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Taisuke Jo,1,2 Nobuaki Michihata,1 Hayato Yamana,1 Yusuke Sasabuchi,3 Hiroki Matsui,4 Hirokazu Urushiyama,2 Akihisa Mitani,2 Yasuhiro Yamauchi,2 Kiyohide Fushimi,5 Takahide Nagase,2 Hideo Yasunaga4 1Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 3Data Science Center, Jichi Medical University, Tochigi, Japan; 4Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan; 5Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan Purpose: Patients with symptomatic COPD are recommended to use inhaled bronchodilators containing long-acting muscarinic receptor antagonists (LAMAs). However, bronchodilators may cause gastrointestinal adverse effects due to anticholinergic reactions, especially in advanced-age patients with COPD. Dai-kenchu-to (TU-100, Da Jian Zhong Tang in Chinese) is the most frequently prescribed Japanese herbal Kampo medicine and is often prescribed to control abdominal bloating and constipation. The purpose of this study was to evaluate the role of Dai-kenchu-to as a supportive therapy in advanced-age patients with COPD. Patients and methods: We used the Japanese Diagnosis Procedure Combination inpatient database and identified patients aged ≥75 years who were hospitalized for COPD exacerbation. We then compared the risk of re-hospitalization for COPD exacerbation or death between patients with and without Dai-kenchu-to using 1-to-4 propensity score matching. A Cox proportional hazards model was used to compare the two groups. We performed subgroup analyses for patients with and without LAMA therapy. Results: Patients treated with Dai-kenchu-to had a significantly lower risk of re-hospitalization or death after discharge; the HR was 0.82 (95% CI, 0.67–0.99) in 1-to-4 propensity score matching. Subgroup analysis of LAMA users showed a significant difference in re-hospitalization or death, while subgroup analysis of LAMA non-users showed no significant difference. Conclusion: Our findings indicate that Dai-kenchu-to may have improved the tolerability of LAMA in advanced-age patients with COPD and, therefore, reduced the risk of re-hospitalization or death from COPD exacerbation. Dai-kenchu-to may be recommended as a useful supportive therapy for advanced-age patients with COPD. Keywords: TU-100, herbal medicine, muscarinic receptor antagonists, propensity score, survival analysis

Yasuhiro Yamauchi,1 Hideo Yasunaga,2 Yukiyo Sakamoto,1 Wakae Hasegawa,1 Hideyuki Takeshima,1 Hirokazu Urushiyama,1 Taisuke Jo,1,3 Hiroki Matsui,2 Kiyohide Fushimi,4 Takahide Nagase1 1Department of Respiratory Medicine, Graduate School of Medicine, 2Department of Clinical Epidemiology and Health Economics, School of Public Health, 3Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, 4Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan Background and objective: COPD is well known to frequently coexist with osteoporosis. Bone fractures often occur and may affect mortality in COPD patients. However, in-hospital mortality related to bone fractures in COPD patients has been poorly studied. This retrospective study investigated in-hospital mortality of COPD patients with bone fractures using a national inpatient database in Japan.Methods: Data of COPD patients admitted with bone fractures, including hip, vertebra, shoulder, and forearm fractures to 1,165 hospitals in Japan between July 2010 and March 2013, were extracted from the Diagnosis Procedure Combination database. The clinical characteristics and mortalities of the patients were determined. Multivariable logistic regression analysis was also performed to determine the factors associated with in-hospital mortality of COPD patients with hip fractures.Results: Among 5,975 eligible patients, those with hip fractures (n=4,059) were older, had lower body mass index (BMI), and had poorer general condition than those with vertebral (n=1,477), shoulder (n=281), or forearm (n=158) fractures. In-hospital mortality was 7.4%, 5.2%, 3.9%, and 1.3%, respectively. Among the hip fracture group, surgical treatment was significantly associated with lower mortality (adjusted odds ratio, 0.43; 95% confidence interval, 0.32–0.56) after adjustment for patient backgrounds. Higher in-hospital mortality was associated with male sex, lower BMI, lower level of consciousness, and having several comorbidities, including pneumonia, lung cancer, congestive heart failure, chronic liver disease, and chronic renal failure.Conclusion: COPD patients with hip fractures had higher mortality than COPD patients with other types of fracture. Surgery for hip fracture was associated with lower mortality than conservative treatment. Keywords: COPD, hip fractures, in-hospital mortality, surgical treatment

