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Hiroki Tashiro, Mizuki Nanri, Yuki Kuwahara, Yuki Kurihara, Shinya Kimura, Koichiro Takahashi Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Saga Prefecture, JapanCorrespondence: Hiroki Tashiro, Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Prefecture, 849-8501, Japan, Tel +81 952 34 2369, Fax + 81 952 34 2017, Email si3222@cc.saga-u.ac.jpBackground: The presence of mucus plugs in the airway is a severe phenotype in patients with asthma; however, the mechanisms and specific treatments are not fully understood.Purpose: To clarify the efficacy of biologics and the mechanisms for mucus plug in patients with asthma.Patients and Methods: A 79-year-old Japanese asthmatic woman with high blood eosinophil and fractional exhaled nitric oxide (FeNO) was pointed massive mucus plugs in airway on chest CT imaging. She was treated with mepolizumab for 3 months; however, those were augmented without improvement of pulmonary function and FeNO. She was switched to dupilumab and, three months later, the mucus plugs were completely disappeared with improvement in pulmonary function, FeNO and asthma-related symptoms. She continues treatment with dupilumab, and her asthma symptoms are stable.Conclusion: Biologics including mepolizumab and dupilumab have been reported to improve mucus plugs in patients with asthma; however, their efficacy might be different depending on the clinical characteristics of patients. Present data remind us of the possibility that, if FeNO levels remain high after treatment with anti-IL-5 antibody in asthma patients with mucus plugs, switching to other biologics, including anti-IL-4Rα antibody, might be considered.Keywords: asthma, biologics, mucus plugs, mechanisms

Sonoko Harada,1,2 Hitoshi Sasano,1 Shoko Ueda,1 Yuuki Sandhu,1 Sumiko Abe,1 Yuki Tanabe,1 Kyoko Shima,3 Tetsuya Kuwano,3 Yuya Uehara,3 Takayoshi Inoue,3 Ko Okumura,2 Kazuhisa Takahashi,1,4 Norihiro Harada1,2,4 1Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 2Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 3Biological Science Research, Kao Corporation, Tochigi, Japan; 4Research Institute for Diseases of Old Ages, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, JapanCorrespondence: Norihiro Harada, Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3 hongo, Bunkyo-ku, Tokyo, 113-8431, Japan, Tel +81-3-5802-1063, Fax +81-3-5802-1617, Email nor@juntendo.ac.jpBackground: Examining human coding and non-coding RNAs present in skin surface lipids (SSL-RNAs) offers a promising approach to understanding the physiological state of the skin. Benralizumab treatment can reduce exacerbations and improve symptom control and quality of life in patients with severe eosinophilic asthma. Although this treatment effectively depletes peripheral blood eosinophils, the impact of benralizumab on SSL-RNA remains completely unknown.Objective: To investigate the effects of benralizumab treatment on SSL-RNA profiles in patients with severe asthma.Methods: Skin samples were non-invasively collected from patients before and after one year of benralizumab treatment. Sixteen patients were enrolled, but the SSL-RNA analysis was only feasible for five patients due to collection challenges, mainly in female participants.Results: Following benralizumab treatment, asthma symptoms, exacerbation rates, and lung function parameters improved. Peripheral blood eosinophils were completely depleted and serum eotaxin-1 levels increased. SSL-RNA analysis revealed differential expression of 134 genes, with significant downregulation of immune-related pathways and genes associated with neutrophilic inflammation.Conclusion: These findings suggest a suppression of both type 2 and non-type 2 inflammation in response to benralizumab treatment, with potential implications for asthma management. However, the limitations of the study include a small sample size and challenges in sebum collection, particularly among female participants. Although the noninvasive nature of this sampling method makes it attractive for both research and clinical applications, additional studies are needed to fully investigate the potential of SSL-RNA analysis as a noninvasive biomarker to assess treatment response in asthma.Keywords: asthma, benralizumab, skin surface lipid, sebum, type 2 inflammation

Ai Goto,1 Sonoko Harada,1,2 Hitoshi Sasano,1 Yuuki Sandhu,1 Yuki Tanabe,1 Sumiko Abe,1 Shoko Ueda,1 Tomohito Takeshige,1 Kei Matsuno,1 Tetsutaro Nagaoka,1 Jun Ito,1 Ryo Atsuta,1 Kazuhisa Takahashi,1,3 Norihiro Harada1– 3 1Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 2Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 3Research Institute for Diseases of Old Ages, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, JapanCorrespondence: Norihiro Harada, Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3 hongo, Bunkyo-ku, Tokyo, 113-8431, Japan, Tel +81-3-5802-1063, Fax +81-3-5802-1617, Email nor@juntendo.ac.jpPurpose: Omalizumab, the anti-IgE monoclonal antibody used to treat severe asthma, reduces asthma exacerbations, hospitalizations, and corticosteroid use. Although allergic asthma is a therapeutic target of omalizumab, omalizumab is not effective in all patients with severe allergic asthma and is not always available for long-term use. We retrospectively investigated factors related to long-term (≥ 2 years) use of omalizumab for severe asthma.Patients and Methods: Of the 116 patients treated with omalizumab for severe asthma at our hospital between 2009 and 2017, 82 were included in this retrospective analysis. Thirty-four were excluded because of adverse events, financial difficulties, or hospital transfers. The number of asthma exacerbations, unscheduled visits, corticosteroid doses, asthma control test scores, pulmonary function test results, and fractional exhaled nitric oxide levels were evaluated.Results: The median age of the study population was 58 years, with 66% female and 26% taking regular oral corticosteroids. After 2 years of treatment, 52 responders were identified using the global evaluation of treatment effectiveness (GETE) score. Improvements in asthma control test scores, airflow limitation, exacerbations, and oral corticosteroid use were observed in the responders. Multivariate analysis revealed that a peripheral blood eosinophil count of ≥ 200 or a perennial antigen-specific IgE antibody positivity of ≥ 2 predicted a response at the 2-year mark. However, Kaplan–Meier analysis demonstrated that neither high eosinophil counts nor perennial antigen-specific IgE positivity influenced the prolongation of treatment beyond 2 years, and responders at 2 years underwent omalizumab treatment for a significantly longer period than non-responders (HR = 9.89, p < 0.001), with GETE at 2 years being the only predictor of long-term omalizumab use.Conclusion: In this retrospective study the GETE after 2 years of omalizumab therapy emerged as the most meaningful predictor of the long-term effectiveness of omalizumab treatment in patients with severe asthma, highlighting the benefits of prolonged therapy in certain populations. These findings may guide future therapeutic strategies for severe asthma.Keywords: antigen-specific IgE antibody, GETE, predictive biomarker

Naomi Matsumoto,1,2 Hirohide Yokokawa,1 Hirotake Mori,1 Makoto Hiki,2,3 Yoko Tabe,4,5 Kazuhisa Takahashi,5,6 Toshio Naito1,5 1Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 2Department of Emergency and Disaster Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 3Department of Cardiovascular Biology and Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 4Department of Clinical Laboratory Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; 5Department of Research Support Utilizing Bioresource Bank, Juntendo University Graduate School of Medicine, Tokyo, Japan; 6Department of Respiratory Medicine Juntendo University Faculty of Medicine, Tokyo, JapanCorrespondence: Hirohide Yokokawa, Department of General Medicine, Juntendo University Faculty of Medicine, 2-1-1 hongo, Bunkyo-ku, Tokyo, 113-8421, Japan, Tel/Fax +81-3-5802-1190, Email hyokoka@juntendo.ac.jpBackground: It has been reported that zinc deficiency is related to severe inflammatory conditions especially those of respiratory diseases. However, studies that have examined the association between the serum zinc concentration and the severity of coronavirus disease 2019 (COVID-19) are still limited. The aim of this study was to assess that association in Japanese inpatients with COVID-19.Methods: This cross-sectional study, conducted from April 2020 to August 2021, included 467 eligible adult inpatients with COVID-19 whose serum zinc concentration was measured. Serum zinc concentration categories were defined as deficiency (< 60 μg/dL), marginal deficiency (≥ 60 to < 80 μg/dL), and normal (≥ 80 μg/dL). Multivariate logistic regression was used to assess the association between serum zinc deficiency and severe COVID-19. Serum zinc concentration levels were compared between mild and other severities of COVID-19 by Dunnett’s method. The P for trend was estimated using the Jonckheere-Terpstra test.Results: The proportions of subjects with serum zinc deficiency (< 60 μg/dL) and marginal zinc deficiency (≥ 60 to < 80 μg/dL) were 39.5% and 54.3% in women, and 36.4% and 57.0% in men, respectively. Serum zinc deficiency was significantly associated with severe COVID-19 compared to marginal deficiency and normal (odds ratio = 3.60, 95% confidence interval = 1.60– 8.13, P < 0.01) after adjusting for confounders. An increase in severity of COVID-19 was inversely related to increases in serum zinc concentration levels (P < 0.01 for trend). Each serum zinc concentration of moderate and severe cases was also significantly lower compared with mild cases (P < 0.01).Conclusion: The severity of COVID-19 was significantly related to serum zinc concentration levels. These results suggest the importance of considering the serum zinc concentration when treating patients with COVID-19.Keywords: COVID-19, Zinc, severity, nutrition, epidemiology

