Search

Background: Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice., Methods: We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS., Results: Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs., Conclusions: There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region., Competing Interests: Masahiro Nomoto reported research funds from Kyowa Kirin in relation to this study; and reported employment by The Social Welfare Organization Imperial Gift Foundation Inc. Saiseikai Imabari Hospital; honoraria from Ehime University, Takeda Pharmaceutical, Kyowa Kirin, Eisai, and Ono Pharmaceutical; consultancies for Kissei Pharmaceutical and SNLD; and has served on advisory boards for the Pharmaceuticals and Medical Devices Agency and Ehime Prefecture. Yoshio Tsuboi reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees from Sumitomo Pharma, Takeda Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, and Eisai; and contributes to courses organized by SUNWELS and Nipro Corporation. Kenichi Kashihara reported research funds from Kyowa Kirin in relation to this study; and reported employment by Okayama Neurology Clinic; and honoraria from Kyowa Kirin, Takeda Pharmaceutical, Ono Pharmaceutical, Sumitomo Pharma, FP Corporation, AbbVie GK, and Eisai. Shih-Wei Chiu reported research funds from Kyowa Kirin in relation to this study. Tetsuya Maeda reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees and scholarship donations from Sumitomo Pharma, Takeda Pharmaceutical Company, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, Nippon Boehringer Ingelheim, Daiichi Sankyo, and Japan Medtronic; lecture fees from AbbVie, FP Corporation, Biogen, and Chugai Pharmaceutical; scholarship donations from Bayer Yakuhin, Teijin, and CSL Behring; and consulting fees from Kyowa Kirin and Ono Pharmaceutical. Hidemoto Saiki reported editorial support from Kyowa Kirin in relation to this study; and reported honoraria from Eisai, Sumitomo Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, and Medtronic Japan; and grants from Otsuka Pharmaceutical and PDRadiopharma Inc. Hirohisa Watanabe reported research funds from Kyowa Kirin in relation to this study; and reported honoraria from Takeda Pharmaceutical, AbbVie, Kyowa Kirin, Sumitomo Pharma, Novartis Pharma, Otsuka Pharmaceutical, and FP Corporation. Yasushi Shimo reported honoraria from Takeda Pharmaceutical, Abbott Japan, Otsuka Pharmaceutical, Medtronic Japan, Kyowa Kirin, Eisai, MDS, Boston Scientific Japan, Sumitomo Pharma, Daiichi Sankyo, Nihon Medi-Physics, and EA Pharma; and a grant from Japan Society for the Promotion of Science (JSPS KAKENHI no. 21K07282). Nobutaka Hattori reported research grants, support for attending advisory boards, and support for a joint research department from Kyowa Kirin; and reported research contracts with Sumitomo Pharma and CellSource; consultancy fees from PARKINSON Laboratories; honoraria from Sumitomo Pharma, AbbVie, Otsuka Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, FP Pharmaceutical, Eisai, and Daiichi Sankyo; support for attending advisory boards from Sumitomo Pharma, Novartis Pharma, Ono Pharmaceutical, Teijin Pharma, and Mitsubishi Tanabe Pharma Corporation; support for an endowed department from Nippon Boehringer Ingelheim, FP Pharmaceutical, Teijin Pharma, Fujifilm Wako Pure Chemical Corporation, and Meiji Seika Pharma; support for a joint research department from Kyowa Kirin, Sumitomo Pharma, Parkinson Laboratories, Takeda Pharmaceutical, Otsuka Pharmaceutical, Ono Pharmaceutical, Nihon Medi-Physics, Mitsubishi Tanabe Pharma Corporation, and Sunwels; scholarship donations from FP Pharmaceutical; holds stock in Parkinson Laboratories; honoraria for a team leader role at RIKEN Center for Brain Science; and is a coauthor on patent applications by Juntendo University. Takuhiro Yamaguchi reported grants from Otsuka Pharmaceutical, Solasia Pharma, Japan Tobacco Inc., Daiichi Sankyo, Eisai, and Cordis Corporation; and personal fees from Intellim Corporation, Chugai Pharmaceutical, SONIRE Therapeutics Inc., Merck and Co Inc., EPS Corporation, Japan Tobacco Inc., Ono Pharmaceutical, Kowa Company, Daiichi Sankyo, Eisai, 3H Clinical Trial Inc., and Incyte Biosciences Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Nomoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice., Methods: This multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment., Results: In total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change -7.0 [p = 0.012], -2.4 [p = 0.007] and - 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild., Conclusion: Safinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns., Study Registration: University Hospital Medical Information Network in Japan; study ID: UMIN000044341., Competing Interests: Declaration of competing interest N.N., S.S. and W.S. report honoraria and consultation fees from Eisai Co., Ltd. during the conduct of the study. T.H., K.N., R.N., A.Y., Y.S. and H.S. report honoraria from Eisai Co., Ltd. during the conduct of the study. S.-I.U., T.O. and Y.F. have no competing interests to declare. T.K. and T.I. are employees of Eisai Co. Ltd. N.H. reports honoraria, consultation fees and grants from Eisai Co., Ltd. during the conduct of the study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aim: Organs of the digestive system are frequent sites of cancer development, and digestive tract cancers are the leading causes of death worldwide, including in Japan. Most of these cancers are associated with smoking or drinking habits. This study focused on the clinical and genomic characteristics of patients with these cancers using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, which comprises a large volume of data on Japanese patients who have undergone tumor profiling gene panel tests., Patients and Methods: The genomic and clinical data from patients with digestive tract cancers registered in C-CAT between 2019 and 2023 were retrospectively reviewed. The data were derived from 412 patients with esophageal squamous cell carcinoma, 558 with gastric adenocarcinoma, 3,368 with colorectal adenocarcinoma, 139 with hepatocellular carcinoma, 2,050 with cholangiocarcinoma, and 2,552 with pancreatic ductal adenocarcinoma., Results: CDKN2A, CDKN2B, and MTAP mutations were associated with both smoking and drinking history, and patients with these mutations had a worse prognosis. Almost all gene alterations in CDKN2B and MTAP were deletions, often accompanied by CDKN2A deletion. CDKN2A mutation emerged as the most decisive prognostic factor among these mutations. Although CDKN2A mutations were frequently seen in esophageal squamous cell carcinoma, cholangiocarcinoma, and pancreatic ductal adenocarcinoma, statistically significant differences in survival outcomes were only identified in the latter two., Conclusion: CDKN2A mutations were associated with smoking and drinking in digestive cancers. This mutation was prevalent among patients with cholangiocarcinoma and pancreatic ductal adenocarcinoma, for whom they could serve as prognostic factors., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Spontaneous intracerebral hemorrhage (SICH) remains a devastating form of stroke. Prior use of antiplatelets or warfarin before SICH is associated with poor outcomes, but the effects of direct oral anticoagulants (DOACs) remain unclear. This study aimed to clarify trends in prior antithrombotic use and to assess the associations between prior use of antithrombotics and in-hospital mortality using a multicenter prospective registry in Japan. In total, 1085 patients were analyzed. Prior antithrombotic medication included antiplatelets in 14.2%, oral anticoagulants in 8.1%, and both in 1.8%. Prior warfarin use was significantly associated with in-hospital mortality (odds ratio [OR] 5.50, 95% confidence interval [CI] 1.30-23.26, P < 0.05) compared to no prior antithrombotic use. No such association was evident between prior DOAC use and no prior antithrombotic use (OR 1.34, 95% CI 0.44-4.05, P = 0.606). Concomitant use of antiplatelets and warfarin further increased the in-hospital mortality rate (37.5%) compared to warfarin alone (17.2%), but no such association was found for antiplatelets plus DOACs (8.3%) compared to DOACs alone (11.9%). Prior use of warfarin remains an independent risk factor for in-hospital mortality after SICH in the era of DOACs. Further strategies are warranted to reduce SICH among patients receiving oral anticoagulants and to prevent serious outcomes., (© 2024. The Author(s).)