Macrophages can contribute to acute and chronic lung allograft rejections. Disulfiram (DSF), an anti-alcoholic drug, has the potential to give an anti-inflammatory effect and regulate the chemotactic activity of macrophages. We hypothesized that DSF could suppress acute allograft rejection after rat lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplantation from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75mg/hr) as therapy or only co-solvent as control was subcutaneously delivered by osmotic pumps for 7 days (n=10 each). No immunosuppressant was administered. Acute rejection, CD68/CD3/CD79a cell infiltrations, and gene expression of monocyte chemoattractant proteins and pro-inflammatory cytokines were assessed on posttransplant day 7. Pathologists evaluated acute rejection grades in a double-blind fashion. After evaluating gene expression by using RNA sequencing (RNA-seq) for representative cases (n=3 each), the results were validated by quantitative polymerase chain reaction (qPCR; the remaining n=7 each). The Mann-Whitney U test was used for comparing the two groups. Adjustment by Benjamin and Hochberg method was conducted to compare them in the RNA-seq. Two-tailed p values <0.05 or q values <0.05 was considered statically significant. On histological findings, the DSF group had significantly milder lymphocytic bronchiolitis (p=0.002). The infiltrations of CD68 or CD3 cells to the peribronchial site in the DSF group were significantly less than those in the control group (p<0.001 both). The alveolar region did not show a difference in cell accumulations. Normalized expression of CCL2 mRNA and IL-6 mRNA in allografts showed less than half-fold expressions in the DSF group (q=0.101 and q=0.037, respectively). Relative gene expression, normalized by GAPDH , in qPCR showed lower IL-6 expression in the DSF group (p=0.042) but the expression of CCL2 was not significantly different between groups (p=0.839). DSF can alleviate acute rejection after lung transplantations by reducing the accumulation of macrophages around peripheral bronchi and suppressing gene expression of a pro-inflammatory cytokine such as IL-6. [ABSTRACT FROM AUTHOR]

The accumulation of monocyte-derived macrophages in the lung tissue during inflammation is important for the pathogenesis of fibrotic lung disease. Deficiencies in chemokine receptors CCR2 and CCR5 and their ligands, which mediate monocyte/macrophage migration, ameliorate bleomycin (BLM)-induced lung fibrosis. Disulfiram (DSF), which is used to treat alcoholism because of its aldehyde dehydrogenase (ALDH)-inhibiting effect, inhibits monocyte/macrophage migration by inhibiting FROUNT, an intracellular regulator of CCR2/CCR5 signalling. Here, we investigated the antifibrotic effect of oral DSF administration in a mouse model of BLM-induced lung fibrosis, focusing on macrophage response and fibrosis progression. The direct inhibitory activity of DSF on monocyte migration was measured using the Boyden chamber assay and compared with that of DSF-related inhibitors with different FROUNT-inhibition activities. Quantitative PCR was used to determine the expression of fibrosis-promoting genes in the lung tissue. DSF significantly suppressed macrophage infiltration into lung tissues and attenuated BLM-induced lung fibrosis. DSF and its metabolites, diethyldithiocarbamate (DDC) and copper diethyldithiocarbamate (Cu(DDC) 2 ), inhibited monocyte migration toward the culture supernatant of primary mouse lung cells mainly comprising CCL2, whereas cyanamide, another ALDH inhibitor, did not. DSF, with higher inhibitory activity against FROUNT than DDC and Cu(DDC) 2 , inhibited monocyte migration most strongly. In BLM-induced fibrotic lung tissues, profibrotic factors were highly expressed but were reduced by DSF treatment. These results suggest DSF inhibits macrophage infiltration, which might be attributed to its inhibitory effect on FROUNT, and attenuates BLM-induced lung fibrosis. In addition, multiplex immunofluorescence imaging revealed reduced infiltration of S100A4 + macrophages into the lungs in DSF-treated mice and high expression of FROUNT in S100A4 + macrophages in idiopathic pulmonary fibrosis (IPF). These findings underscore the potential of macrophage-targeted therapy with DSF as a promising drug repositioning approach for treating fibrotic lung diseases, including IPF., (© 2024. The Author(s).)