Sumiko Abe,1 Mina Yasuda,1,2 Kazunori Tobino,1,2 Sonoko Harada,1,3 Hitoshi Sasano,1 Yuki Tanabe,1 Yuuki Sandhu,1 Tomohito Takeshige,1 Kei Matsuno,1 Tetsuhiko Asao,1 Takuto Sueyasu,2 Saori Nishizawa,2 Kohei Yoshimine,2 Yuki Ko,2 Yuki Yoshimatsu,2 Kosuke Tsuruno,2 Hiromi Ide,2 Haruhi Takagi,1 Jun Ito,1 Tetsutaro Nagaoka,1 Norihiro Harada,1,3,4 Kazuhisa Takahashi1,4 1Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 2Department of Respiratory Medicine, Iizuka Hospital, Fukuoka, Japan; 3Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; 4Research Institute for Diseases of Old Age, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, JapanCorrespondence: Norihiro Harada, Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan, Tel +81-3-5802-1063, Fax +81-3-5802-1617, Email nor@juntendo.ac.jpBackground: Bronchial thermoplasty (BT) improves clinical outcomes and quality of life for patients with severe asthma and has shown sustained reductions in airway narrowing and air trapping in previous CT studies. However, there is a lack of a comprehensive analysis, including CT evaluation, of clinical outcomes in Japanese patients who have undergone BT for severe asthma. This study aimed to evaluate the impact of BT in Japanese asthma patients, with a focus on the CT metric “WA at Pi10” to assess airway disease.Methods: Twelve patients with severe persistent asthma who underwent BT were assessed using ACQ6, AQLQ, pulmonary function tests, FeNO measurement, blood sampling, and chest CT before BT and one year after the third procedure for the upper lobes.Results: The median age of the patient was 62.0 years, 7/12 (58.3%) were male, 4/12 (33.3%) used regular oral corticosteroids, and 8/12 (66.7%) received biologics. Median FEV1% was 73.6%, and median peripheral eosinophil count was 163.8/μL. After one year of BT, ACQ6 scores improved from 2.4 to 0.8 points (p = 0.007), and AQLQ scores improved from 4.3 to 5.8 points (p < 0.001). Significant improvements were also observed in asthma exacerbations, unscheduled visits due to exacerbations, FeNO, and √WA at Pi10 (p < 0.05). The baseline mucus score on the CT findings was negatively correlated with FEV1 (r = − 0.688, p = 0.013) and with the maximum mid-expiratory flow rate (r = − 0.631, p = 0.028), and positively correlated with the peripheral blood eosinophil count (r = − 0.719, p = 0.008). Changes in √WA at Pi10 after one year were positively correlated with changes in the mucus score (r = 0.742, p = 0.007).Conclusion: This study has limitations, including its single-arm observational design and the small sample size. However, BT led to a symptomatic improvement in patients with severe asthma. The validated “√WA at Pi10” metric on CT effectively evaluated the therapeutic response in Japanese asthma patients after BT.Keywords: asthma, bronchial thermoplasty, chest computed tomography, asthma control questionnaire, √WA at Pi10

Shun Nakazawa, Motoyasu Kato, Yuriko Terayama, Naho Sakamoto Matubara, Yoshihiko Sato, Ryoko Murashima, Daisuke Hayakawa, Shouichi Okamoto, Kazuhisa Takahashi Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, JapanCorrespondence: Shun Nakazawa, Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan, Tel +81 3-3813-3111, Fax +81 3-3812-7560, Email shu-nakazawa@juntendo.ac.jpAbstract: We report a case of a 62-year-old male who was diagnosed with advanced rectal cancer. The attending gastro-enterologist initiated chemotherapy using capecitabine plus oxaliplatin and bevacizumab; however, this treatment regimen was discontinued, as the patient developed a skin rash. Once the skin rash improved, chemotherapy was re-initiated using a combination of trifluridine and tipiracil hydrochloride (TAS-102). The patient developed high fever and dyspnea 2 months after initiation of TAS-102. Chest high-resolution computed tomography showed bilateral diffuse ground glass opacities in all lung lobes with traction bronchiectasis. At this time, the gastro-enterologist consulted our department. The patient was put on non-invasive positive pressure ventilation due to worsening respiratory symptoms. The patient was suspected to develop TAS-102-induced interstitial pneumonia based on positive TAS-102 drug-induced lymphocyte stimulation test. The patient’s respiratory symptoms and radiological findings improved after corticosteroid treatment. The corticosteroid dose was gradually decreased by 5 mg. Thereafter, chemotherapy was re-initiated using different anti-cancer agents.Keywords: TAS-102, colorectal cancer, DAD, corticosteroid

Hiroyuki Uchida,1 Chiaki Kuroiwa,2 Sae Ohki,3 Kana Takahashi,4 Kenji Tsuchiya,5 Senichiro Kikuchi,2,3 Kazuki Hirao2,3 1Department of Rehabilitation, Kurashiki Heisei Hospital, Kurashiki, Japan; 2Graduate School of Health Sciences, Gunma University, Maebashi, Japan; 3Department of Occupational Therapy, Faculty of Medicine, Gunma University, Maebashi, Japan; 4Department of Rehabilitation, Okayama Kounan Hospital, Okayama, Japan; 5Department of Rehabilitation, Faculty of Health Sciences, Nagano University of Health and Medicine, Nagano, JapanCorrespondence: Kazuki Hirao, Graduate School of Health Sciences, Gunma University, 3-39-22 Showa, Maebashi, Gunma, 371-8514, Japan, Tel/Fax +81-27-220-8952, Email kazuki.hirao@gunma-u.ac.jpBackground: Psychological distress is prevalent worldwide and can lead to the development of mental conditions such as major depression and anxiety disorders. It is essential to assess the severity of patient-reported outcomes to provide effective treatment for psychological distress. The Kessler Psychological Distress Scale (K6) is one of the most widely used psychological distress scales. However, the smallest detectable change (SDC) of the K6 score has not been elucidated. Therefore, the current study aimed to determine the SDC of the K6 score in a Japanese adult population.Methods: Participants aged 20– 59 years who are native Japanese speakers were recruited from the panel list of a web research firm. The K6 score was assessed at baseline (T1) and at 2-week follow-up (T2). SDCs were calculated at the individual (SDCind) and group (SDCgroup) levels. Intraclass correlation coefficient agreement (ICCagreement) was calculated to assess test–retest reliability and Cronbach’s alpha to evaluate internal consistency.Results: A total of 3254 (1627 [50%] female) responded at T1 and T2. The mean (standard deviation) K6 scores were 5.71 (5.84) at T1 and 5.65 (5.83) at T2. The SDCind and SDCgroup of the K6 score were 8.47 (35.31%) and 0.15 (0.63%), respectively. The ICCagreement was 0.73, and the Cronbach’s alpha was 0.94.Conclusion: Our study provided evidence on the reliability and interpretation of the K6 score. Calculating the SDC of the K6 score can help identify the significance of changes in psychological distress over time and can determine the efficacy of interventions for psychological distress.Keywords: psychological distress, reliability, measurement error, mental health

Hiroki Tashiro, Koichiro Takahashi, Yuki Kurihara, Hironori Sadamatsu, Yuki Kuwahara, Shinya Kimura, Naoko Sueoka-Aragane Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, JapanCorrespondence: Hiroki TashiroDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Prefecture, 849-8501, Japan, Tel +81-952-34-2369, Fax +81-952-34-2017, Email si3222@cc.saga-u.ac.jpPurpose: Idiopathic chronic eosinophilic pneumonia (ICEP) is a rare, chronic respiratory disease. Corticosteroid therapy is effective for ICEP, but relapse is frequent after its tapering, which leads to chronic use and corticosteroid-related adverse effects. Currently, biological agents targeting interleukin 5 (IL-5) are considered alternatives for treating ICEP patients with frequent relapse, but the detailed effects are not fully understood.Patients and Methods: The clinical characteristics of 30 patients with ICEP, especially 12 patients with ICEP who experienced relapse after corticosteroid dose tapering, were evaluated retrospectively. In addition, 4 ICEP patients with frequent relapse treated by IL-5-targeted biological agents were reviewed.Results: Of the 30 patients diagnosed with ICEP, 12 patients (40.0%) recurred after corticosteroid dose tapering, and 9 (30.0%) were treated with maintenance doses of corticosteroid. Of ICEP patients who experienced recurrence, 6 (50.0%) had frequent relapses (2 or more times). All 4 patients treated with anti-IL-5 agents had their corticosteroid dose reduced without any relapses; in 3 patients, corticosteroids were withdrawn.Conclusion: Anti-IL-5 agents might be alternatives for treating ICEP patients with frequent relapses.Keywords: chronic eosinophilic pneumonia, idiopathic, anti-IL-5 agents, mepolizumab, benralizumab

