study using a national clinical database in Japan was conducted. Patients who underwent emergency thoracic aortic surgery from January 1, 2014, to December 31, 2016, were included. Patients with type B dissection were excluded. A multilevel logistic regression analysis was performed to examine the association between prehospital transfer distance and surgical mortality. In addition, an instrumental variable analysis was performed to address unmeasured confounding., Results: A total of 12,004 patients underwent emergency thoracic aortic surgeries at 495 hospitals. Surgical mortality was 13.8%. The risk-adjusted mortality odds ratio for standardized distance (mean 12.8 km, standard deviation 15.2 km) was 0.94 (95% confidence interval, 0.87-1.01; P = .09). Instrumental variable analysis did not reveal a significant association between transfer distance and surgical mortality as well., Conclusions: No significant association was found between surgical mortality and prehospital transfer distance in emergency thoracic aortic surgery cases. Suspected cases of acute thoracic aortic syndrome may be transferred safely to distant high-volume hospitals., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Aim: The post-endovascular treatment outcomes of thrombotic lesions remain unclear. This study aimed to investigate the effects of thrombotic lesions on post-endovascular treatment outcomes in patients with non-acute aortoiliac total occlusions., Methods: This subanalysis of a multicenter prospective observational registry study included patients from 64 institutions in Japan between April 2014 and April 2016. A total of 346 patients (394 limbs; median age, 72 years), including 186 men, underwent endovascular treatment for non-acute aortoiliac total occlusions and were included. The patients were classified as having thrombotic or non-thrombotic lesions. The primary (1-year primary patency rate) and secondary (1-year overall survival rate) endpoints were evaluated., Results: Thrombotic lesions were identified in 18.5% (64/346) of the patients. The 1-year primary patency (85.9% versus 95.4%, log-rank p＜.001) and overall survival (90.6% versus 97.9%, log-rank p=.003) rates were significantly lower in the thrombotic group than in the non-thrombotic group. Thrombotic lesions had significant effects on the post-endovascular treatment outcomes, with adjusted hazard ratios of 3.91 (95% confidence interval, 1.64-9.34, p=.002) for primary patency and 4.93 (95% confidence interval, 1.59-15.3, p=.006) for all-cause mortality., Conclusions: Thrombotic lesions were associated with 1-year restenosis and all-cause mortality after endovascular treatment for non-acute aortoiliac total occlusions. Endovascular treatment strategies should be carefully planned for patients with thrombotic lesions.

Purpose: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer., Materials and Methods: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m 2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m 2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety., Results: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks., Conclusion: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer., Competing Interests: Junzo HamanishiResearch Funding: MSD, Ono Pharmaceutical, Sumitomo Dainippon Pharma Noriyuki KatsumataConsulting or Advisory Role: Nippon Zoki Pharmaceutical Co, Ltd Kimio UshijimaHonoraria: AstraZeneca, Chugai Pharmaceutical, Takeda, Nippon Kayaku, MSD, Kaken Pharmaceutical, Kyowa Kirin InternationalResearch Funding: AstraZeneca, Chugai Pharmaceutical, Takeda, Kaken Pharmaceutical, Nippon Kayaku, Mochida Pharmaceutical Co, Ltd, Taiho Pharmaceutical, Eisai, Ono Pharmaceutical, AbbVie, MSD Tadashi KimuraHonoraria: Nobelpharma Co, Ltd, GE Healthcare Japan, Mochida Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Bayer Pharmaceuticals, Aska PharmaceuticalConsulting