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Yoshihisa Ishiura,1 Masaki Fujimura,2 Noriyuki Ohkura,3 Johsuke Hara,3 Kahori Nakahama,1 Yusuke Sawai,1 Takeshi Tamaki,1 Ryuta Murai,1 Toshiki Shimizu,1 Naoyuki Miyashita,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; 2Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 3Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiura-@p2322.nsk.ne.jp; ishiuray@takii.kmu.ac.jpPurpose: The ‘treatable traits’ strategy for patients with chronic inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease (COPD), is a focus of interest, because it implements precision and personalized medicine. Asthma-COPD overlap (ACO), a phenotype involving both asthma and COPD, is an important disease entity because patients with ACO have significantly worse outcomes, conferring greater economical and social burdens. Some guidelines for ACO recommend add-on therapy of long-acting muscarinic antagonists to inhaled corticosteroids and long-acting β2 agonists. However, this approach is based on extrapolation from patients with asthma or COPD alone. Consequently, a ‘treatable traits’ approach suitable for ACO remains obscure.Methods: A 12-week open-label cross-over pilot study was conducted in patients with ACO to investigate the effect of tiotropium bromide (TIO) 5 μg/day add-on therapy to fluticasone propionate/formoterol fumarate (FP/FM) 500/20 μg/day compared with FP/FM 500/20 μg/day alone. A 4-week run-in period and two 4-week treatment periods were included.Results: A total of 18 male patients with stable ACO participated in this pilot study. All patients were ex-smokers. Mean values ± standard deviation (SD) for forced expiratory volume in 1 second (FEV1) were 1.21 ± 0.49 L after the run-in period, 1.20 ± 0.51 L after the FP/FM combination therapy period, and 1.30 ± 0.48 L after the TIO add-on therapy to FP/FM period. FEV1 values after the TIO add-on therapy FP/FM period were significantly higher than those after the run-in period (p < 0.01).Conclusion: TIO add-on therapy to FP/FM in patients with ACO, considered difficult to treat because of the presence of both asthma and COPD, resulted in improvements in lung function parameters in this real-world pilot study, indicating the potential value of TIO add-on therapy as a “treatable traits” option for standard treatment for ACO.Keywords: treatable trait, asthma-COPD overlap, tiotropium, fluticasone, formoterol, triple therapy

Yoshihisa Ishiura,1,2 Masaki Fujimura,3 Noriyuki Ohkura,4 Johsuke Hara,4 Kazuo Kasahara,4 Nobuyasu Ishii,1 Yusuke Sawai,1 Toshiki Shimizu,1 Takeshi Tamaki,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan; 2Respiratory Medicine, Toyama City Hospital, Toyama, Japan; 3Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 4Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa IshiuraFirst Department of Internal Medicine, Kansai Medical University, Kansai Medical University Medical Center, 10-15 Fumizono-Cho, Moriguchi, Osaka 570-8507, JapanTel +81-6-6992-1001Fax +81-6-6993-9837Email ishiura-@p2322.nsk.ne.jpPurpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone.Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 μg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 μg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization.Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55– 83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods.Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.Keywords: asthma-COPD overlap, budesonide, glycopyrrolate, formoterol fumarate, triple therapy

Tomoyuki Araya,1 Kazuo Kasahara,1 Shingo Nishikawa,1 Hideharu Kimura,1 Takashi Sone,1 Hideo Nagae,2 Yoshio Ikehata,3 Isamu Nagano,3 Masaki Fujimura11Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, 2Cooperative Research Center for Kanazawa University, 3Department of Information and Systems Engineering, Kanazawa University, Kanazawa, JapanBackground: The effects of inductive hyperthermia on lung cancer have yet to be fully investigated. Magnetic nanoparticles used in inductive hyperthermia are made-to-order and expensive. This study was performed to investigate the use of ferucarbotran in inductive hyperthermia and to clarify whether inductive hyperthermia using ferucarbotran promotes antitumor effects in vivo using a lung cancer cell line.Methods: We injected A549 cells subcutaneously into the right thighs of BALB/c nu/nu nude mice. Forty mice with A549 xenografts were then classified into three groups. Group 1 was the control group. All mice in groups 2 and 3 had ferucarbotran injected into their tumors, and mice in group 3 were then subjected to alternating magnetic field irradiation. We evaluated tumor temperature during the hyperthermic procedure, the time course of tumor growth, histologic findings in tumors after hyperthermic treatment, and adverse events.Results: Intratumor temperature rose rapidly and was maintained at 43°C–45°C for 20 minutes in an alternating magnetic field. Tumor volumes in groups 1 and 2 increased exponentially, but tumor growth in group 3 was significantly suppressed. No severe adverse events were observed. Histologic findings for the tumors in group 3 revealed mainly necrosis.Conclusion: Inductive hyperthermia using ferucarbotran is a beneficial and promising approach in the treatment of lung cancer. Ferucarbotran is a novel tool for further development of inductive hyperthermia.Keywords: inductive hyperthermia, ferucarbotran, magnetic nanoparticles, alternating magnetic field, lung cancer, human use