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Kazuki Hashimoto, Takuro Nii, Hitoshi Sumitani, Masashi Yokoyama, Satoshi Miyamoto, Yasuhiro Mihashi, Yuka Nagata, Takanori Matsuki, Kazuyuki Tsujino, Keisuke Miki, Hiroshi Kida Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, Osaka, JapanCorrespondence: Takuro Nii, Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan, Tel +81-6-6853-2001, Fax +81-6-6853-3127, Email nii.takuro.kw@mail.hosp.go.jpAbstract: Amikacin liposome inhalation suspension (ALIS) is a key drug for the treatment of refractory Mycobacterium avium complex pulmonary disease (MAC-PD). Although cases of drug-induced interstitial lung disease (DIILD) by ALIS have been reported, its diagnosis is challenging due to overlapping existing pulmonary shadows, airway bleeding, exacerbation of underlying conditions, and the potential for various concurrent infections. A 72-year-old woman started treatment with ALIS for refractory MAC-PD. Three weeks later, she had a fever, cough, and appetite loss. She was hospitalized because multiple infiltrative opacities were observed on chest X-ray and chest computed tomography. Because the opacities worsened after empiric antibiotic therapy with broad-spectrum antibiotics, we initiated corticosteroid therapy, suspecting DIILD caused by ALIS, although drug lymphocyte stimulation tests for ALIS and amikacin were negative. Three days later, we found signs of improvement and quickly tapered the corticosteroids. After obtaining informed consent, we performed a drug provocation test of ALIS. Seven days later, she exhibited fever, an increased peripheral white blood cell count, and elevated serum C-reactive protein level, all of which returned to baseline 4 days after stopping ALIS, leading to a diagnosis of DIILD caused by ALIS in this patient. DIILD caused by ALIS is rare but should be carefully diagnosed to ensure that patients with refractory MAC-PD do not miss the opportunity to receive ALIS treatment.Keywords: amikacin liposome inhalation suspension, Mycobacterium avium complex pulmonary disease, drug-induced interstitial lung disease, drug provocation test, paradoxical response

Motoko Tachihara,1 Kayoko Tsujino,2 Takeaki Ishihara,3 Hidetoshi Hayashi,4 Yuki Sato,5 Takayasu Kurata,6 Shunichi Sugawara,7 Isamu Okamoto,8 Shunsuke Teraoka,9 Koichi Azuma,10 Haruko Daga,11 Masafumi Yamaguchi,12 Takeshi Kodaira,13 Miyako Satouchi,14 Mototsugu Shimokawa,15 Nobuyuki Yamamoto,9 Kazuhiko Nakagawa4 On behalf of members of the West Japan Oncology Group (WJOG)1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe City, Japan; 2Department of Radiation Oncology, Hyogo Cancer Center, Akashi City, Japan; 3Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe City, Japan; 4Department of Medical Oncology, Kindai University, Osakasayama City, Japan; 5Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe City, Japan; 6Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata City, Japan; 7Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai City, Japan; 8Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan; 9Internal Medicine III, Wakayama Medical University, Wakayama, Japan; 10Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka City, Japan; 11Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan; 12Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan; 13Departments of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya City, Aichi, Japan; 14Department of Thoracic Oncology, Hyogo Cancer Center, Akashi City, Japan; 15Department of Biostatistics, Yamaguchi University Graduate School of Medicine Yamaguchi, Ube City, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpAbstract: Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.Keywords: clinical study, locally advanced non-small cell lung cancer, immunotherapy, programmed cell death ligand-1, durvalumab, radiation