Kanji Takahashi,1 Tomohiro Iida,2 Susumu Ishida,3 Bruce Crawford,4 Yoko Sakai,4 Akikazu Mochizuki,5 Ryuta Tsujiuchi,5 Satoru Tanaka,5 Kota Imai5 1Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka, Japan; 2Department of Ophthalmology, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan; 3Department of Ophthalmology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; 4Syneos Health Clinical K.K., Chuo-ku, Tokyo, Japan; 5Novartis Pharma K.K., Minato-ku, Tokyo, JapanCorrespondence: Akikazu Mochizuki, Novartis Pharma K.K., 23-1, Toranomon 1-chome, Minato-ku, Tokyo, Japan, Tel +81 3 6899 8000, Fax +81 3 6257 3634, Email akikazu.mochizuki@novartis.comPurpose: We conducted a systematic review to investigate the effectiveness of clinical treatments for wet age-related macular degeneration (wAMD) in Japanese patients in the decade since anti-vascular endothelial growth factor (VEGF) therapies were introduced.Methods: PubMed was searched for articles published in English between 1 January 2008 and 30 September 2018 using a multistring search strategy. Reviews were scanned for additional relevant studies and select gray literature was evaluated. Mean and/or median for the logarithm of the minimum angle of resolution (logMAR) visual acuity (VA), central retinal thickness (CRT), and the number of injections after 12 months of treatment were calculated using extracted data. Data were stratified by disease type and treatment modality.Results: Of 335 studies identified, 94 were selected for data extraction (147 treatment arms; typical AMD, n = 25; polypoidal choroidal vasculopathy [PCV], n = 85). Mean (median) logMAR VA was 0.44 (0.32) for typical AMD and 0.34 (0.31) for PCV; the respective mean number of anti-VEGF injections was 5.6 and 4.6. The mean CRT was approximately 220 μm for both groups. For typical AMD, anti-VEGF monotherapy resulted in better VA outcomes than photodynamic therapy (PDT) alone. For PCV, anti-VEGF monotherapy or anti-VEGF plus PDT combination therapy resulted in better VA and CRT outcomes than PDT monotherapy. Combination therapy required fewer injections than anti-VEGF monotherapy (PCV, 3.2 versus 5.3).Conclusion: wAMD treatment has advanced dramatically in the years since anti-VEGF drugs were introduced in Japan. Discrete patient populations may benefit from differing management regimens, including the fewer injections required with combination therapy.Keywords: visual acuity, polypoidal choroidal vasculopathy, anti-vascular endothelial growth factor therapy, photodynamic therapy

Koji Takahashi, Tomoyuki Yamamoto Fukuda Denshi Co., Ltd, Tokyo, JapanCorrespondence: Tomoyuki Yamamoto, Email tomoyuki.yamamoto@fukuda.co.jp

Koichiro Takahashi,1 Hiroki Tashiro,1 Ryo Tajiri,2 Ayako Takamori,2 Masaru Uchida,3 Go Kato,4 Yuki Kurihara,1 Hironori Sadamatsu,1 Takashi Kinoshita,5 Makoto Yoshida,6 Atsushi Kawaguchi,2,7 Shinya Kimura,1 Naoko Sueoka-Aragane,1 Tomotaka Kawayama5 On behalf of Saga-naïve COPD Physical Activity Evaluation (SCOPE) Study Investigator Group1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; 2Clinical Research Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan; 3Division of Internal Medicine, Japan Community Health Care Organization Saga Central Hospital, Saga, Japan; 4Division of Respiratory Medicine, Saga Prefectural Medical Center Koseikan, Saga, Japan; 5Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan; 6Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan; 7Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, JapanCorrespondence: Koichiro TakahashiDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, JapanEmail takahak@cc.saga-u.ac.jpBackground: Prolonged sedentary behavior is associated with worse prognosis in patients with chronic obstructive pulmonary disease (COPD). Our previous study found that first-line dual therapy with tiotropium/olodaterol significantly reduces sedentary time compared to tiotropium monotherapy in Japanese patients with treatment-naïve COPD, although the characteristics of responders to dual-therapy versus monotherapy for COPD are still unclear.Methods: Patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Physical activity was assessed using a triaxle accelerometer for 2 weeks before and after treatment. This analysis focused on the change in sedentary time, indicated by physical activity of 1.0– 1.5 metabolic equivalents (METs), with stratification for the following factors: age, body mass index (BMI), pulmonary function, COPD assessment test (CAT), the 6-minute walk distance (6MWD), and physical activity level at study entry.Results: Thirty-five patients received tiotropium/olodaterol and 34 patients received tiotropium. In patients with lower inspiratory capacity at study entry, a significant reduction in sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: − 12.8 ± 13.5 min, Tio/Olo: − 65.1 ± 21.0 min, mean difference, − 52.2 min, 95% CI − 103.6 to 0.88, p = 0.046). In patients with a shorter duration of physical activity of ≥ 2 METs at study entry, a significant reduction of sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: − 3.3 ± 17.5 min, Tio/Olo: − 72.9 ± 23.1 min, mean difference, − 69.7 min, 95% CI − 128.7 to − 10.6, p = 0.02). There were no differences in terms of age, BMI, CAT score, 6MWD, FEV1, FVC, VC, and physical activity of 1.0– 1.5 METs and ≥ 3.0 METs.Conclusion: This study showed that COPD patients with lower inspiratory capacity or shorter active time of ≥ 2.0 METs at study entry are likely to exhibit significantly greater reduction in sedentary time with tiotropium/olodaterol treatment.Keywords: chronic obstructive pulmonary disease, physical activity, sedentary time, long-acting muscarinic antagonist, long-acting beta 2 agonist

Takashi Miyachi,1 Kyoko Nomura,2 Sachiko Minamizono,2 Kazuki Sakai,1 Toyoto Iwata,2 Yuta Sugano,1 Shun Sawaguchi,3 Kouhei Takahashi,3 Kazuo Mishima4 1Department of Medicine, Akita University Graduate School of Medicine, Akita, Japan; 2Department of Environmental Health Science and Public Health, Akita University Graduate School of Medicine, Akita, Japan; 3Japan Health Insurance Association, Akita Branch, Akita, Japan; 4Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, JapanCorrespondence: Kyoko NomuraDepartment of Environmental Health Science and Public Health, Akita University Graduate School of Medicine, 1– 1– 1 Hondo, Akita, 010-8543, JapanTel +81-18-884-6086Fax +81-18-836-2609Email nomurakyoko@gmail.comPurpose: Truck drivers with insomnia are at a high risk of traffic accidents. We aimed to investigate the prevalence of insomnia and identify its associated factors among truck drivers in Japan.Methods: Participants were 2927 male truck drivers younger than 65 years old. Self-administered questionnaires were used to assess insomnia symptoms, State-Trait Anxiety Inventory, drinking, smoking habits, body mass index, caffeine intake, as well as daily driving hours, consecutive days away from home, and driving distance. Insomnia symptoms included difficulty initiating sleep, maintaining sleep and early morning awakening. Insomnia was defined when any of these symptoms were observed with daily tiredness.Results: The prevalence of insomnia among the subjects was 13.3% (n=356), of which 13.5% had difficulty initiating sleep, 78% had difficulty maintaining sleep, and 26.4% had early morning awakening. After adjusting for covariates, drinking habits, daily driving hours, and STAI score were significantly and linearly associated with insomnia; the adjusted odds ratio (OR) of drinking habits for insomnia was 1.74 [95% confidence interval (CI), 1.23– 2.47] for heavy drinkers compared to non-drinkers (trend p< 0.001); the adjusted OR of daily driving hours was 1.87 (95% CI, 1.00– 3.49) for 12 hours or longer in a day compared to < 8 hours in a day (trend p< 0.001); the adjusted OR of STAI quartiles was 5.30 (95% CI, 3.66– 7.67) for the highest quartile compared to the lowest quartile (trend p< 0.001).Conclusion: The present study demonstrated that insomnia is prevalent among truck drivers in Japan, and its risk factors include drinking habits, daily driving hours, and anxiety.Keywords: insomnia, truck driver, State-Trait Anxiety Inventory, STAI, working environment, lifestyle

