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Masao Yamaguchi,1 Yoshihiro Nishimura,2 Yuko Takumi,3 Nobuya Hayashi,4 Kei Sakamoto,3 Yuji Tohda5 1Division of Respiratory Medicine, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan; 2Kita-Harima Medical Center, Ono, Hyogo, Japan; 3Patient Safety Division, Research and Development, AstraZeneca K.K., Osaka, Japan; 4Data Science and Innovation Division, Research and Development, AstraZeneca K.K., Osaka, Japan; 5Department of Respiratory Medicine and Allergology, Kindai University School of Medicine, Osaka-Sayama, Osaka, JapanCorrespondence: Masao Yamaguchi, Division of Respiratory Medicine, Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan, Tel +81-436-62-1211, Fax +81-436-62-7340, Email myama@med.teikyo-u.ac.jpIntroduction: This study aimed to demonstrate whether benralizumab maintained the safety and effectiveness profiles established in randomized controlled trials among all patients with severe uncontrolled asthma initially prescribed benralizumab in the real-world setting in Japan.Methods: This was a prospective, observational, multicenter post-marketing study (ClinicalTrial.gov, NCT03588546). The safety and tolerability of benralizumab over 1 year were assessed by the incidence of adverse events (AEs), serious AEs, adverse drug reactions (ADRs), and serious ADRs. Patient background characteristics indicating a more frequent onset of ADRs with benralizumab were explored. The main effectiveness assessment was the change in Asthma Control Questionnaire-5 (ACQ-5) score from baseline. Patients with baseline ACQ-5 scores ≥ 1.5 were defined as having severe uncontrolled asthma.Results: In total, 632 patients were evaluated for safety and 274 for effectiveness; 139 patients were included in the severe uncontrolled asthma subgroup. ADRs were reported in 12.7% and serious AEs in 13.0% of patients. Serious infections occurred in 3.8%, serious hypersensitivity in 0.3%, and malignancy in 0.3% of patients. No helminthic infections occurred. In the effectiveness population, benralizumab improved the mean (standard deviation [95% confidence interval]) ACQ-5 score by − 1.16 (1.40 [− 1.36, − 0.96]) from baseline; forced expiratory volume in 1 second by 0.151 (0.440 [0.09, 0.21]) L; and Mini-Asthma Quality of Life questionnaire score by 1.16 (1.29 [0.94, 1.38]) at the last observation. The annual asthma exacerbation rate was 0.42. A greater ACQ-5 score improvement was observed among patients with eosinophilic asthma characteristics.Conclusion: No new safety concerns were raised, and patients experienced benefits consistent with previous studies of benralizumab, thus supporting the use of benralizumab for the add-on maintenance treatment of patients with eosinophilic severe uncontrolled asthma.Keywords: benralizumab, severe uncontrolled asthma, anti-interleukin-5 receptor α monoclonal antibody, eosinophils, exacerbation, asthma control, quality of life

Toshiyuki Koya,1 Kazuhisa Asai,2 Takashi Iwanaga,3 Yu Hara,4 Mai Takahashi,5 Naoyuki Makita,5 Nobuya Hayashi,6 Naoki Tashiro,5 Yuji Tohda7,8 1Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 2Department of Respiratory Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan; 3Center for General Medical Education and Clinical Training, Kindai University Faculty of Medicine, Osakasayama, Japan; 4Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 5Medical Department, AstraZeneca KK, Osaka, Japan; 6R&D, AstraZeneca KK, Osaka, Japan; 7Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Japan; 8Kinki Hokuriku Airway disease Conference (KiHAC) Group, Osakasayama, JapanCorrespondence: Toshiyuki Koya, Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata, 951-8510, Japan, Tel +81 25-368-9325, Fax +81 25-368-9326, Email tkoya@med.niigata-u.ac.jpPurpose: Treatment patterns and patient characteristics are not well elucidated among Japanese patients with severe uncontrolled asthma who currently have various treatment options, including biologics. We analyzed baseline characteristics of patients who did/did not initiate biologic treatment in PROSPECT, a 24-month observational study.Patients and Methods: Patients with severe uncontrolled asthma were prospectively enrolled at 34 sites in Japan from December 2019 to September 2021. The enrolled population was divided based on initiation/non-initiation of biologic treatment within 12 weeks after enrollment. Patient demographics, clinical characteristics, biomarker levels, and asthma-related treatment were assessed at enrollment.Results: Of 289 patients meeting the enrollment criteria, 127 patients initiated biologic treatment (BIO group: omalizumab, n = 16; mepolizumab, n = 10; benralizumab, n = 41; and dupilumab, n = 60) and 162 patients did not (non-BIO group). The proportion of patients with ≥ 2 asthma exacerbations was higher in the BIO group than the non-BIO group (65.0% vs 47.5%). Patients receiving omalizumab had the highest frequency of allergic rhinitis (87.5% vs other BIOs: 40.0%– 53.3%). Patients receiving benralizumab and dupilumab had the highest incidence of nasal polyps (benralizumab: 19.5%, dupilumab: 23.3%, other BIOs: 0.0%). The proportion of patients with blood eosinophils ≥ 300 cells/μL was higher with benralizumab (75.6%) than other BIOs (26.7%– 42.9%).Conclusion: This analysis of baseline data from the PROSPECT study is the first to clarify the characteristics of Japanese patients with severe uncontrolled asthma. BIOs were not necessarily prescribed to patients in whom they were indicated; however, for patients who received them, selection appeared to be made appropriately based on asthma phenotypes.Keywords: benralizumab, biologics, dupilumab, mepolizumab, omalizumab