Background: Shoseiryuto, a Japanese herbal medicine, is used to treat asthma exacerbation; however, the effect of Shoseiryuto in a clinical setting is yet to be elucidated. We aimed to examine the effect of Shoseiryuto for inpatients with asthma exacerbation and the reduction in the total amount of intravenous steroids administered during hospitalization, in-hospital mortality, and length of hospital stay using a national inpatient database in Japan., Methods: Using data from the Japanese Diagnosis Procedure Combination database (July 2010-March 2022), we identified patients aged ≥18 years who were admitted due to asthma exacerbation. We performed propensity score overlap weighting analyses to estimate the in-hospital outcomes between patients who received Shoseiryuto within 3 days of admission (Shoseiryuto group) and those who did not (control group). The outcomes measured were the dose of intravenous steroids administered, in-hospital mortality, and length of hospital stay for patients alive at discharge., Results: Among 51,459 eligible patients, 131 received Shoseiryuto. In the propensity score overlap weighting analyses, the use of Shoseiryuto was significantly associated with reduced amount of intravenous steroid during hospitalization (67 mg versus 149 mg, 95% confidence interval [CI]: -68 to -92), but was not associated with reduced in-hospital mortality (1.9% versus 3.5%, 95% CI: -28 to 25) or length of hospital stay (17.3 days versus 18.3 days, 95% CI: -4.2 to 2.4)., Conclusions: The use Shoseiryuto in inpatients with asthma exacerbation was significantly associated with reduced steroid use. Our results elucidated the potential role of Shoseiryuto in the treatment of asthma exacerbation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Transbronchial lung cryobiopsy (TBLC) is a new technique for obtaining high-quality and large-sized lung tissues, as compared to transbronchial forceps biopsy (TBFB), and is useful in the diagnosis of diffuse lung disease (DLD). We aimed to evaluate the safety of TBLC as compared to TBFB in DLD patients in Japan using a nationwide database., Methods: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from April 1, 2020 to March 31, 2022. Eligible patients (n = 9673) were divided into the following two groups: those who underwent TBFB (TBFB group, n = 8742) and TBLC (TBLC group, n = 931). To compare the outcomes between the two groups, a stabilized inverse probability of treatment weighting (IPTW) was applied using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, complications (mechanical ventilation, pneumothorax, and bleeding), and length of hospital stay after bronchoscopy., Results: The crude in-hospital mortality rates were 3.2% and 0.9% in the TBFB and TBLC groups, respectively. The stabilized IPTW analysis showed no significant difference in the in-hospital mortality rates between the two groups; the odds ratio of the TBLC group as compared with the TBFB group was 0.73 (95% confidence interval: 0.34-1.60; p = 0.44). Moreover, the secondary outcomes did not significantly differ between the two groups., Conclusions: TBLC for DLD patients had a similar mortality and complication rates as TBFB., Competing Interests: Declaration of competing interest Dr. H. Yasunaga reports receiving grants from the Ministry of Health, Labor, and Welfare, Japan and the Ministry of Education, Culture, Sports, Science, and Technology, Japan during the conduct of the study. The other authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The association between reflux esophagitis and pulmonary function remains controversial. Thus, evaluating the relationship between endoscopic reflux esophagitis and changes in pulmonary function over time in a nonsmoking population is an important clinical issue., Methods: In this single-center retrospective cohort study, a medical examination database at Kameda Medical Center Makuhari was employed to identify nonsmokers who underwent upper gastrointestinal endoscopy and spirometry in 2010 and were followed up in 2015. Gastroenterologists carefully double-checked the diagnosis of reflux esophagitis. Multiple linear regression analyses were performed to compare the decline in the percentage of predicted vital capacity (%VC), forced vital capacity (%FVC), and forced expiratory volume in 1 s (%FEV 1 ) between participants with reflux esophagitis and those without. Furthermore, using multivariable logistic regression analyses, we evaluated the factors associated with rapid decline in %VC, %FVC, and %FEV 1 , which is defined as a decrease of >10% in each parameter over the 5-year observation period., Results: We identified 3098 eligible subjects, including 72 and 44 participants who had a Los Angeles classification grade A and B-C (severe) reflux esophagitis in 2010, respectively. The decline in %VC was significantly larger in the participants with severe reflux esophagitis than in the control subjects (standardized coefficient, -0.037; 95% confidence interval, -0.071 to -0.004). Moreover, reflux esophagitis was significantly associated with a rapid decline in %VC and %FVC but not in %FEV 1 (P for trend: 0.009, 0.009, and 0.276, respectively)., Conclusions: Severe reflux esophagitis among nonsmokers had clinical disadvantages in terms of a decline in %VC., (Copyright © 2024. Published by Elsevier B.V.)

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68 + or CD3 + cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yoshiyasu, Matsuki, Sato, Urushiyama, Toda, Terasaki, Suzuki, Shinozaki-Ushiku, Terashima and Nakajima.)