Koji Takahashi,1 Tomoyuki Yamamoto,1 Kohji Shirai2 1Fukuda Denshi Co., Ltd., Tokyo, Japan; 2Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Tomoyuki Yamamoto, Email tomoyuki.yamamoto@fukuda.co.jp

Motoyasu Kato,1 Shinichi Sasaki,1,2 Misa Tateyama,1 Yuta Arai,1 Hiroaki Motomura,1 Issei Sumiyoshi,1 Yusuke Ochi,1 Junko Watanabe,1 Hiroaki Ihara,1 Shinsaku Togo,1 Kazuhisa Takahashi1 1Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 2Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Urayasu, Chiba, JapanCorrespondence: Motoyasu KatoDepartment of Respiratory Medicine, Juntendo University, Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-Ku, Tokyo 113-8431, JapanTel +81-3-5802-1063Fax +81-3-5802-1617Email mtkatou@juntendo.ac.jpPurpose: The INPULSIS-ON study suggested the safety and tolerability of long-term nintedanib treatment for idiopathic pulmonary fibrosis (IPF). However, there are no real-world studies on long-term nintedanib treatment. The main aim of the study was to investigate the efficacy and the tolerability of long-term treatment with nintedanib for IPF in clinical practice.Patients and Methods: This retrospective study enrolled 104 IPF patients who underwent treatment with nintedanib. Among these patients, 51 were able to receive nintedanib for more than 12 months (ie, treatment with nintedanib over 12 months was possible [P group]) and 53 were not able to receive nintedanib for more than 12 months (ie, treatment with nintedanib over 12 months was impossible [I group]). The tolerability and efficacy of nintedanib were compared between the two groups.Results: In the I group, 29 patients were unable to continue nintedanib therapy because of adverse effects, including diarrhea and nausea/anorexia. In addition, 19 and four patients could not continue nintedanib treatment because of IPF progression and worsening of performance status (PS), respectively. One patient suddenly died during nintedanib treatment. The incidence of nausea/anorexia in the I group was significantly higher than in the P group (49.06 vs 25.49%). The survival time was significantly longer in the P group than in the I group (35 vs 12 months). The decline in forced vital capacity was significantly larger in the I group than in the P group (165 vs 10 mL/year). Poor PS at nintedanib initiation was the only significant risk factor for nintedanib treatment discontinuation over 12 months. Finally, the survival time was significantly longer in patients with good PS than in those with poor PS (27 vs 13 months).Conclusion: Poor PS can result in discontinuation of nintedanib after 12 months. Long-term nintedanib treatment may be effective for survival.Keywords: idiopathic pulmonary fibrosis, nintedanib, real-world setting, performance status, nausea

Hiroki Tashiro,1 Koichiro Takahashi,1 Hironori Sadamatsu,1 Yuki Kurihara,1 Tetsuro Haraguchi,1 Ryo Tajiri,2 Ayako Takamori,2 Shinya Kimura,1 Naoko Sueoka-Aragane1 1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; 2Clinical Research Center, Saga University Hospital, Saga, JapanCorrespondence: Koichiro TakahashiDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga Prefecture 849-8501, JapanTel +81-952-34-2369Fax +81-952-34-2017Email takahak@cc.saga-u.ac.jpPurpose: Overweight and obesity are associated with one of the severe phenotypes of asthma, with an increased rate of exacerbations, low level of lung function, and reduced response to corticosteroid therapy. The present study focused on identifying useful biomarkers of severity in overweight patients with adult-onset asthma using real-world data.Patients and Methods: A total of 56 patients with adult-onset asthma who visited Saga University Hospital between 2018 and 2019 were retrospectively reviewed. Overweight was defined as a body mass index (BMI) greater than 25 kg/m2. Blood eosinophils, cytokines, and chemokines were compared between non-overweight asthma and overweight asthma patients.Results: Overweight asthma patients had a higher annual exacerbation rate, lower pulmonary function even when treated frequently with high-dose inhaled corticosteroids, and a significantly lower percentage of eosinophils and lower eosinophil count compared to non-overweight asthma patients (p< 0.01, p=0.03). Moreover, the percentage of eosinophils was significantly negatively correlated with BMI (ρ=− 0.38, p< 0.01) (Figure 1). On serum cytokine and chemokine analyses, the overweight asthma group included significantly more patients with a lower level of tissue growth factor α (TGF-α) (1.1 pg/mL) and higher levels of hsIL-6 (2.5 pg/mL), RANTES/CCL5 (298.5 pg/mL), and vascular endothelial growth factor A (VEGF-A) (63.7 pg/mL), than the non-overweight asthma group (p=0.02, p< 0.01, p=0.02, p=0.01, respectively).Conclusion: The present study showed that overweight patients with adult-onset asthma were characterized by a higher rate of annual exacerbations and worse lung function despite treatment with high-dose inhaled corticosteroids and lower blood eosinophil counts than non-overweight patients with asthma. On blood cytokine and chemokine analyses, a low level of TGF-α and high levels of hsIL-6, RANTES/CCL5, and VEGF-A might be biomarkers reflecting the pathophysiology in overweight patients with asthma.Keywords: asthma, overweight, biomarker

Saito Kobayashi, Kazuto Tajiri, Aiko Murayama, Toshiki Entani, Yuka Futsukaichi, Kohei Nagata, Kosuke Takahashi, Ichiro Yasuda Department of Gastroenterology, Toyama University Hospital, Toyama, JapanCorrespondence: Kazuto TajiriDepartment of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama 930-0194, JapanTel +81-76-434-7301Fax +81-76-434-5027Email tajikazu@med.u-toyama.ac.jpPurpose: To evaluate the potential of drug-eluting bead (DEB)-transcatheter arterial chemoembolization (TACE) as a treatment option for patients with refractory to conventional lipiodol-based TACE (c-TACE) especially with decreased liver function.Patients and Methods: We retrospectively evaluated the treatment results of DEB-TACE for 89 HCC nodules in 27 patients with c-TACE refractory according to liver function.Results: Although overall survival was significantly better in Child–Pugh A patients than in Child–Pugh B patients (median survival time, MST: 561 vs 347 days, p=0.031), progression-free survival was almost similar in both patients between Child–Pugh A and B (MST: 79 vs 87 days, p=0.534). Regarding antitumor response, the objective response rate (ORR) and disease-control rate (DCR) were 5.3/12.5% and 52.7/87.5% in Child–Pugh A/B, respectively. In each 89 HCC nodules, ORR and DCR were almost similar between Child–Pugh A and B (ORR, 20.3 vs 13.3%; DCR, 77.0 vs 73.3%, respectively). Adverse events of DEB-TACE were well-tolerated, and liver function was reserved during DEB-TACE procedures.Conclusion: DEB-TACE could be a therapeutic option for advanced HCC patients with c-TACE refractory and decreased liver function.Keywords: TACE-refractory, drug-eluting bead, post-embolization syndrome, microsphere, tyrosine kinase inhibitor

Motoyasu Kato,1,2 Fumiyuki Takahashi,1,2 Tadashi Sato,1,2 Yoichiro Mitsuishi,1,2 Ken Tajima,1,2 Hiroaki Ihara,1,2 Fariz Nurwidya,1,2 Hario Baskoro,1,2 Akiko Murakami,1,2 Isao Kobayashi,1,2 Moulid Hidayat,1,2 Naoko Shimada,1– 3 Shinichi Sasaki,1,2 Reiko Mineki,4 Tsutomu Fujimura,5 Toshio Kumasaka,6 Shin-ichiro Niwa,7 Kazuhisa Takahashi1– 3 1Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 2Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan; 3Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 4Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; 5Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan; 6Department of Pathology, Japanese Red Cross Medical Center, Tokyo, Japan; 7Link Genomics, Incorporated, Tokyo, JapanCorrespondence: Motoyasu KatoDepartment of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8431, JapanTel +81-3-5802-1063Fax +81-3-5802-1617Email mtkatou@juntendo.ac.jpPurpose: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified.Methods: We investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ 2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin.Results: Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ 2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice.Conclusion: These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.Keywords: tranilast, idiopathic pulmonary fibrosis, TGFβ, SMAD2