Background: Multiple system atrophy (MSA) is a progressive, incurable, life-threatening neurodegenerative disease uniquely characterized by the risk of sudden death, which makes diagnosis delivery challenging for neurologists. Empirical studies on breaking a diagnosis of MSA are scarce, with no guidelines currently established. This study aimed to investigate neurologists' current practices and experiences in delivering the diagnosis of MSA., Methods: We conducted a multicenter online survey and employed a mixed-methods (quantitative and qualitative) study design in which responses to open-ended questions were analyzed qualitatively using critical incident technique., Results: Among the 194 neurologists surveyed, 166 opened the survey (response rate = 85.6%), of whom 144 respondents across various Japanese regions completed the survey. Accordingly, 92.3% and 82.8% of the participating neurologists perceived delivering the diagnosis of MSA and explaining the risk of sudden death as difficult, respectively. Factors independently associated with difficulties in diagnosis delivery included explaining the importance of the family decision making process in life-prolonging treatment, perceived difficulties in delivering information regarding the risk of sudden death, and perceived difficulties in differential diagnosis of MSA., Conclusions: Our findings showed that the majority of neurologists perceived delivering the diagnosis of MSA and explaining the risk of sudden death as difficult, which could have been associated with the difficulty of breaking the diagnosis of MSA. Difficulty in conveying bad news in MSA are caused by various factors, such as empathic burden on neurologists caused by the progressive and incurable nature of MSA, the need to explain complex and important details, including the importance of the family decision-making process in life-prolonging treatment, difficulty of MSA diagnosis, and communication barriers posed by mental status and cognitive impairment in patients or their family members. Neurologists consider various factors in explaining the risk of sudden death (e.g., patient's personality, mental state, and degree of acceptance and understanding) and adjust their manner of communication, such as limiting their communication on such matters or avoiding the use of the term "sudden death" in the early stages of the disease. Although neurologists endeavor to meet the basic standards of good practice, there is room for the multiple aspects for improvement., (© 2024. The Author(s).)

Background: Rasagiline is a monoamine oxidase B inhibitor for the treatment of Parkinson's disease (PD). This study assessed the safety and effectiveness of rasagiline in patients with PD in routine clinical practice in Japan., Research Design and Methods: This multicenter, prospective, observational study (148 sites) enrolled patients (1 November 2018-31 October 2020) with PD. Patients received rasagiline orally 1 mg once daily; maximum observation period was 24 months. The incidence of adverse drug reactions (ADRs) was evaluated; effectiveness was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III total score., Results: The safety analysis set comprised 961 patients (mean age, 72.50 years; 53.80% female; mean duration of PD, 6.82 years). Mean treatment duration was 14.74 months, with 42.25% receiving rasagiline for ≥ 19 months; 189 (19.67%) had ≥ 1 ADR. Common ADRs were dyskinesia (4.06%), orthostatic hypotension (2.29%), hallucination (1.87%), visual hallucination, nausea, fall (1.56% each), dizziness (1.35%), and somnolence (1.25%). Mean (standard deviation) UPDRS Part III total score was 28.5 (14.35) at baseline and 25.5 (14.98) at the final assessment., Conclusions: No new concerns in safety and effectiveness regarding rasagiline in Japanese patients with PD were raised., Trial Registration: ClinicalTrials.gov: NCT03727139; Japan Pharmaceutical Information Center Clinical Trials Information: JapicCTI-184181.

Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocytes glycoprotein-antibody disease (MOGAD) are distinct autoimmune demyelinating disorders characterized by varying clinical and pathological characteristics. While the precise origins of these diseases remain elusive, a combination of genetic and environmental factors, including viral elements, have been suggested as potential contributors to their development. Our goal was to assess the occurrence of antibodies against pathogenic peptides associated with Epstein-Barr virus (EBV) and the human endogenous retrovirus-W (HERV-W) in serum samples obtained from Japanese individuals diagnosed with MS, NMOSD, and MOGAD and to make comparisons with a group of healthy controls (HCs). We conducted a retrospective analysis involving 114 Japanese participants, comprising individuals with MS (34), NMOSD (20), MOGAD (20), and HCs (40). These individuals were tested using a peptide-based enzyme-linked immunosorbent assay. A marked increase in antibody response against EBV nuclear antigen 1 (EBNA1) 386-405 was observed in the serum of MS and MOGAD patients, as compared to HCs. Notably, we observed a correlation between antibodies against EBNA1 386-405 and HERV-W 486-504 peptides in a subset of the antibody-positive MS patients. These findings emphasize the involvement of EBV in the pathogenesis of MS and potentially MOGAD, suggesting its role in the reactivation of HERV-W.