Objective The effect of Rikkunshito, a Japanese herbal Kampo medicine, on chemotherapy-induced nausea and vomiting (CINV) has been evaluated in several small prospective studies, with mixed results. We retrospectively evaluated the antiemetic effects of Rikkunshito in patients undergoing cisplatin-based chemotherapy using a large-scale database in Japan. Methods The Diagnosis Procedure Combination inpatient database from July 2010 to March 2019 was used to compare adult patients with malignant tumors who had received Rikkunshito on or before the day of cisplatin administration (Rikkunshito group) and those who had not (control group). Antiemetics on days 2 and 3 and days 4 and beyond following cisplatin administration were used as surrogate outcomes for CINV. Patient backgrounds were adjusted using the stabilized inverse probability of treatment weighting, and outcomes were compared using univariable regression models. Results We identified 669 and 123,378 patients in the Rikkunshito and control groups, respectively. There were significantly fewer patients using intravenous 5-HT 3 -receptor antagonists in the Rikkunshito group (odds ratio, 0.38; 95% confidence interval, 0.16-0.87; p=0.023) on days 2 and 3 of cisplatin-based chemotherapy. Conclusion The reduced use of antiemetics on day 2 and beyond of cisplatin administration suggested a beneficial effect of Rikkunshito in palliating the symptoms of CINV.

Aim: Behavioral and psychological symptoms and delirium frequently occur in hospitalized older patients with pneumonia and are associated with longer hospital stays. Yokukan-San (YKS, traditional Japanese [Kampo] medicine) and antipsychotics are often used to treat delirium and behavioral and psychological symptoms in Japan. Hence, this study aimed to assess the effectiveness and safety of the co-administration of YKS with atypical antipsychotics in older patients with pneumonia., Methods: We used the Japanese Diagnosis Procedure Combination inpatient database to retrospectively identify older patients (≥65 years) hospitalized for pneumonia who received antipsychotics within 3 days of hospitalization. The patients were divided into two groups: those who received atypical antipsychotics alone (control group) and those who received both atypical antipsychotics and YKS (YKS group). We compared length of hospital stay, in-hospital mortality, bone fractures, and administration of potassium products between the two groups using propensity score overlap weighting., Result: We identified 4789 patients in the YKS group and 61 641 in the control group. After propensity score overlap weighting, length of hospital stay was statistically significantly shorter in the YKS group (percentage difference -3.0%; 95% confidence interval -5.8% to -0.3%). The proportion of patients who received potassium products was higher in the YKS group (odds ratio 1.34; 95% confidence interval 1.15-1.55). In-hospital death and bone fractures were not significantly different., Conclusion: Co-administration of YKS with atypical antipsychotics could be a reasonable treatment option for hospitalized older patients with pneumonia and aggressive psychiatric symptoms. Geriatr Gerontol Int 2023; 23: 849-854., (© 2023 Japan Geriatrics Society.)