Koichiro Takahashi,1 Masaru Uchida,2 Go Kato,3 Ayako Takamori,4 Takashi Kinoshita,5 Makoto Yoshida,6 Ryo Tajiri,4 Keisuke Kojima,7 Hiroshi Inoue,8 Hiromi Kobayashi,9 Hironori Sadamatsu,1 Hiroki Tashiro,1 Masahide Tanaka,1 Shinichiro Hayashi,10 Atsushi Kawaguchi,4,11 Shinya Kimura,1 Naoko Sueoka-Aragane,1 Tomotaka Kawayama5 Saga-naïve COPD Physical Activity Evaluation (SCOPE) Study Investigator Group1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; 2Division of Internal Medicine, Japan Community Health Care Organization Saga Central Hospital, Saga, Japan; 3Division of Respiratory Medicine, Saga Prefectural Medical Center Koseikan, Saga, Japan; 4Clinical Research Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan; 5Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan; 6Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan; 7Division of Internal Medicine, Imari Arita Kyouritsu Hospital, Saga, Japan; 8Division of Internal Medicine, Karatsu Red Cross Hospital, Saga, Japan; 9Division of Respiratory Medicine, National Hospital Organization East Saga Hospital, Saga, Japan; 10Division of Internal Medicine, Kouhoukai Takagi Hospital, Fukuoka, Japan; 11Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, JapanCorrespondence: Koichiro TakahashiDivision of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, JapanEmail takahak@cc.saga-u.ac.jpBackground: Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients.Methods: A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment.Results: There were no differences in the mean age (69.8 vs 70.4 years), body mass index (BMI) (22.5 vs 22.6 kg/m2) and mean % forced expiratory volume in 1 second (%FEV1) at baseline (61.5 vs 62.6%) between the two groups. Changes in FEV1 (mean±standard error, 242.8± 28.8 mL) and transient dyspnea index (TDI) (2.4± 0.3 points) before and after tiotropium/olodaterol treatment were greater than with tiotropium treatment (104.1± 31.9 mL, p< 0.01 and 1.5± 0.3, p=0.02, respectively). Changes in the duration of physical activity with 1.0– 1.5 metabolic equivalents (METs) estimated in the sedentary position following tiotropium/olodaterol treatment (− 38.7± 14.7 min) tended to be reduced more than with tiotropium treatment (− 4.6± 10.6 min) (p=0.06), although those with ≥ 2.0 METs numerically increased with both treatments (+10.8± 7.6 min for tiotropium/olodaterol vs +8.3± 7.6 min for tiotropium, p=0.82). Tiotropium/olodaterol treatment reduced the duration of physical activity with 1.0– 1.5 METs (regression coefficient, − 43.6 [95% CI − 84.1, − 3.1], p=0.04) in a multiple regression model adjusted for cofounding factors such as age, FEV1, total CAT scores, 6MWD, and TDI.Conclusion: This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.Keywords: chronic obstructive pulmonary disease, physical activity, long-acting muscarinic antagonist, long-acting beta 2 agonist

Koji Takahashi,1 Tomoyuki Yamamoto,1 Shinichi Tsuda,1 Mitsuya Maruyama,1 Kohji Shirai2 1Fukuda Denshi Co., Ltd., Tokyo, Japan; 2Mihama Hospital, Chiba, JapanCorrespondence: Tomoyuki YamamotoFukuda Denshi Co., Ltd., 35-8 Hongo-2-Chome Bunkyo-Ku, Tokyo 113-8420, JapanTel +81-3-5684-1249Fax +81-3-5684-1322Email tomoyuki.yamamoto@fukuda.co.jpAbstract: Arterial stiffness is a good predictor of cardiovascular events. As a substitute for elastic modulus representing stiffness, pulse wave velocity (PWV) has been used for over a century as it is easy to measure; however, PWV is known to essentially depend on blood pressure at the time of measurement. The cardio-ankle vascular index (CAVI) is a relatively new index of global arterial stiffness of the origin of the aorta to the ankle arteries. The characteristic feature is its independency from blood pressure at the measuring time. Recently, a variant index CAVI0 was proposed, which was claimed to be a more accurate arterial stiffness index than CAVI, considering independency from blood pressure. The purpose of this review is to evaluate the properties of CAVI more precisely by comparing with CAVI0, and to confirm the true meaning of CAVI as an index of arterial stiffness. First, the properties of PWV depending on the blood pressure and the variation of PWV values in the cardiac cycle were analyzed. Then, we attempted to clarify the point at which the PWV, adopted in CAVI or in CAVI0, was measured in cardiac cycle. A comprehensive comparison of the clinical data of CAVI and CAVI0 showed that CAVI is more appropriate than CAVI0. In conclusion, CAVI is reconfirmed to be a reliable and useful index of blood pressure-independent arterial stiffness composed of both organic and functional stiffness.Keywords: CAVI, CAVI0, PWV, Bramwell–Hill’s equation, stiffness parameter β

Takeshi Joko,1 Yoshimi Nagai,2 Ryusaburo Mori,3 Koji Tanaka,3 Yuji Oshima,4 Yusuke Hikichi,5 Tetsushi Komori,6 Joao Carrasco,7 Martine C Maculaitis,8 Oliver Will,8 Kathleen Beusterien,8 Kanji Takahashi2 1Department of Ophthalmology, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan; 2Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka, Japan; 3Division of Ophthalmology, Department of Visual Sciences, Nihon University of School of Medicine, Chiyoda-ku, Tokyo, Japan; 4Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 5Department of Market Access, Bayer Yakuhin, Ltd., Chiyoda-ku, Tokyo, Japan; 6Department of Research & Product Development, Bayer Yakuhin, Ltd., Kita-Ku, Osaka, Japan; 7Department of Market Access, Bayer Consumer Care AG, Basel, Canton of Basel-Stadt, Switzerland; 8Health Division, Kantar, New York, NY, USACorrespondence: Takeshi JokoDepartment of Ophthalmology, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime 790-8524, JapanTel +81 89 924 1111Email takeshijoko@matsuyama.jrc.or.jpBackground: In Japan, intravitreal anti-vascular endothelial growth factor (anti-VEGF) dosing regimens for wet age-related macular degeneration (wAMD) include pro re nata, every 2 months, and treat-and-extend, resulting in different outcomes and patient burden. Although reflecting patient preferences in treatment decision-making is desirable, few studies have examined this in Japan. This study assessed the patients willingness to trade-off between different dosing regimens.Patients and Methods: Patients with wAMD were recruited from four Japanese university hospitals to complete a face-to-face cross-sectional survey. In a discrete choice experiment, patients were asked to choose their preferred option from two anti-VEGF treatment profiles shown side-by-side across a series of choice tasks. The profiles varied on four attributes: number of injections in 12 months, number of physician consultations in 12 months, chance of 1-year visual acuity (VA) improvement, and chance of 2-year VA maintenance. Preference weights were estimated using hierarchical Bayes’ models.Results: Overall, 120 patients (30 treatment naïve and 90 anti-VEGF experienced) completed the survey. Patients were willing to accept an increase from three to approximately eight injections in 12 months to increase the chance of 1-year VA improvement from 25% to 40%. They would be willing to accept 11 injections in 12 months if the chance of 2-year VA maintenance increased from 80% to 96%. The most valued attributes were increasing the chance of 2-year VA maintenance and reducing the number of injections in 12 months, which were each about twice as important as decreasing physician consultations in 12 months and increasing the chance of 1-year VA improvement (p< 0.001). Among the dosing regimens, patients most preferred treat-and-extend because of its higher chance of 2-year VA maintenance.Conclusion: Informing patients with wAMD about the likelihood of long-term VA maintenance when selecting treatment may increase the acceptance of an optimal treatment regimen and number of injections.Keywords: wet age-related macular degeneration, patient preference, anti-vascular endothelial growth factor treatment, dosing regimen, treat-and-extend

Yuen Yee Cheng, 1, 2 Emma M Rath, 3 Anthony Linton, 1, 2, 4 Man Lee Yuen, 1 Ken Takahashi, 1 Kenneth Lee 1, 2, 4 1Asbestos Disease Research Institute, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; 2Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; 3Garvan Institute of Medical Research, Sydney, New South Wales, Australia; 4Concord Repatriation General Hospital, Sydney, New South Wales, AustraliaCorrespondence: Yuen Yee ChengAsbestos Disease Research Institute, PO Box 3628, Rhodes, New South Wales 2139, AustraliaTel +61 2 9767 9800Fax +61 2 9767 9860Email yycheng@adri.org.auAbstract: Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. Occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. This review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. Genomic mutations of DNA nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. The genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. Currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. Epigenetic DNA methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. Asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. These efforts hold the promise of non-invasive cancer diagnosis in the future. Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.Keywords: lung cancer, epigenetic biomarkers, microRNA, DNA methylation, immunohistochemistry, IHC, fluorescence in situ hybridization, FISH

Takumi Yasuno,1 Tomoyuki Ohe,1 Hitomi Ikeda,1 Kyoko Takahashi,1 Shigeo Nakamura,2 Tadahiko Mashino11Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan; 2Department of Chemistry, Nippon Medical School, Tokyo, JapanPurpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined.Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer.Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer.Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.Keywords: fullerene, anticancer agents, cisplatin-resistant cancer, doxorubicin-resistant cancer, P-glycoprotein