or Advisory Role: Fermata Pharma, Rohto PharmaceuticalResearch Funding: Fuji Pharma, Nippon Shinyaku, Takeda Yakuhin, Taihou Yakuhin, Mochida Pharmaceutical Co, Ltd, Nihon Seiyaku, Zeria Pharmaceutical Koji MatsumotoHonoraria: Chugai Pharmaceutical, AstraZeneca, Kyowa Hakko Kirin, Eisai, MSD K.K., Eli Lilly Japan K.K., Taiho Oncology, AbbVie, PfizerResearch Funding: Ono Pharmaceutical, MSD, AstraZeneca, Novartis, Chugai Pharmaceutical, Eisai Kimihiko ItoHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca, AbbVie, Nippon Shinyaku, TerumoUncompensated Relationships: Kansai Clinical Oncology Group Hidemichi WatariHonoraria: MSD K.K., Tsumura & Co, AstraZeneca, Aska Pharmaceutical Co, Ltd, Terumo, Bayer Yakuhin, Kaken Pharmaceutical, Mochida Pharmaceutical Co, Ltd, Daiichi Sankyo/UCB Japan, Chugai Pharmaceutical, TakedaConsulting or Advisory Role: Decision Resources Group Japan, Kaken Pharmaceutical, Chugai PharmaceuticalResearch Funding: Hokkaido Welfare Federation of Agricultural Cooperatives, Kaken Pharmaceutical, Mochida Pharmaceutical Co, Ltd, Taiho Pharmaceutical, Chugai Pharmaceutical, Hokkaido Cancer Society, TakedaOther Relationship: T-PEC Nobutaka TakahashiHonoraria: Olympus, Ethicon/Johnson & Johnson, Intuitive Surgical, Kaken Pharmaceutical Kosei HasegawaHonoraria: MSD K.K., Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, AstraZeneca, EisaiConsulting or Advisory Role: MSD K.K., Kaken PharmaceuticalResearch Funding: Ono Pharmaceutical, Daiichi Sankyo, Takeda Kan YonemoriHonoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharmaceutical, Ono Pharmaceutical, Novartis, EisaiResearch Funding: Ono Pharmaceutical Kazuhiro TakeharaHonoraria: Takeda Pharmaceutical Company, AstraZeneca, Eisai, Chugai Pharmaceutical, MSD, Mochida Pharmaceutical Co, LtdResearch Funding: Chugai Pharmaceutical Hitoshi NiikuraHonoraria: Takeda Sari NakaoUncompensated Relationships: Japanese Gynecologic Oncology Group Toshiaki SaitoHonoraria: Nippon Kayaku, Kyowa Hakko Kirin, Eisai, Kaken Pharmaceutical CompanyResearch Funding: Chugai Pharmaceutical, Taiho Pharmaceutical Takayuki EnomotoHonoraria: AstraZeneca, MSD, Chugai Pharmaceutical Satoru NagaseHonoraria: Chugai Pharmaceutical, AstraZeneca Aikou OkamotoHonoraria: AstraZeneca K.K., MSD, Chugai Pharmaceutical, TakedaConsulting or Advisory Role: AstraZeneca K.K., Chugai PharmaceuticalSpeakers' Bureau: AstraZeneca K.K.Research Funding: Kissei Pharmaceutical, Meiji Holdings, Pfizer, Fuji Pharma, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharmaceutical, Tsumura & Co, Daiichi Sankyo Company, Ltd, Shinnihonseiyaku, Mochida Pharmaceutical Co, Ltd, Aska Pharmaceutical Co, Ltd, Takeda, Terumo Yoshito TeraiResearch Funding: Ethicon/Johnson & Johnson, MSD, Covidien, Terumo, Daiichi Sankyo/UCB Japan, Chugai Pharmaceutical, Taiho Pharmaceutical Akira TakazawaEmployment: Ono Pharmaceutical Yusuke TakahashiEmployment: Ono PharmaceuticalStock and Other Ownership Interests: Ono Pharmaceutical Yoshinobu NambaEmployment: Ono PharmaceuticalHonoraria: Boehringer Ingelheim Daisuke AokiHonoraria: AstraZeneca K.K., MSD K.K., Takeda, Chugai Pharmaceutical, Myriad GeneticsConsulting or Advisory Role: Takeda, MSD K.K., AstraZeneca K.K.Speakers' Bureau: AstraZeneca K.K., Takeda Keiichi FujiwaraHonoraria: Kyowa Hakko Kirin, Zeria Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Eisai, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, TakedaConsulting or Advisory Role: AstraZeneca, MSD, Taiho Pharmaceutical, Eisai, Takeda, Genmab, AbbVie, Pfizer, NanoCarrierResearch Funding: Eisai, Kaken Pharmaceutical, Chugai Pharmaceutical, Shionogi, ImmunoGen, ONCOtherapeutics, AstraZeneca, Eli Lilly, Zeria Pharmaceutical, Ono Pharmaceutical, MSD, Genmab, Regeneron, Merck KGaA, Ono PharmaceuticalTravel, Accommodations, Expenses: Pfizer, AbbVie, MSDNo other potential conflicts of interest were reported.