Background: Interstitial lung diseases (ILDs) are a group of diffuse parenchymal lung disorders that cause inflammation and fibrosis in the interstitium of the lungs. Histopathological examination is pivotal to accurately diagnose the type of ILD, and bronchoscopy (BS) is often performed to collect lung tissue. This study aimed to determine the relationship between hospital volume and outcomes following BS in patients with ILD., Methods: Inpatient data on patients with ILD who underwent BS between July 1, 2010 and March 31, 2021 were extracted from the Japanese Diagnosis Procedure Combination database. The annual hospital volume of BS was categorized into four (very low- [≤15 cases/year], low- [16-29 cases/year], high- [30-54 cases/year], and very high- [≥55 cases/year] volume) groups. The primary outcome was all-cause 14-day mortality after BS. Multiple imputation methods followed by multivariable logistic regression analyses fitted with generalized estimating equations were used to estimate the association between hospital volume and 14-day mortality after BS., Results: A total of 89,454 patients with ILD from 1002 hospitals underwent BS. The all-cause mortality within 14 days after BS was 0.77%. An inverse trend was observed between mortality and hospital volume. Compared with the very low-hospital volume group, the very high-hospital volume group was significantly associated with a lower mortality (adjusted odds ratio = 0.63, 95% confidence interval: 0.48-0.85, p = 0.002)., Conclusions: Hospital volume was inversely associated with all-cause mortality within 14 days after BS for hospitalized patients with ILD., Competing Interests: Conflict of Interest Dr. H. Yasunaga reports receiving grants from the Ministry of Health, Labor, and Welfare, Japan and the Ministry of Education, Culture, Sports, Science, and Technology, Japan during the conduct of the study. The other authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The prognosis for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is poor, and there is no established treatment. Hence, we aimed to investigate the effectiveness of a polymyxin B-immobilised fibre column (PMX) for the treatment of AE-IPF., Methods: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from 1 July 2010 to 31 March 2018. We identified adult patients with idiopathic pulmonary fibrosis who received high-dose methylprednisolone (mPSL) therapy and mechanical ventilation upon admission. Eligible patients (n = 5616) were divided into those receiving PMX treatment combined with high-dose mPSL (PMX group, n = 199) and high-dose mPSL alone (mPSL alone group, n = 5417). To compare outcomes between the two groups, we applied a stabilised inverse probability of treatment weighting (IPTW) using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 14- and 28-day mortality and length of hospital stay., Results: The in-hospital mortality rates of the PMX and mPSL alone groups were 79.9% and 76.4%, respectively. The results did not significantly differ between the two groups after performing a stabilised IPTW. The odds ratio of the PMX group compared with the mPSL alone group was 1.56 (95% confidence interval 0.80-3.06; p = 0.19). The 14- and 28-day mortality and length of hospital stay (secondary outcomes) also did not significantly differ between the two groups., Conclusions: In AE-IPF patients using mechanical ventilation, the treatment outcome was not significantly better for PMX combined with high-dose mPSL than for high-dose mPSL alone., (© 2023. The Japanese Society of Intensive Care Medicine.)

Background: Validating the information recorded in administrative databases is essential. However, no study has comprehensively validated the accuracy of Japanese Diagnosis Procedure Combination (DPC) data on various respiratory diseases. Therefore, this study aimed to evaluate the validity of diagnoses of respiratory diseases in the DPC database., Methods: We conducted chart reviews of 400 patients hospitalized in the departments of respiratory medicine in two acute-care hospitals in Tokyo, between April 1, 2019 and March 31, 2021, and used them as reference standards. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DPC data on 25 respiratory diseases were determined., Results: Sensitivity ranged from 22.2% (aspiration pneumonia) to 100% (chronic eosinophilic pneumonia and malignant pleural mesothelioma) and was <50% for eight diseases, while specificity was >90% for all diseases. PPV ranged from 40.0% (aspiration pneumonia) to 100% (coronavirus disease 2019, bronchiectasis, chronic eosinophilic pneumonia, pulmonary hypertension, squamous cell carcinoma, small cell carcinoma, lung cancer of other histological types, and malignant pleural mesothelioma) and was >80% for 16 diseases. Except for chronic obstructive pulmonary disease (82.9%) and interstitial pneumonia (other than idiopathic pulmonary fibrosis) (85.4%), NPV was >90% for all diseases. These validity indices were similar in both hospitals., Conclusions: The validity of diagnoses of respiratory diseases in the DPC database was high in general, thereby providing an important basis for future studies., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Acute exacerbation is a life-threatening event in patients with fibrosing interstitial lung diseases (ILDs). Although nintedanib reduces acute exacerbation incidence, its effectiveness during acute exacerbation is unclear., Methods: Using data from the Diagnosis Procedure Combination database (September 2015-March 2020) in Japan, we identified patients with fibrosing ILDs who received intravenous injection of high-dose corticosteroid within 3 days post-admission and analysed their first hospitalisation. We performed overlap propensity score weighting to compare in-hospital outcomes between patients who received nintedanib within 14 days post-admission and those who did not. The primary and secondary outcomes were in-hospital mortality and length of hospitalisation in the patients discharged alive, respectively., Results: Among the 6235 identified patients, 353 patients received nintedanib within 14 days post-admission. In-hospital mortality occurred in 13.7% and 6.0% patients in the control (n=5882) and nintedanib-treated (n=353) patients, respectively. The mean length of hospitalisation was 39.9 and 30.4 days in the control and nintedanib-treated patients, respectively. After overlap propensity score weighting, nintedanib treatment was significantly associated with lower in-hospital mortality in the adjusted cohort (OR 0.43, 95% CI 0.27-0.70; p=0.001). The mean length of hospitalisation in nintedanib-treated patients (30.7 days) was significantly shorter than that in the control group (37.5 days; p<0.001)., Conclusions: Nintedanib initiation during acute exacerbation was significantly associated with a lower risk of in-hospital death and shorter length of hospitalisation in patients with fibrosing ILDs. Our results elucidate the potential role of nintedanib in the treatment of acute exacerbation in patients with fibrosing ILDs. Further prospective studies are warranted., Competing Interests: Conflict of interest: All authors declare no conflicts of interest related to this study., (Copyright ©The authors 2022.)