Naoko Koike,1 Tsuyoshi Otsuji,1 Akiko Tsumura,1 Katsuaki Miki,1 Yukio Sakai,1 Tetsuya Nishimura,1 Kanji Takahashi21Department of Ophthalmology, Kansai Medical University Medical Center, Osaka, Japan; 2Department of Ophthalmology, Kansai Medical University, Osaka, JapanPurpose: Intravitreal injection of anti-VEGF drugs has become standard therapy for patients with exudative age-related macular degeneration (AMD). However, some patients do not exhibit sufficient response to the drugs for suppression of choroidal neovascularization activity. We investigated the efficacy of switchback from ranibizumab to aflibercept in patients with AMD who could not achieve further benefit beyond initial therapy of aflibercept injection.Methods: Eleven eyes of eleven patients were included in this study. Two patients were nonresponders, and nine exhibited tachyphylaxis to aflibercept. All patients received three monthly injections of ranibizumab as an initial phase of switching and received aflibercept as a switchback drug. We investigated changes in injection interval, visual acuity, and central retinal thickness.Results: In four patients (36.4%), injection interval was extended. The interval was 6.73 weeks before switch and 9.27 weeks after switchback (P=0.96). LogMAR visual acuity was 0.22 before switch and 0.24 after switchback (P=0.62). Central retinal thickness was 306.8 μm before switch and 256.1 after switchback (P=0.13). In all patients who were nonresponders to aflibercept, injection interval could not be extended.Conclusion: A switchback from ranibizumab to aflibercept may be beneficial in some patients with AMD who exhibit tachyphylaxis to aflibercept.Keywords: AMD, aflibercept, ranibizumab, switchback, anti-VEGF drugs

Shigeto Nishikawa,1 Toshi Menju,1 Koji Takahashi,1 Ryo Miyata,1 Toyofumi Fengshi Chen-Yoshikawa,1 Makoto Sonobe,1 Akihiko Yoshizawa,2 Hisataka Sabe,3 Tosiya Sato,4 Hiroshi Date11Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; 3Department of Molecular Biology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; 4Department of Biostatistics, Kyoto University School of Public Health, Kyoto, JapanPurpose: The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma.Materials and methods: Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model.Results: Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14–3.85).Conclusion: Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.Keywords: p53, epithelial to mesenchymal transition, statin, survival analysis, non-small cell lung cancer

Fuminori Takayama,1,2 Atsushi Aoyagi,3 Keigo Takahashi,2,3 Yoshiharu Nabekura1 1Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan; 2Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan; 3Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan Purpose: Individual variations in response of C-reactive protein (CRP) to acute strenuous exercise are less well known. The purpose of this study was to investigate the relationship between running economy and systemic inflammation following a marathon. Materials and methods: Sixteen college recreational runners participated in this study. To measure maximal oxygen uptake and running economy, the treadmill running test was performed 1–2 weeks before the marathon race. Running economy was defined as oxygen cost (mL/kg/km) at submaximal running. CRP and muscle damage markers (creatine kinase and lactate dehydrogenase) were measured before and 1, 2, and 3 days after the race. Results: All subjects completed the race in 4 hours 7 minutes 43 seconds±44 minute 29 seconds [mean±SD]. The marathon running significantly increased CRP and muscle damage markers. The levels of inflammation and muscle damage peaked after 1 day and remained high throughout the 3-day recovery period compared to that before the race. Spearman correlation analysis showed that the change in CRP level was significantly positively correlated with oxygen cost (r=0.619, P=0.011) but not maximal oxygen uptake. There was no significant relationship in responses between muscle damage markers and CRP. Conclusion: These findings suggest that running economy is related to postmarathon race CRP response. Further study to clarify the cause of the relationship and clinical significance of transient increase in CRP is necessary. Keywords: inflammation, oxygen consumption, C-reactive protein, muscle damage

Kanji Takahashi,1 Masahito Ohji,2 Hiroko Terasaki,3 Shigeru Honda,4 Philippe Margaron,5 Tadhg Guerin,6 Mitsuko Yuzawa,7 On behalf of the EVEREST II Japanese investigators 1Department of Ophthalmology, Kansai Medical University, Osaka, Japan; 2Department of Ophthalmology, Shiga University of Medical Science, Otsu, Japan; 3Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 4Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan; 5Department of Ophthalmology, Novartis Pharma AG, Basel, Switzerland; 6Department of Ophthalmology, Novartis Ireland Limited, Dublin, Ireland; 7Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, Tokyo, Japan Purpose: To compare the efficacy and safety of ranibizumab 0.5 mg with or without verteporfin photodynamic therapy in Japanese patients with polypoidal choroidal vasculopathy over 12 months. Study design: EVEREST II was a 24-month, Phase IV, multicenter, randomized, double-masked study in Asian patients with symptomatic macular polypoidal choroidal vasculopathy. Methods: Of the 322 enrolled patients, 84 patients, including 46 patients who received ranibizumab + verteporfin photodynamic therapy (combination therapy arm) and 38 patients who received ranibizumab/sham PDT (monotherapy arm), were Japanese who were evaluated in this subanalysis. Mean change in best-corrected visual acuity (BCVA) and complete polyp regression at Month 12, ranibizumab treatment exposure, and safety over 12 months were assessed. Results: Baseline demographics were well balanced between the arms. At Month 12, mean change in BCVA letter score was +8.5 with combination therapy versus +6.4 with monotherapy. Complete polyp regression was higher with combination therapy than with monotherapy at Month 12 (70.5% vs 27.3%). Over 12 months, patients in the combination arm received a median of 4.0 ranibizumab injections vs 7.0 in the monotherapy arm. Serious adverse events were generally low in both arms, and retinal hemorrhage, an adverse event, was reported in one patient (2.2%). Conclusion: The results from the Japanese cohort were in agreement with the EVEREST II study. Combination therapy was effective in improving BCVA and achieving a higher rate of complete polyp regression with a lower number of ranibizumab injections than monotherapy. No new safety signals were reported, and safety events were comparable between both arms over 12 months. Keywords: Japanese, polypoidal choroidal vasculopathy, ranibizumab, neovascular age-related macular degeneration, verteporfin photodynamic therapy

Nobuaki Ochi,1 Kento Takahashi,2 Hiromichi Yamane,1 Nagio Takigawa1 1Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan; 2Clinical Education and Training Center, Kawasaki General Medical Center, Kawasaki Medical School, Okayama, Japan Abstract: Acute necrotizing encephalopathy following influenza infection is a rapidly progressing disease with high morbidity. Although the neurological disorder is sometimes reported in children, it is very rare in adults. We herein describe an adult with acute necrotizing encephalopathy captured on a series of brain magnetic resonance images. A 55-year-old man had fever and impaired consciousness. He was diagnosed with influenza A (H1N1). Brain magnetic resonance imaging revealed symmetrical lesions in the cerebellum and basal nucleus, showing typical acute necrotizing encephalopathy. Physicians should know that influenza-associated acute necrotizing encephalopathy can occur even in middle-aged adults. Keywords: acute necrotizing encephalopathy, influenza A, magnetic resonance imaging, adult

Yasuaki Kanada, Ayami Katayama, Hideshi Ikemoto, Kana Takahashi, Mana Tsukada, Akio Nakamura, Shogo Ishino, Tadashi Hisamitsu, Masataka Sunagawa Department of Physiology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan Objectives: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with symptoms of abnormal defecation and abdominal discomfort. Psychological factors are well known to be involved in onset and exacerbation of IBS. A few studies have reported effectiveness of traditional herbal (Kampo) medicines in IBS treatment. Yokukansan (YKS) has been shown to have anti-stress and anxiolytic effects. We investigated the effect of YKS on defecation induced by stress and involvement of oxytocin (OT), a peptide hormone produced by the hypothalamus, in order to elucidate the mechanism of YKS action. Methods and results: Male Wistar rats were divided into four groups; control, YKS (300 mg/kg PO)-treated non-stress (YKS), acute stress (Stress), and YKS (300 mg/kg PO)-treated acute stress (Stress+YKS) groups. Rats in the Stress and Stress+YKS groups were exposed to a 15-min psychological stress procedure involving novel environmental stress. Levels of plasma OT in the YKS group were significantly higher compared with those in the Control group (P < 0.05), and OT levels in the Stress+YKS group were remarkably higher than those in the other groups (P < 0.01). Next, rats were divided into four groups; Stress, Stress+YKS, Atosiban (OT receptor antagonist; 1 mg/kg IP)-treated Stress+YKS (Stress+YKS+B), and OT (0.04 mg/kg IP)-treated acute stress (Stress+OT) groups. Rats were exposed to acute stress as in the previous experiment, and defecation during the stress load was measured. Administration of YKS or OT significantly inhibited defecation; however, administration of Atosiban partially abolished the inhibitory effect of YKS. Finally, direct action of YKS on motility of isolated colon was assessed. YKS (1 mg/mL, 5 mg/mL) did not inhibit spontaneous contraction. Conclusion: These results suggested that YKS influences stress-induced defecation and that increased OT secretion may be a mechanism underlying this phenomenon. Keywords: Yokukansan, oxytocin, irritable bowel syndrome, acute stress, corticosterone, Kampo medicine