Shu Hashimoto1,2 ,† Yuri Yoshida,3 Naoyuki Makita,3 Ryoko Sorimachi,3 Satoko Sugaya,4 Yoshifumi Arita,3 Nobuya Hayashi,4 Naoki Tashiro,3 Masakazu Ichinose5,6 1Nihon University, Tokyo, Japan; 2Hibiya Kokusai Clinic, Tokyo, Japan; 3Medical Department, AstraZeneca K.K., Osaka, Japan; 4R&D, AstraZeneca K.K., Osaka, Japan; 5Academic Center of Osaki Citizen Hospital, Miyagi, Japan; 6Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan†Dr Shu Hashimoto passed away on July 03, 2022Correspondence: Masakazu Ichinose, Academic Center of Osaki Citizen Hospital, 3-8-1 Honami, Furukawa, Osaki, 989-6183, Japan, Tel +81-229-23-3311, Fax +81-229-23-5380, Email ichinose@h-osaki.jpIntroduction: The ACO Japan Cohort Study, a multicenter observational study, investigated the proportion of patients with chronic obstructive pulmonary disease (COPD) who met the Japanese Respiratory Society (JRS) asthma–COPD overlap (ACO) diagnostic criteria, characteristics of ACO and non-ACO patients, and the patient transitions between ACO/non-ACO diagnosis over 2 years.Patients and Methods: Patients with COPD were consecutively enrolled between June and December 2018 and followed up continuously for 2 years. All participating study sites were medical institutions where respiratory specialists routinely conducted medical examinations/tests required for ACO diagnosis.Results: Among 708 patients with COPD, 101 (14.3%), 118 (16.7%), and 125 (17.7%) were diagnosed with ACO at registration, 1 year, and 2 years, respectively. In total, 22.6% of patients lacked the data necessary for ACO diagnosis throughout the 2 years. Among patients who had the necessary data for ACO diagnosis, 24.7% were diagnosed with ACO at 2 years. More ACO patients had moderate or severe exacerbations in the past year than non-ACO patients at registration (15.8% vs 6.3%, p = 0.049) and 1 year (19.4% vs 7.6%, p = 0.025). ACO patients had a greater decrease in mean forced expiratory volume in one second over 2 years than non-ACO patients (− 92.0 vs 43.4 mL). Among patients diagnosed with ACO at registration, 21.4% transitioned to non-ACO after 1 year. Conversely, almost all non-ACO patients at registration remained non-ACO after 1 year.Conclusion: COPD patients with ACO determined by the JRS criteria had a high risk of exacerbations and a rapid decline in respiratory function, indicating that the JRS criteria for ACO are useful for identifying high-risk COPD patients. Testing necessary for ACO diagnosis is insufficiently performed even in real-world clinical practice of COPD specialists.Keywords: asthma, chronic obstructive pulmonary disease, exacerbation, FEV1 decline, inhaled corticosteroid

Naomi Hayashi,1 Yasuyoshi Sato,1 Yu Fujiwara,1,2 Naoki Fukuda,1 Xiaofei Wang,1 Kenji Nakano,1 Testuya Urasaki,1 Akihiro Ohmoto,1 Makiko Ono,1 Junichi Tomomatsu,1 Yukiko Sato,3 Hiroki Mitani,4 Takashi Toshiyasu,5 Shunji Takahashi1 1Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York City, NY, USA; 3Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 4Head and Neck Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 5Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanCorrespondence: Yasuyoshi SatoThe Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, JapanTel +8135200111Fax +81335200141Email yasuyoshi.sato@jfcr.or.jpPurpose: There have been few reports on the evaluation of cancer cachexia based on skeletal muscle mass index (SMI) in patients with head and neck cancer.Patients and Methods: One hundred and ninety-two head and neck cancer patients were enrolled. In definitive and adjuvant chemoradiotherapy settings, clinical outcomes were compared between cachexia and non-cachexia patients.Results: Forty patients were diagnosed with cachexia (20.8%). In the definitive setting, overall survival (OS) was significantly shorter in the cachexia group (3-year OS: 50.0% vs 88.5%; p < 0.01), and multivariate analysis identified UICC stage IV, baseline albumin of < 4 and cachexia as poor prognostic factors. However, cachexia was not significant in the adjuvant setting.Conclusion: Cancer cachexia was negatively associated with prognosis in patients with HNC who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients.Keywords: head and neck cancer, squamous cell carcinoma of head and neck, sarcopenia, cachexia, muscle, skeletal, chemoradiotherapy, prognosis