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1, and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3, and H3K27ac) by CUT&Tag assay and ASCL1 knockdown followed by RNA sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs, such as miR-7, miR-375, miR-200b-3p, and miR-429, leading to repression of their targets, whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC (e.g., co-targeting of YAP1 by miR-9 and miR-375). Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Acute exacerbation of idiopathic interstitial pneumonias (AE-IIPs) has a high mortality. However, there is no established treatment for AE-IIPs. Therefore, we aimed to compare the efficacy of high- and low-dose corticosteroid therapies in AE-IIPs patients., Methods: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from July 2010 to March 2018. Adult patients with AE-IIPs who received high-dose (methylprednisolone at a dose of 500-1000 mg/day for 3 days starting within 4 days after admission) or low-dose (methylprednisolone at a dose of 100-200 mg/day for at least 5 days starting within 4 days after admission) corticosteroid therapy were identified. Eligible patients (n = 17,317) were divided into the high-dose (n = 16,998) and low-dose (n = 319) groups. A stabilized inverse probability of treatment weighting using propensity scores was performed to compare outcomes between the groups., Results: The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, infections during hospitalization, length of hospitalization, duration of steroid use, and discharge to home. The in-hospital mortality rates of the high- and low-dose corticosteroid groups were 50.6% and 47.0%, respectively. In-hospital mortality did not significantly differ between the two groups after stabilized inverse probability of treatment weighting, and the odds ratio in the low-dose corticosteroid group was 0.86 (95% confidence interval: 0.64-1.16; p = 0.33). The secondary outcomes also did not significantly differ between the groups., Conclusions: There was no significant difference in outcomes between patients with AE-IIPs who received high- and low-dose corticosteroid therapies., Competing Interests: T.J. received research funds from Tsumura. H.Y. received research grants from the Ministry of Health, Labour and Welfare, Japan (21AA2007 and 20AA2005) and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (20H03907). The funding bodies had no role in the design of the study; collection, analysis, or interpretation of the data; or writing of the manuscript., (© 2023 Society for Clinical Epidemiology.)

Background: Standardized uptake values (SUVs) derived from 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) are valuable but insufficient for detecting lung allograft rejection (AR). Using a rat lung transplantation (LTx) model, we investigated correlations of AR with the SUV max and PET-derived radiomics and further evaluated the performance of machine learning (ML)-based radiomics for monitoring AR., Methods: LTx was performed on 4 groups of rats: isograft, allograft-cyclosporine continuous (CsA cont ), allograft-CsA delayed , and allograft-CsA 1week . Each rat underwent 18 F-FDG PET at week 3 or 6. The SUV max and radiomic features were extracted from the PET images. Least absolute shrinkage and selection operator regression was used to construct a radiomics score (Rad-score). Ten modeling algorithms with 7 feature selection methods were performed to develop 70 radiomics models (49 ML models and 21 logistic regression models) for monitoring AR, validated using the bootstrap method., Results: In total, 837 radiomic features were extracted from each PET image. The SUV max and Rad-score showed significant positive correlations with histopathology (p < .05). The area under the curve (AUC) of SUV max for detecting AR was 0.783. The median AUC of ML models was 0.921, which was superior to that of logistic regression models (median AUC, 0.721). The optimal ML model using a random forest modeling algorithm with random forest feature selection method exhibited the highest AUC of 0.982 (95% confidence interval, 0.875-1.000) in all models., Conclusions: SUV max provided a good correlation with AR, but ML-based PET radiomics further strengthened the power of 18 F-FDG PET functional imaging for monitoring AR in LTx., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the leading cause of death among patients with IPF. However, there is no established treatment for this condition. Hence, we aimed to investigate the effectiveness and safety of recombinant human soluble thrombomodulin (rTM) for the treatment of AE-IPF., Methods: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from 1 January 2014 to 31 March 2018. We identified adult patients with IPF who received high-dose methylprednisolone (mPSL) therapy and mechanical ventilation upon admission. Eligible patients (n = 2814) were divided into those receiving high-dose mPSL alone (mPSL alone group, n = 2602) and rTM combined with high-dose mPSL (rTM group, n = 212). A stabilised inverse probability of treatment weighting (IPTW) using propensity scores was performed to compare outcomes between the two groups. The primary outcome was in-hospital mortality, and the secondary outcomes were 14- and 28-day mortality, bleeding events and length of hospital stay., Results: The in-hospital mortality rates of the mPSL alone and rTM groups were 75.9% and 76.9%, respectively. The results did not significantly differ between the two groups after performing a stabilised IPTW. The odds ratio of the rTM group compared to the mPSL alone group was 1.15 (95% confidence interval: 0.71-1.84; p = 0.57). Moreover, the secondary outcomes did not differ significantly between the two groups., Conclusions: In patients with AE-IPF who developed severe respiratory failure, rTM in addition to high-dose mPSL was not associated with a better outcome., (© 2022. The Author(s).)