Hiroyuki Onodera,1 Takeru Urayama,2 Kazue Hirota,3 Kazuhiro Maeda,3 Ritsuko Kubota-Koketsu,3,4 Kazuo Takahashi,5 Katsuro Hagiwara,6 Yoshinobu Okuno,3 Kazuyoshi Ikuta,3,4 Mikihiro Yunoki,2,4,6 1Medical Information Department, 2Research and Development Division, Japan Blood Products Organization, Tokyo, 3Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 4Former Department of Virology, Research Institute for Microbial Diseases, Osaka University, 5Virology Division, Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka, 6Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan Abstract: Influenza viruses A/H1N1, A/H3N2, and B are known seasonal viruses that undergo annual mutation. Intravenous immunoglobulin (IVIG) contains anti-seasonal influenza virus globulins. Although the virus-neutralizing (VN) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. In this study, variations in hemagglutination inhibition (HI) and VN titers against seasonal influenza viruses in IVIG lots over extended time periods were examined. In addition, the importance of monitoring the reactivity of IVIG against seasonal influenza viruses with varying antigenicity was evaluated. A/H1N1, A/H3N2, and B influenza virus strains and IVIG lots manufactured from 1999 to 2014 were examined. The HI titer was measured by standard methods. The VN titer was measured using a micro-focus method. IVIG exhibited significant HI and VN titers against all investigated strains. Our results suggest that the donor population maintains both specific and cross-reactive antibodies against seasonal influenza viruses, except in cases of pandemic viruses, despite major antigen changes. The titers against seasonal influenza vaccine strains, including past strains, were stable over short time periods but increased slowly over time. Keywords: IVIG, influenza, seasonal, neutralization, vaccine

Mikihiro Yunoki,1-3 Takeshi Kurosu,2 Ritsuko Kubota Koketsu,2,4 Kazuo Takahashi,5 Yoshinobu Okuno,4 Kazuyoshi Ikuta2,4 1Research and Development Division, Japan Blood Products Organization, Tokyo, 2Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 3Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, 4Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 5Osaka Prefectural Institute of Public Health, Osaka, Japan Abstract: Japanese encephalitis virus (JEV), West Nile virus (WNV), and dengue virus (DenV) are causal agents of Japanese encephalitis, West Nile fever, and dengue fever, respectively. JEV is considered to be indigenized and widespread in Japan, whereas WNV and DenV are not indigenized in Japan. Globulin products seem to reflect the status of the donor population according to antivirus neutralization activity. However, the anti-JEV, -WNV, and -DenV neutralization activities of globulin products derived from donors in Japan have not been clarified. Furthermore, potential candidates for the development of an effective immunotherapeutic drug for encephalitis caused by JEV, WNV, or DenV have also not been identified. Therefore, the aim of this study was to determine the overall status of the donor population in Japan based on globulin products by evaluating anti-JEV, -WNV, and -DenV neutralizing activities of intravenous immunoglobulin. Overall, intravenous immunoglobulin products showed stable neutralizing activity against JEV but showed no or only weak activity against WNV or DenV. These results suggest that the epidemiological level against WNV and DenV in the donor population of Japan is still low, suggesting that these viruses are not yet indigenized. In addition, JEV vaccinations and/or infections in the donor population do not induce a cross-reactive antibody against WNV. Keywords: Japanese encephalitis virus, West Nile virus, dengue virus, intravenous immunoglobulin, neutralization

Tsuyoshi Otsuji,1 Kenichiro Sho,2 Akiko Tsumura,1 Naoko Koike,1 Tetsuya Nishimura,1 Kanji Takahashi2 1Department of Ophthalmology, Kansai Medical University, Takii Hospital, 2Department of Ophthalmology, Kansai Medical University, Hirakata Hospital, Osaka, Japan Background: To evaluate the effect of photodynamic therapy (PDT) using a modified procedure on exudative age-related macular degeneration having been conventionally difficult to treat. Methods: The medical records of eight consecutive patients (eight eyes) with age-related macular degeneration treated with modified PDT were reviewed retrospectively. Modified PDT was used for the lesions that could not be covered by conventional use of PDT, either because the lesion was too large or too close to the optic disc. A moving PDT laser spot at constant speed, for 83 seconds, was used to cover the entire lesion, and was named “Ironing PDT.” This retrospective study was performed with informed patient consent. It was approved by the Institutional Review Board of Kansai Medical University.Results: No exudation could be found 36 months after treatment in five eyes (62.5%). There was no significant difference between the best-corrected visual acuity before PDT (0.95 logMAR) and after PDT (1.09 logMAR). The logMAR best-corrected visual acuity was improved in one eye, maintained in five eyes, and deteriorated in two eyes. Conclusion: Ironing PDT decreased subfoveal fluid and preserved visual acuity in some patients with age-related macular degeneration difficult to treat with conventional therapy. Keywords: AMD, PCV, PDT, Ironing PDT, modified PDT, large lesions

The Japan Atomic Energy Agency (JAEA) started the Research and Development (R&D) to improve nuclear prediction techniques for High Temperature Gas-cooled Reactors (HTGRs). The objectives are to introduce a generalized bias factor method to avoid full mock-up experiment for the first commercial HTGR and to introduce reactor noise analysis to High Temperature Engineering Test Reactor (HTTR) experiment to observe sub-criticality. To achieve the objectives, the reactor core of graphite-moderation system named B7/4”G2/8”p8EUNU+3/8”p38EU(1) was newly composed in the B-rack of Kyoto University Critical Assembly (KUCA). The core is composed of the fuel assembly, driver fuel assembly, graphite reflector, and polyethylene reflector. The fuel assembly is composed of enriched uranium plate, natural uranium plate and graphite plates to realize the average fuel enrichment of HTTR and it’s spectrum. However, driver fuel assembly is necessary to achieve the criticality with the small-sized core. The core plays a role of the reference core of the bias factor method, and the reactor noise was measured to develop the noise analysis scheme. In this study, the overview of the criticality experiments is reported. The reactor configuration with graphite moderation system is rare case in the KUCA experiments, and this experiment is expected to contribute not only for an HTGR development but also for other types of a reactor in the graphite moderation system such as a molten salt reactor development.

Kaori Nomura,1 Kunihiko Takahashi,2 Yasushi Hinomura,3 Genta Kawaguchi,4 Yasuyuki Matsushita,5 Hiroko Marui,6 Tatsuhiko Anzai,7 Masayuki Hashiguchi,8 Mayumi Mochizuki8 1Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, 2Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, 3Japan Pharmaceutical Information Center, 4Global Pharmacovigilance, Kissei Pharmaceutical Co Ltd, Tokyo, 5Medical Affairs Department, Daiichi Sankyo Co Ltd, 6Drug Safety Division, Chugai Pharmaceutical Co Ltd, 7Data Science Center, EPS Corporation, 8Faculty of Pharmacy, Keio University, Tokyo, Japan Background: The use of a statistical approach to analyze cumulative adverse event (AE) reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection). Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration Adverse Event Reporting System (FAERS), and how they affect signal detection.Methods: Two AE data sources from 2010 were examined, ie, JADER cases (JP) and Japanese cases extracted from the FAERS (FAERS-JP). Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS), were used on drug-event combinations for three substances frequently recorded in both systems.Results: The two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6±1.3 (maximum 37) in the JP and 3.3±3.5 (maximum 62) in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and paroxetine. Signals identified by GPS for the JP and FAERS-JP, as referenced by Japanese labeling, showed higher positive sensitivity than was expected. Conclusion: The FAERS-JP was different from the JADER. Signals derived from both datasets identified different results, but shared certain signals. Discrepancies in type of AEs, drugs reported, and average number of AEs per case were potential contributing factors. This study will help those concerned with pharmacovigilance better understand the use and pitfalls of using spontaneous AE data. Keywords: drug safety, spontaneous reports system, Japan, reporting disproportionality