Masakazu Ichinose,1 Yoshiaki Minakata,2 Takashi Motegi,3 Tsuneyuki Takahashi,4 Munehiro Seki,5 Satoko Sugaya,5 Nobuya Hayashi,6 Ichiro Kuwahira7 1Academic Center of Osaki Citizen Hospital, Osaki 989-6183, Japan; 2Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama 644-0044, Japan; 3Respiratory Care Clinic Tokyo, Institute of Clinical Respirology, Tokyo 104-0031, Japan; 4Department of Internal Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Sendai 984-8560, Japan; 5Medical Department, AstraZeneca K.K., Osaka 530-0011, Japan; 6Biometrics Department, AstraZeneca K.K., Osaka 530-0011, Japan; 7Department of Pulmonary Medicine, Tokai University Tokyo Hospital, Tokyo 151-0053, JapanCorrespondence: Masakazu Ichinose Email ichinose@h-osaki.jpPurpose: Patients with chronic obstructive pulmonary disease (COPD) have decreased physical activity (PA) compared with healthy adults. As lower PA is associated with increased mortality, improving PA is an important objective for COPD management. This large-scale, multicenter, non-interventional, cross-sectional study examined the activity status of COPD patients in Japan and explored factors related to PA.Patients and Methods: Outpatients aged ≥ 40 years with confirmed COPD diagnosis and pulmonary function test data were enrolled. Primary study outcomes were measurement of daily steps (over 14 consecutive days, using an activity monitor), assessment of activity time by activity intensity (using metabolic equivalents [METs]), and evaluation of correlation between PA and patient characteristics. Secondary outcomes included further investigation of the influence of patient characteristics on PA.Results: Data from 417 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I (29.5%), II (43.9%), III (23.5%), and IV (3.1%) were evaluated. Median (Q1, Q3) daily step count was 3440.8 (1831.3, 5709.3). Median (Q1, Q3) durations of PA at ≥ 3 (moderate-to-vigorous) and ≥ 2 METs (light-to-vigorous) were 18.7 (6.5, 41.3) and 186.9 (126.9, 259.2) minutes, respectively. For > 30% of patients, time spent in ≥ 3 METs activity was ≤ 10 minutes. Unemployment was significantly correlated with reduced activity time (≥ 3 and ≥ 2 METs) and step count. Severe GOLD stage was significantly correlated with reduced activity time (≥ 3 and ≥ 2 METs). High modified Medical Research Council (mMRC) dyspnea score was significantly correlated with reduced activity time (≥ 3 METs) and step count. Patients tended to overestimate the time spent in activities requiring ≥ 2 METs in their subjective reports compared with activity monitor measurements.Conclusion: Reduced PA was observed in the Japanese COPD patients with the majority of them being GOLD stage I/II. Employment status, GOLD stage, and mMRC dyspnea score could help identify patients at risk of reduced PA.Clinical Trial Registration: NCT03642613 (ClinicalTrials.gov); UMIN000032962 (UMIN-CTR, umin.ac.jp).Keywords: COPD, physical activity, pulmonary function, activity monitor, step counts

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Paul Dorinsky,8 Colin Reisner9 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS.Methods: Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over Weeks 12–24. Symptoms, quality of life, exacerbations, and safety were also assessed.Results: In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV1 over Weeks 12–24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; P=0.0337) and BFF MDI (67 mL; 95% CI 25, 109; P=0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; P=0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (P≤0.3899). All treatments were generally well tolerated.Conclusion: BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Colin Reisner,9 Paul Dorinsky8 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Großhansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).Materials and methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Laminar-type spherical diffraction gratings overcoated with carbon-based materials were designed, fabricated, and evaluated for the purpose of enhancing the analytical sensitivity of the flat-field spectrograph in a vacuum ultraviolet region of 35–110 eV. As the design benchmark for numerical calculations, diffraction efficiency (DE) and spectral flux, which are defined by the product of the DE and numerical aperture and correlate with the analytical sensitivity of the spectrograph, were used. To simplify the feasibility study on the overcoating effects, we assumed a laminar-type grating having a grating constant of 1/1000 mm and coated with a Au layer of 30.0 nm thickness and an incidence angle of 84.0°. The optimized groove depth and duty ratio were 30.0 nm and 0.3, respectively. In addition, the optimum thicknesses of the overcoating layer were 44, 46, 24, and 30 nm for B4C, C, diamond-like-carbon, and SiC, respectively. Based on these results, we have fabricated a varied-line-spacing holographic grating overcoated with B4C with a thickness of 47 nm. For the experimental evaluation, we used the light source of Mg-L and Al-L emissions excited by the electron beam generated from an electron microscope, an objective flat-field spectrograph, and a CCD imaging detector. The experimental results showed that the spectrograph employing a new grating overcoated with the B4C layer indicated almost the same spectral resolution and 2.9–4.2 times higher analytical sensitivity compared with those obtained with a previously designed Au-coated grating having a grating constant of 1/1200 mm and used at an incidence of 86.0°. [ABSTRACT FROM AUTHOR]