Introduction: KW-6356 is a novel selective adenosine A 2A receptor antagonist/inverse agonist. We evaluated the efficacy and safety of KW-6356 as monotherapy in patients with early, untreated Parkinson's disease (PD)., Methods: This was a randomized, placebo-controlled, double-blind study conducted in Japan to investigate the efficacy and safety of once-daily KW-6356 (3 or 6 mg/day) orally administered as monotherapy for 12 weeks in patients with early PD (NCT02939391). The primary endpoint was the least squares means of change from baseline in the MDS-UPDRS Part III total score., Results: Overall, 168 patients were randomized and treated (KW-6356 3 mg/day n = 55; 6 mg/day n = 58, placebo n = 55); Week 12 completion rates were >90% per group. LS mean [95% CI] changes from baseline to Week 12 in MDS-UPDRS Part III total scores were -5.37 [-7.25, -3.48] for 3 mg/day, -4.76 [-6.55, -2.96] for 6 mg/day and -3.14 [-4.97, -1.30] for placebo. Changes from baseline were larger for both KW-6356 groups than for the placebo group at all time points. Secondary endpoints supported the primary findings with larger changes in MDS-UPDRS Part II, Parts II + III, and Total scores in the KW-6356 groups than in the placebo group. Treatment was well-tolerated; the most common treatment-emergent adverse events with KW-6356 were constipation (n = 4 [7.3%] and n = 6 [10.3%] in the 3 and 6 mg/day groups, respectively) followed by nasopharyngitis (n = 4 [7.3%] and n = 5 [8.6%] in the 3 and 6 mg/day groups, respectively)., Conclusion: KW-6356 monotherapy is well tolerated and more effective than placebo in patients with early, untreated PD., Competing Interests: Declaration of competing interest Tetsuya Maeda was the responsible medical officer for the study and reports receiving personal fees from Kyowa Kirin Co., Ltd. Takashi Kimura was a study investigator and Nobutaka Hattori was the coordinating investigator; both report receiving personal fees from Kyowa Kirin Co., Ltd. Kenichiro Sugiyama, Kana Yamada, Ren Hiraiwa and Masato Nishi are employed by Kyowa Kirin Co., Ltd., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The prevalence of nontuberculous mycobacteria (NTM) infections is increasing worldwide. Although NTM can affect extrapulmonary organs, studies on the clinical characteristics of extrapulmonary NTM are rare., Methods: We retrospectively analyzed patients who were newly diagnosed with NTM infections at Hiroshima University Hospital between 2001 and 2021 to investigate species distribution, infected sites, and risk factors of extrapulmonary NTM compared to pulmonary NTM., Results: Of the 261 NTM infections, 9.6% and 90.4% had extrapulmonary and pulmonary NTM, respectively. The mean ages of patients with extrapulmonary and pulmonary NTM were 53.4 and 69.3 years, 64.0% and 42.8% were male, 36.0% and 9.3% received corticosteroids, 20.0% and 0% had acquired immune deficiency syndrome (AIDS), and 56.0% and 16.1% had any immunosuppressive conditions, respectively. Younger age, corticosteroid use, and AIDS were associated with extrapulmonary NTM. In pulmonary NTM, Mycobacterium avium complex (MAC) accounted for 86.4% of NTM species, followed by M. abscessus complex (4.2%), whereas in extrapulmonary NTM, M. abscessus complex, MAC, M. chelonae, and M. fortuitum accounted for 36.0%, 28.0%, 12.0%, and 8.0%, respectively. Compared to pulmonary NTM, extrapulmonary NTM were significantly more likely to be rapid-growing mycobacteria (RGM) (56.0% vs. 5.5%). The most common sites of infection were the skin and soft tissues (44.0%), followed by the blood (20.0%), tenosynovium, and lymph nodes (12.0%)., Conclusion: Younger age and immunosuppressive conditions are associated with extrapulmonary NTM, with a higher prevalence of RGM in extrapulmonary NTM than in pulmonary NTM. These results provide a better understanding of extrapulmonary NTM., Competing Interests: Declarations of competing interest None., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Machine Learning has been increasingly used in the medical field, including managing patients undergoing hemodialysis. The random forest classifier is a Machine Learning method that can generate high accuracy and interpretability in the data analysis of various diseases. We attempted to apply Machine Learning to adjust dry weight, the appropriate volume status of patients undergoing hemodialysis, which requires a complex decision-making process considering multiple indicators and the patient's physical conditions., Methods: All medical data and 69,375 dialysis records of 314 Asian patients undergoing hemodialysis at a single dialysis center in Japan between July 2018 and April 2020 were collected from the electronic medical record system. Using the random forest classifier, we developed models to predict the probabilities of adjusting the dry weight at each dialysis session., Results: The areas under the receiver-operating-characteristic curves of the models for adjusting the dry weight upward and downward were 0.70 and 0.74, respectively. The average probability of upward adjustment of the dry weight had sharp a peak around the actual change over time, while the average probability of downward adjustment of the dry weight formed a gradual peak. Feature importance analysis revealed that median blood pressure decline was a strong predictor for adjusting the dry weight upward. In contrast, elevated serum levels of C-reactive protein and hypoalbuminemia were important indicators for adjusting the dry weight downward., Conclusions: The random forest classifier should provide a helpful guide to predict the optimal changes to the dry weight with relative accuracy and may be useful in clinical practice., (© 2023. The Author(s).)

Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson's disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor-derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51-1.44 for clinical assessments and 0.56-1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62-0.80 for scores derived from weekly averages and 0.24-0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings.Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019., (© 2023. The Author(s).)

Background: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs)., Methods: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated., Discussion: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs., Ethics and Dissemination: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences., Trial Registration: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017)., Competing Interests: Conflict of Interest R. Okuda has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Ogura has received advisory board fees from Nippon Boehringer Ingelheim Gmb, Taiho Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., and Bristol Myers Squibb Co. T. Ogura also has received lecture fees from Nippon Boehringer Ingelheim Gmb., Shionogi & Co. Ltd., Astellas Co., AstraZeneca K.K., and Eizai Inc. S. Hisata has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Baba has received lecture fees from Nippon Boehringer Ingelheim Gmb. Y. Kondoh has received advisory board fees and personal fees from Nippon Boehringer Ingelheim Gmb., Asahi Kasei Pharma Corp., and Shionogi & Co. Ltd., advisory board fees from Janssen Pharmaceutical K.K., Healios K.K., Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and personal fees from Astellas, AstraZeneca K.K., Eisai inc., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, and Novartis Pharma K.K., outside the presentation work. T. Suda has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. T. Johkoh has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Iwasawa has received grants from Canon Medical systems and received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H. Tomioka has received lecture fees from Nippon Boehringer Ingelheim Gmb. M. Bando has received lecture fees from Nippon Boehringer Ingelheim Gmb. A. Azuma has received a steering committee member fee, consultant fee, and lecture fee. Y. Inoue has received payments as lecture fees, participation on the steering committees, or advisor of Boehringer Ingelheim Gmb. T. Arai has received lecture fees from Boehringer Ingelheim Gmb, and Shionogi & Co. Ltd. R. Nakamura has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. A. Miyamoto has received a lecture fee from Nippon Boehringer Ingelheim Gmb. Y. Miyazaki has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H Chiba has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H. Ishii has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hamada received grants from Nippon Boehringer Ingelheim Gmb. S. Sato has received grants and lecture fees from Nippon Boehringer Ingelheim Gmb. T. Suzuki has received a lecture fee from Nippon Boehringer Ingelheim Gmb. Y. Nishioka has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hattori has received grants and lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hashimoto received research grants and lecture fees from Boehringer Ingelheim Gmb. K. Hagiwara has received lecture fees from Nippon Boehringer Ingelheim Gmb. K. Kobayashi has received lecture fees from AstraZeneca K.K. and Takeda Pharmaceutical Co. Y. Terasaki, I. Kuwahira, S. Kato, S. Sakamoto, N. Ichihara, H. Miyata and T. Nukiwa have no competing interests., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: While immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs, the prevalence of irAEs and potential risk factors have not been clarified. We identified irAE predictive factors and examined the relationship between the effect of ICIs and irAEs for patients with malignancies., Methods: A total of 533 cases treated with ICIs, including programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), for various malignancies were included retrospectively. We recorded irAEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 5. Prevalence and predictive factors associated with immune-related liver injury and the relationship between irAE and treatment response were analyzed., Results: During a median of 10 (1-103) cycles with a median follow-up after several ICI initiations of 384 (21-1715) days, irAEs with all grades and with grade ≥ 3 developed in 144 (27.0%) and 57 (10.7%) cases. Cumulative irAE development rates were 21.9, 33.5, and 43.0% in all grades and 8.8, 14.9, and 20.7% in grade ≥ 3 at 5, 10, and 20 cycles, respectively. Patients who received anti-CTLA4 therapy were more likely to develop irAEs compared to those who received anti-PD-1 or anti-PD-L1 monotherapy. Liver injury was the most common irAE. Multivariate analysis identified the combination of PD-1 and anti-CTL-4 antibodies (hazard ratio [HR], 17.04; P < 0.0001) and baseline eosinophil count ≥130/μL (HR, 3.01 for < 130; P = 0.012) as independent risk factors for the incidence of immune-related liver injury with grade ≥ 2. Patients who developed irAEs had a higher disease control rate (P < 0.0001) and an increased overall survival rate compared to those without irAEs (P < 0.0001)., Conclusion: Combination therapy with anti-PD-1 and anti-CTL-4 antibodies resulted in higher a frequency of irAEs. Baseline absolute eosinophil count was found to be a predictive factor for immune-related liver injury. Occurrence of irAEs may be associated with higher efficacy of ICI treatment and longer survival among patients who receive ICI therapy., (© 2022. The Author(s).)