Tadanobu Yoshikawa, Kanji Takahashi Department of Ophthalmology, Kansai Medical University, Osaka, Japan Purpose: To describe the outcomes of intravitreal injections of bevacizumab for choroidal neovascularization (CNV) associated with choroidal osteoma. Methods: Retrospective consecutive case series. Three eyes of three patients were studied. All patients were treated with intravitreal injections of bevacizumab for CNV associated with choroidal osteoma. Best-corrected visual acuity, central foveal thickness, tumor thickness on spectral domain optical coherence tomography, and subretinal pigmentation around the CNV were evaluated. Results: The mean number of intravitreal injections of bevacizumab was 2.0 (range 1–3). The mean follow-up time was 56.0 months (range 25–99 months). The mean LogMAR visual acuity worsened from 0.1 to 0.6. LogMAR visual acuity loss of 0.7 or worse occurred in two of three eyes. CNV was located in the subfoveal area in two eyes, and CNV was located in the juxtafoveal area in one eye. The mean central foveal thickness decreased from 407 µm to 251 µm. The mean tumor thickness decreased from 709 µm to 608 µm. All eyes had subretinal pigmentation around the CNV. Conclusion: Intravitreal injections of bevacizumab for subfoveal CNV associated with decalcified choroidal osteoma resulted in poor visual acuity. Keywords: choroidal osteoma, choroidal neovascularization, bevacizumab, Avastin, vascular endothelial growth factor

Yusuke Suzuki,1 Hitoshi Suzuki,1 Yuko Makita,1 Akiko Takahata,1 Keiko Takahashi,1 Masahiro Muto,1 Yohei Sasaki,1 Atikemu Kelimu,1 Keiichi Matsuzaki,2 Hiroyuki Yanagawa,1 Keiko Okazaki,1 Yasuhiko Tomino1 1Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, 2Kyoto University Health Service, Kyoto, Japan Abstract: Immunoglobulin (Ig) A nephropathy (IgAN) is the most common form of glomerular disease worldwide and is associated with a poor prognosis. Thus, development of a curative treatment and strategies for early diagnosis and treatment are urgently needed. Pathological analysis of renal biopsy is the gold standard for the diagnosis and assessment of disease activity; however, immediate and frequent assessment based on biopsy specimens is difficult. Therefore, a simple and safe alternative is desirable. On the other hand, it is now widely accepted that multi-hit steps, including production of aberrantly glycosylated serum IgA1 (first hit), and IgG or IgA autoantibodies that recognize glycan containing epitopes on glycosylated serum IgA1 (second hit) and their subsequent immune complex formation (third hit) and glomerular deposition (fourth hit), are required for continued progression of IgAN. Although the prognostic and predictive values of several markers have been discussed elsewhere, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of glycosylated serum IgA1 and related IgA immune complex. In addition, we confirmed a significant correlation between serum levels of these essential effector molecules and disease activity after treatment, suggesting that each can be considered as a practical surrogate marker of therapeutic effects in this slowly progressive disease. Such a noninvasive diagnostic and activity assessment method using these disease-oriented specific biomarkers may be useful in the early diagnosis of and intervention in IgAN, with appropriate indication for treatment, and thus aid in the future development and dissemination of specific and curative treatments. Keywords: galactose-deficient immunoglobulin A1, anti-glycan antibody, immune complex, N-acetylgalactosamine, surrogate marker

Tomohiro Mizuno,1,2 Takahiro Hayashi,3 Sayo Hikosaka,1 Yuka Shimabukuro,1 Maho Murase,1 Kazuo Takahashi,2 Hiroki Hayashi,2 Yukio Yuzawa,2 Tadashi Nagamatsu,1 Shigeki Yamada3 1Department of Analytical Pharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan; 2Department of Nephrology, School of Medicine, Fujita Health University, Toyoake, Japan; 3Department of Clinical Pharmacy, School of Medicine, Fujita Health University, Toyoake, Japan Background: Maintenance of low serum urate levels is important for the management of gout. Achieving the recommended serum urate levels of less than 6.0 mg/dL is difficult in elderly (65 years of age or older) patients with renal impairment. Xanthine oxidase inhibitors allopurinol and febuxostat are used for this purpose. Although febuxostat had been shown to be efficacious in elderly patients, its safety and efficacy in elderly female patients with hyper­uricemia remain unclear.Objective: The aim of this study was to assess the efficacy and safety of febuxostat in elderly female patients.Methods: We studied a retrospective cohort study. The study included elderly Japanese patients (65 years of age or older) who were treated with febuxostat at Fujita Health University Hospital from January 2012 to December 2013. The treatment goal was defined as achievement of serum urate levels of 6.0 mg/dL or lower within 16 weeks; this was the primary endpoint in the present study. Adverse events of febuxostat were defined as more than twofold increases in Common Terminology Criteria for adverse events scores from baseline. Results: We evaluated 82 patients treated with febuxostat during the observation period and classified them into male (n=53) and female (n=29) groups. The mean time to achievement of the treatment goal was significantly shorter in the female group (53 days) than in the male group (71 days). There were no significant differences in adverse events between the 2 groups.Conclusion: Our findings suggest that the efficacy of febuxostat in elderly female patients is superior to that in elderly male patients and that the safety is equivalent. Keywords: febuxostat, elderly female patients, hyperuricemia

Mariko Kawai,1 Tadanobu Yoshikawa,1 Ryuta Nishikomori,2 Toshio Heike,2 Kanji Takahashi11Department of Ophthalmology, Kansai Medical University, Osaka, 2Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, JapanAbstract: Cryopyrin-associated periodic syndrome (CAPS) is a group of rare hereditary autoinflammatory diseases caused by mutations of the NLRP3 gene, and leads to excessive production of the proinflammatory cytokine, interleukin-lß. A 35-year-old male presented with recurrent symptoms of urticarial-like rash, periodic fever, arthralgia, headache, and eye redness. His best-corrected visual acuity was 1.0 OD and 0.9 OS. Slit-lamp examination showed conjunctival and episcleral injection in both eyes. Ophthalmoscopy revealed obvious bilateral optic disc swelling and retinal vascular sheathing around the optic discs. Spectral domain optical coherence tomography also showed obvious optic disc swelling. Steroid and nonsteroidal anti-inflammatory drugs did not improve these symptoms. Genetic testing detected a heterozygous mutation of c.907G>A. Thus, the patient was genetically confirmed with CAPS. Visual acuity did not decrease for 3 years, although the optic discs became white in color. CAPS should therefore be distinguished from other disorders when examining optic disc swelling and/or uveitis patients with urticarial-like rash and periodic fever.Keywords: interleukin-lß, chronic infantile cutaneous and articular syndrome, cryopyrin-associated periodic syndrome, leucine-rich repeat-containing protein 3, optic disc swelling

Tsuyoshi Otsuji,1 Yoshimi Nagai,2 Kenichiro Sho,1 Akiko Tsumura,1 Naoko Koike,1 Mei Tsuda,1 Tetsuya Nishimura,1 Kanji Takahashi2 1Department of Ophthalmology, Kansai Medical University, Takii Hospital, Osaka, Japan; 2Department of Ophthalmology, Kansai Medical University, Hirakata Hospital, Osaka, Japan Background: Patients with exudative age-related macular degeneration (AMD) who did not respond to ranibizumab at the induction phase were assessed and referred to as initial non-responders. Methods: We retrospectively reviewed the medical records of 215 patients (218 eyes) with exudative AMD. For the initial treatments, patients received three intravitreal injections of ranibizumab (IVR) every 4 weeks. Minimum follow-up period was 12 months. We defined patients with no improvement of best corrected logMAR visual acuity (BCVA), and with no decrease of central retinal thickness (CRT) at the end of the initial treatment, as initial non-responders. Patients who had previous treatment history prior to this investigation were included, but patients who had photodynamic therapy (PDT) with IVR were excluded. Results: Twenty-two eyes (10.1%) were identified as initial non-responders. The mean BCVA of initial non-responders before IVR and after induction phase were 0.39 and 0.36, respectively. There was no significant difference between these values, however the mean BCVA decreased significantly to 0.55 at 12 months after the beginning of the induction phase (P = 0.021). The mean greatest linear dimension (GLD) of the lesion before IVR of initial non-responders was 4,121 µm. We found 16 eyes with typical AMD, and six eyes with polypoidal choroidal vasculopathy. One eye had predominantly classic choroidal neovascularization (CNV), and others had occult CNV of typical AMD. As additional treatments, twelve eyes received PDT, and in three of the eyes exudation remained after PDT. Conclusion: Initial non-responders were more prevalent in patients with occult CNV than in patients with other CNV types. Some of the initial non-responders did not respond to PDT. This study suggested possible involvement of other factors, in addition to vascular endothelial growth factor, in the occurrence of CNV in initial non-responder patients. Keywords: AMD, anti-VEGF drug, ranibizumab, initial non-responders