Aging of the population has led to an increase in the prevalence of cancer among older adults. In Japan, single agent chemotherapy was recommended for advanced non-small cell lung cancer (NSCLC) for those, who were aged ≥75 years, while the Western guidelines did not recommend a specific regimen. In clinical practice, physicians are required to decide the treatment based on a lack of enough evidence. This study aimed to examine the prescribing patterns of first-line chemotherapy according to age in the real-world practice. Data from the survey database of Diagnostic Procedure Combination and hospital-based cancer registries of designated cancer centers nationwide were used. The first-line chemotherapy regimens among 9,737 patients who were diagnosed with advanced lung cancer between January and December 2013, were identified and compared based on age. We found that the proportion of patients receiving chemotherapy decreased with age; 80.0%, 70.4%, 50.6%, and 30.2% of patients aged 70-74, 75-79, 80-84, and ≥ 85 years, respectively, received chemotherapy. Among them, platinum doublets were prescribed for 62.7% of the patients who were aged ≥ 70 years, and 60.7% of the patients who were aged ≥ 75 years with no driver mutations in NSCLC; only 37.6% of them received single agents. Patients who were aged ≥ 80 years also preferred platinum doublets (35.6%). Carboplatin was commonly prescribed in all age groups; only 28.4% of those receiving platinum doublets selected cisplatin. In this study, platinum doublets were identified as the most commonly prescribed regimen in those who were aged ≥ 70 years. Despite recommendations of Japanese guidelines for NSCLC, 60.7% of those who were aged ≥75 years received platinum doublets. Additionally, patients who were aged ≥ 80 years also received systemic chemotherapy, including platinum doublets; age did not solely influence regimen selection., Competing Interests: I have read journal’s policy and the authors of this manuscript have the following competing interests: Ayako Okuyama reports grants and other from National Cancer Center in Japan, during the conduct of the study. Akihiro Hirakawa reports grants and personal fees from Ono Pharmaceutical, and personal fees from Astellas Pharma, AbbVie, Nippon Boehringer Ingelheim, Kissei Pharmaceutical, Pfizer, and Nippon Shinyaku, outside the submitted work. Yasushi Goto reports grants and personal fees from Eli Lilly, Chugai, Taiho Pharmaceutical, Pfizer, Novartis, MSD, Guardant Health, and Ono Pharmaceutical, and grants from Kyorin, and Dai-ichi Sankyo, and personal fees from Boehringer Ingelheim, AstraZeneca, and Glaxo Smith Kline, outside the submitted work. Yasuhiro Fujiwara reports grants and committee member from Japan Agency for Medical Research and Development, and The Ministry of Health Labor and Welfare, Japan, during the conduct of the study, and lecture fee from Astra Zeneca KK, Daiichi Sankyo Co., Ltd, Taiho Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Novartis Pharma KK, SRL Inc, Bristol-Myers Squibb KK, and Santen Pharmaceutical Co., Ltd, outside the submitted work. Takahiro Higashi is employed by the National Cancer Center Japan, which is responsible for operating hospital-based cancer registries nationwide, during the conduct of the study, and the data collection was funded by the internal grant of National Cancer Center. Kan Yonemori reports personal fees from Novartis, Pfizer, Chugai, Eisai, Taiho, and AstraZeneca, outside the submitted work. Shoko Noda-Narita, Asuka Kawachi, and Ryo Sadachi, have nothing to disclose. The competing interests stated do not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1., Methods: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint)., Results: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11-1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16-2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab., Conclusion: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02477644., Competing Interests: Professor Keiichi Fujiwara reports receiving consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, and Takeda Pharmaceutical Company, receiving grant support from Immunogen, Oncotherapy, and Regeneron, and receiving consulting fees from Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, and NanoCarrier; Dr Toyomi Satoh reports receiving consulting fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, Eisai, Tsumura, Nippon Kayaku, Mochida Pharmaceutical, Bayer Yakuhin, ASKA Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Takeda Pharmaceutical Company, Kaken Pharmaceutical, Nobelpharma, and Ono Pharmaceutical; Dr Kan Yonemori reports receiving lecture fees and advisory fees from Takeda Pharmaceutical Company and Esai, receiving lecture fees from AstraZeneca, Pfizer, and Daiichi Sankyo, and advisory fees from Chugai Pharmaceutical, Ono Pharmaceutical, and Novartis; Dr Shogi Nagao reports receiving consulting fees and grant support from Takeda Pharmaceutical Company, consulting fees from Chugai Pharmaceutical, AstraZeneca, Asahi Kasei Medical, and Mochida Pharmaceutical, and grant support from AbbVie, Clovis Oncology, Pfizer, Toray, Tosoh, and Preferred Networks; Dr Philipp Harter reports receiving consulting fees and grant support AstraZeneca, Roche, Tesaro, and GlaxoSmithKline, consulting