This post-hoc analysis investigated the long-term effects of safinamide on the course of dyskinesia and efficacy outcomes using data from a phase III, open-label 52-week study of safinamide 50 or 100 mg/day in Japanese patients with Parkinson's disease (PD) with wearing-off. Patients (N = 194) were grouped using the UPDRS Part IV item 32: with and without pre-existing dyskinesia (pre-D subgroup; item 32 &gt; 0 at baseline [n = 81], without pre-D subgroup; item 32 = 0 at baseline [n = 113]). ON-time with troublesome dyskinesia (ON-TD) increased significantly from baseline to Week 4 in the pre-D subgroup (+ 0.25 ± 0.11 h [mean ± SE], p = 0.0355) but gradually decreased up to Week 52 (change from baseline: - 0.08 ± 0.17 h, p = 0.6224); ON-TD did not change significantly in the Without pre-D subgroup. UPDRS Part IV item 32 score increased significantly at Week 52 compared with baseline in the Without pre-D subgroup, but no UPDRS Part IV dyskinesia related-domains changed in the pre-D subgroup. Both subgroups improved in ON-time without TD, UPDRS Part III, and Part II [OFF-phase] scores. The cumulative incidence of new or worsening dyskinesia (adverse drug reaction) at Week 52 was 32.5 and 5.0% in the pre-D and Without pre-D subgroups, respectively. This study suggested that safinamide led to short-term increasing dyskinesia but may be not associated with marked dyskinesia at 1-year follow-up in patients with pre-existing dyskinesia, and that it improved motor symptoms regardless of the presence or absence of dyskinesia at baseline. Further studies are warranted to investigate this association in more details.Trial registration: JapicCTI-153057 (Registered: 2015/11/02)., (© 2022. The Author(s).)

Introduction: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123 I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy., Methods: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG., Results: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score., Conclusion: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores., Competing Interests: Declaration of competing interest Funding sources: This study was supported by a grant from the AMED under grant numbers JP18dm0207022 and JP19dm0207070, Japan Science and Technology Agency Moonshot Research and Development Program (JPMJMS2024-5), FUJIFILM Toyama Chemical Co., Ltd., and Nihon Medi-Physics Co., Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Context: The Dyspnea-12 questionnaire is a simple tool to assess dyspnea using qualitative descriptors that include both physical and emotional domains. However, the reliability and validity of the Japanese version in patients with lung cancer have not been assessed., Objective: To determine the reliability and validity of the Japanese version of the Dyspnea-12 questionnaire in patients with lung cancer., Methods: The assessment was based on the numerical rating scale (NRS), cancer dyspnea scale (CDS), and hospital anxiety and depression scale (HADS). Spearman's correlation assessed the convergent validity of Dyspnea-12 using these three scales. Exploratory factor analysis examined the construct validity. The reliability was verified using Cronbach's alpha. Anxiety, depression, clinical dyspnea, presence of chronic obstructive pulmonary disease (COPD), and patient status were identified by discriminating performance., Results: The analysis included 113 patients with lung cancer. A significant positive correlation was found between Dyspnea-12 and NRS, CDS, and HADS scores. Similar to the original version, factor analysis clearly classified Dyspnea-12 into two components (physical and emotional), thereby confirming its construct validity. Cronbach's alpha values for the total Dyspnea-12 and its physical and emotional components were 0.97, 0.95, and 0.96, respectively. Patients with anxiety, depression, and clinical dyspnea and those in the palliative phase had significantly higher Dyspnea-12 scores than their respective counterparts. The Dyspnea-12 scores of patients with and without COPD were similar., Conclusion: The Japanese version of the Dyspnea-12 questionnaire is a useful and reliable tool to assess the multi-dimensional aspects of dyspnea in patients with lung cancer., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

DNAJC7 has recently been identified as an amyotrophic lateral sclerosis (ALS) gene via large-scale exome analysis, and its involvement in ALS is still unclear in various populations. This study aimed to determine the frequencies and characteristics of the DNAJC7 variants in a Japanese ALS cohort. A total of 807 unrelated Japanese patients with sporadic ALS were screened via exome analysis. In total, we detected six rare missense variants and one splice-site variant of the DNAJC7 gene, which are not reported in the Japanese public database. Furthermore, the missense variants are located around the TPR domain, which is important for the function of DNAJC7. The total frequency of the DNAJC7 variants in Japanese ALS patients was estimated at 0.87%. Collectively, these results suggest that variants of DNAJC7 are rare cause of Japanese patients with sporadic ALS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The COVID-19 pandemic has forced lockdowns and declarations of states of emergency, resulting in marked changes to daily life such as dietary habits in many countries. Though serum omega-3 polyunsaturated fatty acids levels have been shown to be useful markers for recurrent vascular events or worse prognosis in cardiovascular diseases and ischemic stroke, the relationship between serum omega-3 PUFA levels and the occurrence of intracerebral hemorrhage has essentially been unknown. We explored the association of serum omega-3 polyunsaturated fatty acids with intracerebral hemorrhage during the COVID-19 pandemic., Methods: Participants comprised patients admitted to Juntendo University Hospital (Tokyo, Japan) with intracerebral hemorrhage between January 1, 2016 and April 30, 2020. Clinical characteristics including serum omega-3 polyunsaturated fatty acid levels were compared between patients developing intracerebral hemorrhage during the period from January 1, 2016 to February 29, 2020, and the subsequent COVID-19 pandemic period (March 1 to April 30, 2020). Clinical characteristics independently related to intracerebral hemorrhage during the COVID-19 pandemic were analyzed by comparing these two cohorts of intracerebral hemorrhage patients in different periods., Results: A total of 103 patients (age, 67.0 ± 13.9 years; 67 males) with intracerebral hemorrhage were enrolled. Intracerebral hemorrhage developed in 91 patients before and 12 patients during the COVID-19 pandemic. Monthly averages of intracerebral hemorrhage patients admitted to our hospital during and before the COVID-19 pandemic were 6 and 1.82, respectively. Serum eicosapentaenoic acid levels were significantly lower in intracerebral hemorrhage patients during the COVID-19 pandemic than before (31.87 ± 12.93 μg/ml vs. 63.74 ± 43.29 μg/ml, p = 0.007). Multiple logistic regression analysis showed that, compared to before the COVID-19 pandemic, dyslipidemia (odds ratio 0.163, 95% confidence interval 0.031-0.852; p = 0.032) and eicosapentaenoic acid levels (odds ratio 0.947, 95% confidence interval 0.901-0.994; p = 0.029) were associated with intracerebral hemorrhage during the COVID-19 pandemic., Conclusions: From our preliminary results, low eicosapentaenoic acid levels were linked with intracerebral hemorrhage during the COVID-19 pandemic. Low levels of eicosapentaenoic acid might be an endogenous surrogate marker for intracerebral hemorrhage during the COVID-19 pandemic., (© 2022. The Author(s).)