Yuji Yamamoto, Keisuke Miki, Takanori Matsuki, Kiyoharu Fukushima, Yohei Oshitani, Hiroyuki Kagawa, Kazuyuki Tsujino, Kenji Yoshimura, Mari Miki, Hiroshi Kida Department of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, Osaka, JapanCorrespondence: Keisuke MikiDepartment of Respiratory Medicine, National Hospital Organization Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka 560-8552, JapanTel +81-6-6853-2001Fax +81-6-6853-3127Email miki.keisuke.pu@mail.hosp.go.jpBackground: Oscillometry is a tool to measure respiratory impedance that requires minimal patients’ effort. In patients with chronic obstructive pulmonary disease (COPD), the correlation of respiratory impedance at rest with exertional ventilatory parameters, including exercise tolerance, has scarcely been reported. In addition, the utility of oscillometric parameters might differ between the inspiratory and expiratory phases due to airflow obstruction during expiration, but the hypothesis had not been validated. The aim of the present study was to investigate whether oscillometric parameters are associated with exertional ventilatory parameters in patients with COPD.Methods: Fifty-five subjects with COPD who attended clinics at the National Hospital Organization Osaka Toneyama Medical Center performed spirometry, oscillometry, and cardiopulmonary exercise testing (CPET) within 2 weeks. The correlations between parameters of spirometry, oscillometry, and CPET were analyzed using Spearman’s rank correlation coefficient, univariate, and multivariate analyses.Results: Respiratory reactance had better correlations with the CPET parameters than respiratory resistance. Moreover, inspiratory reactance at rest correlated with the CPET parameters stronger than expiratory reactance. In particular, inspiratory resonant frequency (Fres-ins) correlated with peak oxygen uptake (rS=− 0.549, p< 0.01) and dead space to tidal volume ratio at peak exercise (rS=0.677, p< 0.01) and the best predicted expiratory tidal volume (VT ex) at peak exercise of all the oscillometric parameters (rS=− 0.679, p< 0.01). However, the correlation between Fres-ins and VT ex at peak exercise became weak in subjects with severe and very severe COPD during exercise.Conclusion: Measurement of respiratory reactance is useful for the effortless evaluation of not only exertional ventilatory parameters but exercise tolerance in patients with COPD. The correlation of respiratory impedance with exertional ventilatory parameters can become weak in patients with advanced COPD; thus, the measurement of oscillometry might not be appropriate for evaluating exertional ventilatory parameters of patients with advanced COPD.Keywords: dyspnea, dynamic hyperinflation, airflow obstruction, resonant frequency, tidal volume

Yoshito Takeda,1 Kazuyuki Tsujino,2 Takashi Kijima,1 Atsushi Kumanogoh1 1Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; 2Department of Respiratory Medicine, Kinki Central Hospital of the Mutual Aid Association of Public School Teachers, Itami, Hyogo, Japan Abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating chronic fibrotic lung disease. Although the precise cause of the disease is still unknown, recent studies have shown that the pathogenesis of pulmonary fibrosis involves multiple mechanisms, with abnormal behavior of alveolar epithelial cells considered a primary event. Pirfenidone is a multifunctional, orally available small molecule with anti-fibrotic, anti-inflammatory, and antioxidative activities, and has been shown to be a modulator of cytokines and growth factors, including TGF-ß1, TNF-α, bFGF, IFN-γ, IL-1ß, and IL-18 in animal models. Although its precise mechanism of action is not currently clear, pirfenidone is considered to exert inhibitory effects on multiple pathways involved in the pathogenesis of IPF. Two randomized placebo-controlled clinical trials in Japan demonstrated that pirfenidone significantly reduced the rate of decline of vital capacity in IPF patients. A Phase III study showed a significant increase in progression-free survival of patients in pirfenidone-treated groups compared to the placebo group. These results paved the way for the approval of pirfenidone for the treatment of IPF patients in Japan in 2008. The promising results of the Phase II study in Japan led to a larger international Phase III trial (CAPACITY). Subsequently, pirfenidone has also been approved in the European Union, South Korea, and Canada to date. Pirfenidone treatment is generally tolerated. Major adverse events are gastrointestinal symptoms, including decreased appetite, abdominal discomfort and nausea, photosensitivity, and fatigue, but many of these are mild and manageable. Clinical experience has shown that reduction in pirfenidone dose and the supportive use of gastrointestinal drugs are effective ways to manage these symptoms. Thus, pirfenidone treatment provides a means of intervention in the clinical course of IPF, and is a promising candidate for improving patient prognosis. For future development, it is important to establish the appropriate modality of treatment with pirfenidone and/or novel potential drugs. Keywords: pirfenidone, safety, efficacy, anti-fibrotic drugs