fees from Sotio, Zai Lab, Merck Sharp & Dohme, Clovis Oncology, and Immunogen, and grant support from Boehringer Ingelheim, Medac, Genmab, the European Union, Deutsche Krebshilfe, and Deutsche Forschungsgemeinschaft; Dr Isabel Palacio Vazquez reports receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Novartis, GlaxoSmithKline, and Bristol-Myers Squibb, travel fees from Novartis, GlaxoSmithKline, and Roche, and advisory board fees from AstraZeneca, Bristol, GSK, and Clovis Oncology; Tomoko Fujita reports being employed by AstraZeneca and being a shareholder of AstraZeneca; Philip Rowe reports being employed by AstraZeneca; Professor Eric Pujade-Lauraine reports receiving consulting and other non-financial support from AstraZeneca, Roche, and Tesaro, consulting fees from Clovis Oncology, Incyte, and Pfizer, and holds the role as chairperson in ARCAGY Research; Professor Isabelle Ray-Coquard reports receiving consulting fees, grant and travel support from AstraZeneca and Roche, consulting fees and travel support from GlaxoSmithKline, consulting fees from Clovis Oncology, PharmaMar, Mersana Therapeutics, Deciphera Pharmaceutical, Amgen, and Chugai Pharmaceutical, grant support from Bristol Myers Squibb, and consulting fees and grant support from Merck Sharp & Dohme; Dr Hiroyuki Fujiwara, Dr Hiroyuki Yoshida, Dr Takashi Matsumoto, Dr Hiroaki Kobayashi, Dr Hugues Bourgeois, Dr Anna Maria Mosconi, and Dr Alexander Reinthaller report no potential conflict of interest relevant to this article., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: There are no reports of a large-scale survey on the infection prevention measures against coronavirus disease 2019 (COVID-19) in nephrology facilities. This study investigated the facility-level nephrology practices adopted during the COVID-19 pandemic and their associated challenges. Additionally, the treatment patterns and outcomes of chronic kidney disease (CKD) patients with COVID-19 were reviewed., Methods: We conducted a nationwide questionnaire survey of 704 educational facilities that were certified by the Japanese Society of Nephrology (JSN) from October 20, 2020 to November 16, 2020. The questionnaire reviewed the facility characteristics, infection prevention measures taken during routine nephrology practice, impact of COVID-19 on nephrology practice, experiences in managing CKD patients with COVID-19, and nosocomial transmission in the nephrology unit., Results: Of the 347 facilities that responded, 95.1% checked outpatients' body temperatures and COVID-19 symptoms at their visits. To reduce face-to-face contact, 80% and 70% of the facilities lengthened the intervals between outpatient visits and introduced online/telephonic consultations, respectively. As a result, more than half of the hospitals experienced a decrease in the numbers of outpatients and inpatients (64% and 50%, respectively). During the study period, 347 facilities managed 479 CKD patients with COVID-19. Oxygen administration and mechanical ventilation were performed for 47.8% and 16.5% of the patients, respectively, with a 9.2% total mortality rate., Conclusion: This survey demonstrated that JSN-certified educational nephrology facilities adopted multiple measures to manage the COVID-19 pandemic; however, they faced several challenges. Sharing these experiences could standardize these approaches and prepare us better for the future., (© 2021. Japanese Society of Nephrology.)

Introduction: Atypical femoral fractures (AFFs) have been correlated with long-term use of bisphosphonates (BPs), glucocorticoids (GCs), and femoral geometry. We investigated the incidence and characteristics of subtrochanteric (ST) and diaphyseal (DP) AFFs in all institutes in a super-aging prefectural area., Materials and Methods: We performed a blinded analysis of radiographic data in 87 patients with 98 AFFs in all institutes in Yamagata prefectural area from 2009 to 2014. Among the 98 AFFs, 57 AFFs comprising 11 ST fractures in 9 patients and 46 DP fractures in 41 patients with adequate medical records and X-rays were surveyed for time to bone healing and geometry., Results: Of the 87 patients, 67 received BPs/denosumab (77%) and 10 received GCs (11%). Surgery was performed in 94 AFFs. Among 4 AFFs with conservative therapy, 3 required additional surgery. In univariate regression analyses for ST group versus DP group, male-to-female ratio was 2/7 versus 1/40, mean age at fracture was 58.2 (37-75) versus 78 (60-89) years, rheumatic diseases affected 55.5% (5/9) versus 4.9% (2/41), femoral lateral bowing angle was 1.7 (0-6) versus 11.8 (0.8-24)°, GC usage was 67% (6/9) versus 4.9% (2/41), and bone healing time was 12.1 (6-20) versus 8.1 (3-38) months (p < 0.05). In multivariate analyses, higher male-to-female ratio, younger age, greater proportion affected by rheumatic diseases, and higher GC usage remained significant (p < 0.05)., Conclusions: The incidence of AFFs in our prefectural area was 1.43 cases/100,000 persons/year. This study suggests that the onset of ST AFFs have greater correlation with the worse bone quality, vice versa, the onset of DP AFFs correlated with the bone geometry. The developmental mechanisms of AFFs may differ significantly between ST and DP fractures.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)