Introduction: Patients with Parkinson's disease (PD) experience various motor and non-motor symptoms. We conducted a post hoc analysis of a Japanese phase 2/3 study of safinamide (50 or 100 mg/day) in patients with Parkinson's disease and wearing-off to evaluate response according to background factors. Safinamide efficacy against major motor symptoms was also assessed., Methods: Multiple regression analyses in safinamide-treated patients (50 or 100 mg/day) assessed changes in daily ON-time without troublesome dyskinesia (hereafter referred to as ON-time) according to baseline clinical variables. Subgroup analyses by baseline Unified Parkinson's Disease Rating Scale (UPDRS) part III score were also conducted. We evaluated cardinal motor symptoms using the UPDRS., Results: In the multiple regression analysis, changes in ON-time were related to baseline non-motor symptoms (UPDRS part I score) and ON-time in the 50-mg group, but no relationships with non-motor symptoms were observed in the 100-mg group. Additionally, in the subgroup analysis of patients with more severe motor symptoms (UPDRS part III score > 20), a significant improvement in ON-time was observed only with 100 mg/day (p = 0.01). At both doses, safinamide significantly improved cardinal motor symptom scores (bradykinesia, rigidity, tremor, axial symptoms, and gait disturbances)., Conclusions: The observed response profile to the 50-mg/day dose may be related to baseline non-motor symptoms, but this was not true for the 100-mg/day dose. Both safinamide doses improved major motor symptoms in levodopa-treated patients with PD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Identifying the factors that influence health-related quality of life (HRQoL) is of great scientific interest, but a potential causal relationship between treatment and HRQoL has yet to be fully elucidated. Japanese patients reported better HRQoL outcomes on the Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain, a 6-question subset of the PDQ-39 which is considered to reflect the emotional aspects of the disease-specific HRQoL, when treated with rasagiline, than placebo, in both a monotherapy clinical trial (NCT02337725) and an adjunctive therapy clinical trial in patients with wearing-off phenomena (NCT02337738)., Objective: To investigate how rasagiline exerts its effect on the PDQ-39 emotional well-being domain in Japanese patients with Parkinson's disease., Methods: A path analysis was performed to assess the direct treatment effects of rasagiline on the PDQ-39 emotional well-being domain and the effects mediated indirectly through the influence on items related to motor symptoms by a post-hoc analysis of two clinical trials in Japan., Results: In the monotherapy trial, the PDQ-39 emotional well-being domain was mainly affected indirectly through items related to motor symptoms (80.7%) composed of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II (67.2%) and Part III (13.5%). In the adjunctive therapy trial, the PDQ-39 emotional well-being domain was also mainly influenced indirectly through effects on items related to motor symptoms (1 mg/day: 54.7%, 0.5 mg/day: 57.6%) composed of MDS-UPDRS Part II (1 mg/day: 35.6%, 0.5 mg/day: 40.9%), Part III (1 mg/day: 8.0%, 0.5 mg/day: 8.3%) and mean daily OFF-time (1 mg/day: 11.1%, 0.5 mg/day: 8.4%)., Conclusions: The effects of rasagiline on the PDQ-39 emotional well-being domain were mediated primarily by influence on the subjective aspects of motor experiences of daily living., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: YH, TK, MA, and YF are paid employees of Takeda Pharmaceutical Company Limited. NH received lecture fees and grants from Takeda Pharmaceutical Co., Ltd. AT has served on advisory boards for Takeda Pharmaceutical Co., Ltd.; and has received honoraria from Takeda Pharmaceutical Co., Ltd. HM has served on advisory boards for Takeda Pharmaceutical Co., Ltd. MN has served on advisory boards for Takeda Pharmaceutical Co., Ltd.; and has received honoraria from Takeda Pharmaceutical Co., Ltd. RT has performed corporate-sponsored research for Takeda Pharmaceutical Co., Ltd. There are no patents to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

To investigate whether antibody production against mycobacterium avium subsp. paratuberculosis (MAP) is related to clinical characteristics of multiple sclerosis (MS) and human leukocyte antigen (HLA) alleles, IgG antibody against three MAP peptides and two human peptides homologous to MAP were measured in sera from 103 MS patients and 50 healthy controls (HCs). MS patients had higher IgG levels against MAP2694 295-303 (MAP2694-IgG) than HCs, while the other antibodies were comparable. Multivariate analysis demonstrated that higher MAP2694-IgG titers were associated with higher EDSS scores, but not with HLA alleles or dairy product consumption. Immune response against MAP may worsen MS disability., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Insulin resistance and muscle weakness are risk factors for silent lacunar infarcts (SLI), but it is unclear whether they are still independent risk factors when adjusted for each other. In addition, the effect of their combination on SLI is completely unknown. We evaluated SLI, insulin sensitivity, and knee extensor muscle strength by magnetic resonance imaging, PREDIM, and dynamometer, respectively, in 1531 elderly people aged 65-84 years living in an urban area of Tokyo. Among the study subjects, 251 (16.4%) had SLI. Impaired insulin sensitivity (High; 1.00 [reference], Medium; 1.53 [95% confidence interval (CI) 0.94-2.48], Low; 1.86 [1.02-3.39], p for trend 0.047) and reduced muscle strength (High; 1.00 [reference], Medium; 1.40 [0.98-2.02], Low; 1.49 [1.04-2.15], p for trend 0.037) were independently associated with increased risk for SLI in the fully adjusted model. In terms of combined, subjects classified as having the lowest insulin sensitivity and lowest strength were 4.33 times (95% CI 1.64-11.45) more likely to have a SLI than those classified as having the highest insulin sensitivity and highest strength. Impaired insulin sensitivity and reduced muscle strength were independently associated with higher risk of SLI in elderly subjects, and their combination synergistically increased this risk., (© 2021. The Author(s).)

Introduction: The non-dopaminergic and dopaminergic actions of safinamide may alleviate pain in patients with Parkinson's disease (PD). We investigated the efficacy of safinamide for pain when administered as an adjunct to levodopa in Japanese patients with PD., Methods: This was a post hoc analysis of a phase 2/3 clinical study of safinamide in Japanese patients with PD who were experiencing wearing-off. Pain was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part II 'sensory symptoms' item 17, on a scale of 0-4, and the 39-item Parkinson's Disease Questionnaire (PDQ-39) 'bodily discomfort' domain score. Subgroup analyses, according to baseline symptoms and concomitant medications, were also performed., Results: Least square (LS) mean changes in the UPDRS item 17 score from baseline to Week 24 in the placebo, safinamide 50-mg and safinamide 100-mg groups during the OFF phase were 0.08, -0.15 (p = 0.0133 vs placebo) and -0.18 (p = 0.0054), respectively, and during the ON phase were 0.04, -0.08 (p = 0.0529) and -0.08 (p = 0.0505), respectively. Changes from baseline to Week 24 in PDQ-39 'bodily discomfort' scores were not significantly different in safinamide groups vs placebo. The presence of moderate-to-severe bradykinesia or early-morning dystonia at baseline resulted in numerically greater effect sizes in UPDRS item 17 scores during the OFF phase., Conclusions: Safinamide 50 mg and 100 mg reduced the UPDRS item 17 score in patients with PD, especially during the OFF phase. Patients with moderate-to-severe bradykinesia and early-morning dystonia may benefit from safinamide treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

'Yips' in golf is a complex spectrum of anxiety and movement-disorder that affects competitive sporting performance. With unclear etiology and high prevalence documented in western literature, the perception and management of this psycho-neuromuscular problem among Japanese elite golfers is unknown. The objective of this study was to explore factors associated with yips, investigate the performance deficits and the strategies implemented to prevent yips. We surveyed approx. 1300 professional golfers on their golfing habits, anxiety and musculoskeletal problems, kinematic deficits, changes in training and their outcomes. Statistical procedures included multiple logistic regression and network analysis. 35% of the respondents had experienced yips in their career, their odds increasing proportionally to their golfing experience. Regardless of musculoskeletal symptoms, about 57% of all yips-golfers attributed their symptoms to psychological causes. Network analysis highlighted characteristic movement patterns, i.e. slowing, forceful or freezing of movement for putting, approach and teeing shots respectively. Golfers' self-administered strategies to relieve yips were mostly inconsequential. Within the limits of our self-reported survey, most golfers perceived yips as a psychological phenomenon despite evidence pointing to a movement-disorder. While self-administered interventions were satisfactory at best, it may be imperative to sensitize golfers from a movement-disorder standpoint for early management of the problem., (© 2021. The Author(s).)