Introduction: Information on drug-induced interstitial lung disease (DILD) is limited due to its low incidence. This study investigated the frequencies of drug categories with potential risk in patients developing DILD during hospitalisation and analysed the risk of developing DILD associated with each of these drugs., Methods: Using a Japanese national inpatient database, we identified patients without interstitial pneumonia on admission who developed DILD and required corticosteroid therapy during hospitalisation from July 2010 to March 2016. We conducted a nested case-control study; four controls from the entire non-DILD patient cohort were matched to each DILD case on age, sex, main diagnosis, admission year and hospital. We defined 42 classified categories of drugs with 216 generic names as drugs with potential risk of DILD, and we identified the use of these drugs during hospitalisation for each patient. We analysed the association between each drug category and DILD development using conditional logistic regression analyses., Results: We retrospectively identified 2342 patients who developed DILD. After one-to-four case-control matching, 1541 case patients were matched with 5677 control patients. Six drug categories were significantly associated with the increased occurrence of DILD. These included epidermal growth factor receptor inhibitors (OR: 16.84, 95% CI 9.32 to 30.41) and class III antiarrhythmic drugs (OR: 7.01, 95% CI 3.86 to 12.73). Statins were associated with reduced risk of DILD (OR: 0.68, 95% CI 0.50 to 0.92)., Conclusions: We demonstrated significant associations between various drug categories and DILD. Our findings provide useful information on drug categories with potential risk to help physicians prevent and treat DILD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes. Cancer cells undergo EMT to acquire malignant features and TGF-β is a key regulator of EMT. Here, we demonstrate for the first time that TGF-β could elicit EMT in a mouse lung adenocarcinoma cell line. TGF-β signaling activation led to cell morphological changes corresponding to EMT and enhanced the expression of mesenchymal markers and EMT-associated transcription factors in CMT64 lung cancer cells. RNA-sequencing analyses revealed that TGF-β increases expression of Tead transcription factors and an array of Tead2 target genes. TGF-β stimulation also resulted in alternative splicing of several genes including Cd44, tight junction protein 1 (Tjp1), and Cortactin (Cttn). In parallel with EMT, TGF-β enhanced cell growth of CMT64 cells and promoted tumor formation in a syngeneic transplantation model. Of clinical importance, the expression of TGF-β-induced genes identified in CMT64 cells correlated with EMT gene signatures in human lung adenocarcinoma tissue samples. Furthermore, TGF-β-induced gene enrichment was related to poor prognosis, underscoring the tumor-promoting role of TGF-β signaling in lung adenocarcinoma. Our cellular and syngeneic transplantation model would provide a simple and useful experimental tool to study the significance of TGF-β signaling and EMT., (© 2021. The Author(s).)