Introduction: The non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A 2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD., Methods: Patients with PD and ≥1 NMS and 'wearing-off' with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model., Results: Overall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score., Conclusion: NMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Mitochondrial dysfunction has been suggested to play an important role in all stages of multiple sclerosis (MS)., Objective: To determine the expression of two mitophagy-related proteins, PTEN-induced kinase 1 (PINK1) and PARKIN, in a cohort of Japanese patients with different neuroinflammatory disorders., Methods: Protein concentrations were measured using commercial ELISA in paired cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), and from age- and sex-matched controls., Results: CSF and serum concentrations of PINK1 were higher in patients with MS than in patients with NMOSD ( p = 0.004 and p < 0.001, respectively), MOGAD ( p = 0.008 and p = 0.011, respectively), and controls ( p = 0.021 and p = 0.002, respectively). CSF and concentrations of PARKIN were elevated in patients with MS in comparison with those in controls ( p = 0.016 and p = 0.05, respectively)., Conclusions: Our study highlighted the importance of mitophagy in MS and suggested the potential application of PINK1 and PARKIN as biomarkers to predict disease activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cossu, Yokoyama, Sechi and Hattori.)

Objective: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score., Materials and Methods: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis., Results: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores., Conclusions: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A long-term study was conducted in Japanese patients with primary axillary hyperhidrosis who completed the preceding 6-week phase III, confirmatory study of 5% sofpironium bromide gel (hereinafter referred to as sofpironium) to evaluate the safety and efficacy of 52-week treatment with sofpironium. In the long-term study, 185 patients who completed the confirmatory study (94 and 91 patients in the vehicle and sofpironium groups, respectively) started to receive sofpironium (switching and extension groups, respectively), and all these patients were included in both the full analysis set (FAS) and the safety analysis set (SAF). In the FAS, there were more females than males (73.0% vs. 27.0%), and median age was 38.0 years. A total of 161 patients (86 and 75 patients in the switching and extension groups, respectively) completed the study at week 52. The proportions of patients with hyperhidrosis disease severity score of 1 or 2 and a 50% or more reduction in total gravimetric weight of sweat were 57.4% in the switching group and 58.2% in the extension group at week 52. The proportions of patients who achieved this efficacy end-point in the long-term study were similar to that (53.9%) in the sofpironium group in the confirmatory study. In the SAF, the incidences of adverse events (AEs) were 80.9% in the switching group and 83.5% in the extension group, and the incidences of adverse drug reactions were 39.4% and 45.1%, respectively. AEs that occurred in at least 20% of patients in both treatment groups were application site dermatitis (25.5% and 33.0%, respectively) and nasopharyngitis (31.9% and 23.1%, respectively). Reported AEs were generally mild, and there were no deaths. Serious AEs occurred in three patients, but none were considered related to the study drug. In this study, the efficacy of sofpironium was maintained during 52-week treatment, and no new safety risk was observed., (© 2021 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

The availability of alternative donor sources could allow elderly patients to receive allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the outcomes of single-unit cord blood transplantation (CBT) in 1577 patients aged ≥60 years with acute myeloid leukemia (AML) in Japan between 2002 and 2017. In total, 990 (63%) patients were not in complete remission (CR) at the time of CBT. A myeloablative conditioning regimen (52%) and calcineurin inhibitor (CI) + mycophenolate mofetil (MMF)-based graft-versus-host disease (GVHD) prophylaxis (45%) were more commonly used. With a median follow-up for survivors of 31 months, the probability of overall survival and the cumulative incidence of leukemia-related mortality at 3 years was 31% and 29%, respectively. The cumulative incidence of non-relapse mortality (NRM) at 100 days and 3 years were 24% and 41%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 100 days and extensive chronic GVHD at 2 years were 44%, 16%, and 14%, respectively. The cumulative incidence of neutrophil engraftment was 80% at 42 days. Results of multivariate analysis indicated that the following factors were significantly associated with higher overall mortality: performance status ≥1, hematopoietic cell transplantation-specific comorbidity index ≥3, adverse cytogenetics, extramedullary disease at diagnosis, and non-CR status at CBT. By contrast, female sex, HLA disparities ≥2, mycophenolate mofetil-based GVHD prophylaxis, and recent CBT were significantly associated with lower overall mortality. In conclusion, single CBT offers a curative option for AML patients aged ≥60 years with careful patient selection.

Background/aim: Hepatocellular carcinoma (HCC) mainly develops in the damaged liver from hepatitis C virus (HCV) or hepatitis B virus (HBV) infection in Japan. On the other hand, the occurrence of HCCs derived from the liver without viral infection has recently been increasing. Our aim was to identify characteristics specific to HCCs with virus-infected liver (HCC-BC) or those with non-B- and non-C-infected liver (HCC-NBNC), Patients and Methods: We collected preoperative serum α-fetoprotein (AFP) and Des-Gamma-Carboxy Prothrombin (DCP), also known as PIVKA-II values from surgically resected HCC cases during 1994-2017 in our department., Results: Preoperative serum AFP values of HCC-BC cases (n=284) were higher compared to HCC-NBNC cases (n=88) (p=0.016), whereas serum DCP values of HCC-NBNC cases were higher compared to HCC-BC cases (p<0.001). Multivariable analyses indicated that abnormal serum AFP [hazard ratio (HR)=1.46, 95% conficdence interval (CI)=1.03-2.07, p=0.035) was one of the significant recurrence-free survival predictors of HCC-BC cases, while abnormal serum DCP (HR=4.99, 95%CI=1.91-13.01, p=0.001) was one of the significant recurrence-free survival predictors of HCC-NBNC cases., Conclusion: HCC-NBNC cases have a different tumor marker profile from HCC-BC cases. Elevated DCP could be both a diagnostic and prognostic marker of HCC-NBNC patients., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke., Methods: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients' clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed., Results: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p＜0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959-6.500, p= 0.061)., Conclusions: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA's clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.

A questionnaire survey was conducted on 8,402 members of the Japanese Neurological Society to examine the current status and countermeasures for physician burnout, and 1,261 respondents (15.0%) responded. In this paper, we report the results of a comparison between male and female physicians. There was a significant difference in working and living conditions only for married people. It was confirmed that men work under stricter conditions in terms of working hours, and that the burden on women is heavier in the division of housework. Analysis using the Japanese Burnout Scale revealed no gender differences in overall scores, but as for factors related to burnout, in addition to factors common to both men and women, factors specific to men or women were clarified.

A phase 3 study was conducted to verify the efficacy and safety of 5% sofpironium bromide (BBI-4000) gel (hereinafter referred to as sofpironium) administrated for 6 weeks in Japanese patients with primary axillary hyperhidrosis. The primary efficacy end-point was the proportion of patients who satisfied both criteria of a Hyperhidrosis Disease Severity Score (HDSS) of 1 or 2 at the end of 6-week treatment and a 50% or more reduction in total gravimetric weight of sweat at the end of treatment relative to baseline. A total of 281 patients were randomized to receive 5% sofpironium (141 patients) or vehicle (140 patients), and all patients were included in the full analysis set (FAS). In the FAS, 70.1% of patients were female, and the median age was 35.0 years. The proportion of patients who achieved the primary efficacy end-point was 53.9% in the sofpironium group and 36.4% in the vehicle group, with a statistically significant difference of 17.5% (95% confidence interval, 6.02-28.93) between these two groups (P = 0.003). The incidence of adverse events was 44.0% in the sofpironium group and 30.7% in the vehicle group, and the incidence of adverse drug reactions was 16.3% in the sofpironium group and 5.0% in the vehicle group. Reported adverse events were generally mild or moderate in severity. In the sofpironium group, common events (incidence, ≥5%) were nasopharyngitis (14.2%) and dermatitis/erythema at the application site (8.5%/5.7%), with no serious adverse events reported. This study demonstrated the efficacy and safety of 5% sofpironium., (© 2021 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

The double-blind part of the COMFORT-PD (COMt-inhibitor Findings from Opicapone Repeated Treatment for Parkinson's Disease) study in Japanese levodopa-treated patients with Parkinson's disease and motor fluctuations found that both opicapone 25 and 50 mg were significantly more effective than placebo. This 52-week open-label extension study evaluated the long-term safety and efficacy of opicapone 50 mg tablets in patients who completed the double-blind part of the COMFORT-PD study. Safety was monitored via adverse events, laboratory testing, and physical, cardiovascular and neurological examinations. Efficacy was primarily assessed by change in OFF-time. Secondary efficacy measures included: ON-time, percentage of OFF/ON-time responders, other outcomes from the double-blind part. 391/437 patients were transferred to the open-label extension period and included in the safety analysis set (full analysis set, n = 387; open-label completers, n = 316). Adverse events were frequently reported (n = 338, 86.4%), but < 50% were considered drug-related (39.9%) and few were considered serious (2.6%) or led to discontinuation (2.8%). Decreased OFF-time was consistently observed over the open-label period regardless of initial randomization. Change [LSM (SE)] in OFF-time from the open-label baseline to the last visit showed a persistent effect in patients initially randomized to opicapone 25 mg [- 0.37 (0.20) h, P = 0.0689] and opicapone 50 mg [- 0.07 (0.21) h, P = 0.6913] whereas opicapone 50 mg led to a statistically significant reduction in the previous placebo group [- 1.26 (0.19) h, P < 0.05]. Once-daily opicapone 50 mg was generally well tolerated and consistently reduced OFF-time over 52 weeks in Japanese levodopa-treated patients with motor fluctuations.Trial registration JapicCTI-153112; date of registration: December 25, 2015.

Introduction: To identify and investigate patients with Parkinson's disease (PD) harboring VPS35 variants in Japan., Methods: Using targeted gene panel screening, we analyzed 393 familial, 294 young-onset, and 52 late-onset sporadic PD patients derived from the Juntendo PD DNA bank, and obtained clinical information from the medical records on each patient in whom we found VPS35 p.D620N variants., Results: We identified VPS35 p.D620N in three new patients: two patients with familial PD and one patient with sporadic PD. Additionally, we newly confirmed p.D620 from a patient of a family reported previously. The prevalence of familial PD was 0.7% (2/307), young-onset sporadic PD was 0.3% (1/294), and late-onset sporadic PD was 0% (0/52) in our cohort. Combining four patients with p.D620N from our previous reports, haplotype analysis indicated at least two founders in our cohort. Patients commonly showed a slow progression of parkinsonism with onset in middle or late age and mild parkinsonism with good response to levodopa and little cognitive decline even for more than 10 years of disease duration. Psychosis was occurred in two patients. One-half of patients required device-aided therapies such as deep brain stimulation or levodopa-carbidopa intestinal gel. Brain magnetic resonance imaging mostly showed normal findings, even at more than 10 years after onset. 123 I-metaiodobenzylguanidine myocardial scintigraphy indicated normal heart-to-mediastinum ratio values among three of four patients., Conclusions: Patients with VPS35 p.D620N showed distinctive symptoms and neuroimaging. Our findings expand the clinical findings of patients with VPS35 variants., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To identify factors associated with burnout among Japanese physician and to use them in future measures, the Japanese Society of Neurology conducted a survey of neurologists on burnout using a web-based questionnaire in October 2019. A total of 1,261 respondents, 15.0% of the 8,402 members, responded to the survey. The mean of the subscales of the Japanese Burnout Scale was 2.86/5 points for emotional exhaustion, 2.21/5 points for depersonalization, and 3.17/5 points for lack of personal accomplishment. In addition, the burnout of our country's neurologists is not related to workloads such as working hours and the number of patients in charge, but also to a decreased meaningfulness and professional accomplishment. Therefore, it is necessary to take comprehensive measures to improve these issues at the individual, hospital, academic and national levels.

Background: Rapid eye movement sleep behavior disorder (RBD) and olfactory dysfunction are useful for early diagnosis of Parkinson's disease (PD). RBD and severe olfactory dysfunction are also regarded as risk factors for cognitive impairment in PD. This study aimed to assess the associations between RBD, olfactory function, and clinical symptoms in patients with PD., Methods: The participants were 404 patients with non-demented PD. Probable RBD (pRBD) was determined using the Japanese version of the RBD screening questionnaire (RBDSQ-J) and the RBD Single-Question Screen (RBD1Q). Olfactory function was evaluated using the odor identification test for Japanese. Clinical symptoms were evaluated using the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts I-IV., Results: In total, 134 (33.2%) patients indicated a history of pRBD as determined by the RBD1Q and 136 (33.7%) by the RBDSQ-J based on a cutoff value of 6 points. Moreover, 101 patients were diagnosed as pRBD by both questionnaires, 35 by the RBDSQ-J only, and 33 by the RBD1Q only. The MDS-UPDRS parts I-III scores were significantly higher and disease duration significantly longer in the pRBD group. pRBD was significantly associated with male gender and the MDS-UPDRS part I score. The olfactory identification function was significantly reduced in the pRBD group., Conclusions: About 33% of the patients with PD had pRBD based on the questionnaires, and both motor and non-motor functions were significantly decreased in these patients. These results suggest that more extensive degeneration occurred in patients with non-demented PD with RBD., Competing Interests: The authors have declared that no competing interests exist.

Objectives: This placebo-controlled, randomized study evaluated the efficacy and safety of opicapone 25-mg and 50-mg tablets in Japanese levodopa-treated patients with Parkinson's disease and motor fluctuations., Methods: Japanese adults (n = 437, age 39-83 years) with Parkinson's disease (United Kingdom Parkinson's Disease Society criteria) received opicapone 25-mg (n = 145), opicapone 50-mg (n = 145), or placebo (n = 147) tablets over the double-blind treatment period (14-15 weeks). The primary efficacy assessment was change in OFF-time; secondary efficacy assessments included OFF/ON-time responders (≥1 hour change from baseline), total ON-time, ON-time with and without troublesome dyskinesia, and Unified Parkinson's Disease Rating Scale., Results: The least squares mean (standard error) change in OFF-time from baseline to the last visit was -0.42 (0.21) hour for the placebo group, -1.16 (0.22) hour for the opicapone 25 mg group, and -1.04 (0.21) hour for the opicapone 50 mg group. The percentage of ON-time responders, changes in total ON-time/ON-time without troublesome dyskinesia, and Unified Parkinson's Disease Rating Scale II (at OFF) all showed statistically significant improvements versus placebo for both opicapone tablet doses (P < 0.05). Unified Parkinson's Disease Rating Scale III (at ON) was improved versus placebo in patients who received opicapone 50 mg (P < 0.05). Adverse events were more common in patients treated with opicapone 25 mg (60.0%) or opicapone 50 mg (54.5%) versus placebo (48.3%). The most commonly reported adverse event was dyskinesia (placebo, 2.7%; opicapone 25 mg, 9.0%; opicapone 50 mg, 12.4%)., Conclusions: In Japanese patients, both opicapone 25 and 50 mg were significantly more effective than placebo with no dose-dependent difference in efficacy, and both doses were well tolerated. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease., Methods: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy., Results: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension., Conclusions: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown., Methods: This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide ( D LCO ) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability., Results: 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in D , 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups.LCO , 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups., Conclusions: Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF., Competing Interests: Conflict of interest: S. Sakamoto has nothing to disclose. Conflict of interest: K. Kataoka has nothing to disclose. Conflict of interest: Y. Kondoh reports advisory board fees and personal fees from Asahi Kasei Pharma Corp., Boehringer Ingelheim Co. Ltd and Shionogi & Co. Ltd; advisory board fees from Janssen Pharmaceutical K.K; and personal fees from Eisai Inc., Kyorin Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma and Novartis Pharma K.K, outside the submitted work. Conflict of interest: M. Kato has nothing to disclose. Conflict of interest: M. Okamoto has nothing to disclose. Conflict of interest: H. Mukae reports grants and personal fees from Shionogi & Co, Ltd, during the conduct of the study. Conflict of interest: M. Bando reports personal fees from Shionogi & Co, Ltd, outside the submitted work. Conflict of interest: T. Suda has nothing to disclose. Conflict of interest: K. Yatera reports grants from Kirigaoka Tsuda Hospital, Tochiku Hospital, Hagiwara Central Hospital, Kurate Hospital, Saiseikai Yamaguchi Hospital, Ono Pharmaceutical Co. Ltd, Teijin Home Healthcare Limited, Taiho Pharmaceutical Co. Ltd, Daiichi Sankyo Company, Limited, GlaxoSmithKline K.K, Pfizer Japan Inc., Taisho Pharma Co. Ltd, MSD K.K, Novartis Pharma K.K, Nippon Boehringer Ingelheim Co. Ltd, Daiwa Securities Health Foundation, Actelion Pharmaceuticals Japan Ltd, Astellas Pharma Inc., AstraZeneca K.K, Eisai Co., Ltd, Shionogi & Co., Ltd, KYORIN Pharmaceutical Co. Ltd, Taisho Pharma Co. Ltd, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co. Ltd, Chugai Pharmaceutical Co. Ltd, Teijin Pharma Limited, and Eli Lilly Japan K.K, outside the submitted work. Conflict of interest: Y. Tanino has nothing to disclose. Conflict of interest: T. Kishaba has nothing to disclose. Conflict of interest: N. Hattori has nothing to disclose. Conflict of interest: Y. Taguchi has nothing to disclose. Conflict of interest: T. Saito has nothing to disclose. Conflict of interest: Y. Nishioka reports grants and personal fees from Shionogi & Co. Ltd, during the conduct of the study; and grants and personal fees from Nippon Boehringer Ingelheim Co. Ltd, MSD K.K, Ono Pharmaceutical Co. Ltd, Taiho Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Asahi Kasei Pharma Corporation and Eli Lilly Japan K.K, and grants from Bonac Corporation, outside the submitted work. Conflict of interest: K. Kuwano has nothing to disclose. Conflict of interest: K. Kishi reports personal fees from Shionogi, outside the submitted work. Conflict of interest: N. Inase has nothing to disclose. Conflict of interest: S. Sasaki has nothing to disclose. Conflict of interest: H. Takizawa has nothing to disclose. Conflict of interest: T. Johkoh has nothing to disclose. Conflict of interest: F. Sakai has nothing to disclose. Conflict of interest: S. Homma has nothing to disclose., (Copyright ©ERS 2021.)

Two recent genetic studies reported that loss-of-function mutation of the C-terminal cargo-binding tail domain of the KIF5A gene cause amyotrophic lateral sclerosis (ALS). The aim of this study is to investigate the frequency of KIF5A variants in Japanese patients with sporadic ALS. In total, 807 sporadic ALS patients and 191 normal controls from a multicenter ALS cohort in Japan were included. Whole exome sequencing on an Illumina HiSeq 2000/2500 sequencer was used to identify and select variants within the KIF5A gene. Thirteen patients harbored a nonsynonymous variant in the KIF5A gene; These were considered variants of uncertain significance. One patient harbored a novel splice-site variant (c.2993-3C>A) in the C-terminal cargo-binding tail domain of the KIF5A gene. Functional analysis of this variant revealed that it caused skipping of exon 27. The frequency of KIF5A mutations in Japanese patients with sporadic ALS was 0.12% (1/807). This study reports a novel loss-of-function variant in KIF5A, and indicates that loss-of-function variant in KIF5A is a rare cause of sporadic ALS in Japanese patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD) is clinically serious and life-threatening. Preexisting interstitial lung abnormalities have been shown to be risk factors for ICI-ILD in patients with lung cancer., Objective: To evaluate whether interstitial lung abnormalities are associated with ICI-ILD in patients with nonlung cancers., Design, Setting, and Participants: This cohort study was conducted between December 2015 and May 2019 at Hiroshima University Hospital. A total of 199 consecutive patients with head and neck cancer, malignant melanoma, oral cavity cancer, urological cancer, and gastrointestinal cancer who received anti-programmed cell death 1 (PD-1) antibody monotherapy were included. Data analysis was conducted from December 2015 to May 2019., Main Outcomes and Measures: The associations between potential risk factors and the development of ICI-ILD were examined. Information on patient characteristics before antibody administration, including chest computed tomography findings, was obtained. The diagnosis of ICI-ILD was defined as abnormal computed tomography shadows occurring during treatment with anti-PD-1 antibodies., Results: A total of 199 patients were enrolled in the study. The median (range) age was 66 (20-93) years, and most patients (133 [66.8%]) were men. Nineteen patients (9.5%) developed ICI-ILD. There was no significant difference in the baseline characteristics between patients with and without ICI-ILD. The logistic regression analyses revealed that interstitial lung abnormalities were associated with increased risk of ICI-ILD (odds ratio, 6.29; 95% CI, 2.34-16.92; P < .001), and ground glass attenuation in interstitial lung abnormalities was an independently associated risk factor (odds ratio, 4.05; 95% CI, 1.29-12.71; P = .01)., Conclusions and Relevance: In this cohort study, preexisting interstitial lung abnormalities, including ground glass attenuation, were risk factors associated with ICI-ILD in patients with nonlung cancers. This observation is consistent with previously reported findings in patients with lung cancer. Therefore, we should pay more attention to the development of ICI-ILD in patients with interstitial lung abnormalities, regardless of cancer type.

Lessons Learned: Two courses of neoadjuvant therapy using S-1 plus cisplatin for clinical stage III esophageal squamous cell carcinoma did not achieve expected response rate according to endoscopic evaluation of primary tumors. Subsequent esophagectomy was safely performed., Background: In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the need for a more effective regimen., Methods: A single-arm, open-label phase II trial was conducted to evaluate the safety and efficacy of two courses of neoadjuvant chemotherapy using S-1 plus cisplatin (NAC-SP) for clinical stage III ESCC. The primary endpoint was overall response rate as defined by endoscopic evaluation of primary tumors., Results: We enrolled 26 patients. The completion rate for the two courses of NAC-SP was 61.5%. Grade 3 or higher adverse events were experienced by 38.4% of patients. The treatment response rate according to endoscopic findings, acquired before the second course, was 34.6% and below the expected level (55.0%). The morbidity rate of patients who underwent radical subtotal esophagectomy (96.2%) was 32.0%. Repeat surgery was unnecessary, and surgery-associated deaths did not occur. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 84.6% and 92.2%, respectively., Conclusion: We demonstrate safety of NAC-SP, but not its efficacy, for patients with clinical stage III ESCC. Subsequent esophagectomy was safely performed., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Although non-urgent hospital visits should be avoided during the pandemic, patients with chronic neurological diseases still require a specialist even in such a situation. Telemedicine is a favorable solution to improve patients' access to specialists, and its use has rapidly accelerated worldwide. The need for telemedicine in neurological disorders, the brief history of telemedicine in Japan before and after the pandemic, and how to set up online visits and perform virtual neurological examinations will be discussed in this review.