Living-donor lobar lung transplantation is often indicated for acute exacerbation of idiopathic interstitial pneumonia because of the long waiting time for cadaveric lung transplantation in Japan. Donors without major underlying diseases are selected after medical screening. A 44-year-old man donated his right lower lobe to his sibling with idiopathic interstitial pneumonia. Although he was free of any major medical problems before transplantation, fibrotic changes appeared in both the donated lung and the donor's remaining lungs in a case of familial interstitial pneumonia. For living-donor lobar lung transplantation for idiopathic interstitial pneumonia, donor candidates should be informed of the potential issue of a familial disease., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Transfusion-related acute lung injury (TRALI) is a severe condition characterised by noncardiogenic pulmonary oedema that develops within 6 h of blood transfusion. Patient factors and blood products have both been implicated in the development of TRALI; however, the role of pulmonary disease has not been investigated. We aimed to determine whether pulmonary disease is a risk factor for TRALI. We conducted a nested case-control study using data from the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan, between July 2010 and March 2015. Case patients who developed TRALI were 1:4-matched with control patients for sex, age and same hospital for receipt of blood transfusion. We conducted a multivariable conditional logistic regression analysis to evaluate the associations of TRALI with various factors including comorbidities, body mass index (BMI) and plasma-containing blood products. We identified 2 019 501 hospitalised patients who received a blood transfusion. Among these patients, 72 developed TRALI. The 72 case patients had higher proportions of haematological malignancy, trauma and interstitial lung disease (ILD) than the 288 matched control patients. The multivariable conditional logistic regression analysis showed that occurrence of TRALI was associated with ILD (odds ratio, 3.88; 95% confidence interval, 1.11-13.6), BMI ≥25.0 kg·m -2 (2.10; 1.05-4.24) and plasma-containing blood products (1.94; 1.10-3.42), but not with infectious lung disease or obstructive airway disease. In conclusion, ILD was an independent risk factor for the development of TRALI. Physicians should be aware of the increased risk of TRALI in patients with ILD., Competing Interests: Conflict of interest: A. Yokoyama has nothing to disclose. Conflict of interest: Y. Sakamoto has nothing to disclose. Conflict of interest: T. Jo received consigned research funding from Tsumura & Co. and belongs to a laboratory that is a joint programme with Tsumura & Co. Conflict of interest: H. Urushiyama has nothing to disclose. Conflict of interest: H. Tamiya has nothing to disclose. Conflict of interest: G. Tanaka has nothing to disclose. Conflict of interest: H. Matsui has nothing to disclose. Conflict of interest: K. Fushimi has nothing to disclose. Conflict of interest: H. Yasunaga reports grants from Ministry of Health, Labour and Welfare, Japan, during the conduct of the study. Conflict of interest: T. Nagase has nothing to disclose., (Copyright ©The authors 2021.)

Background and Objective: Patients with idiopathic pulmonary fibrosis (IPF) often develop postoperative severe respiratory complications such as acute exacerbation. Pirfenidone, an oral anti-fibrotic drug, may reduce the incidence of such complications. However, the preventive effect of pirfenidone on postoperative severe respiratory complications remains unclear., Methods: We identified patients with IPF who underwent surgery with general anaesthesia from July 2010 to March 2018 using the Diagnosis Procedure Combination database. We compared the occurrence of postoperative severe respiratory complications (receiving mechanical ventilation under endotracheal intubation and/or intravenous infusion of a high-dose corticosteroid and in-hospital death within 30 days after surgery) between patients who did and did not receive preoperative treatment with pirfenidone. Pearson's chi-square test and logistic regression analysis fitted with a generalized estimating equation were conducted in 1:4 propensity score-matched patients., Results: Among 631 patients identified, 19% were treated with pirfenidone before surgery. The 30-day mortality rate was 3.1% and 1.7% in the control patients (n = 510) and pirfenidone-treated patients (n = 121), respectively. In the propensity score-matched population, preoperative treatment with pirfenidone was significantly associated with a lower proportion of postoperative severe respiratory complications (OR: 0.24; 95% CI: 0.07-0.76; p = 0.015)., Conclusion: In this Japanese nationwide cohort, preoperative treatment with pirfenidone was significantly associated with a lower risk of postoperative severe respiratory complications in patients with IPF. Preoperative pirfenidone may thus be useful in preventing postoperative severe respiratory complications in patients with IPF who are planning to undergo surgery with general anaesthesia., (© 2021 Asian Pacific Society of Respirology.)

Background: The number of people with lifestyle-related diseases continues to increase worldwide. Improving lifestyle behavior with health literacy may be the key to address lifestyle-related diseases. The delivery of educational videos using mobile health (mHealth) services can replace the conventional way of educating individuals, and visualization can replace the provision of health checkup data., Objective: This paper aimed to describe the development of educational content for MIRAMED, a mobile app aimed at improving users' lifestyle behaviors and health literacy for lifestyle-related diseases., Methods: All videos were based on a single unified framework to provide users with a consistent flow of information. The framework was later turned into a storyboard. The final video contents were created based on this storyboard and further discussions with leading experts and specialist physicians on effective communication with app users about lifestyle-related diseases., Results: The app uses visualization of personal health checkup data and educational videos on lifestyle-related diseases based on the current health guidelines, scientific evidence, and expert opinions of leading specialist physicians in the respective fields. A total of 8 videos were created for specific lifestyle-related diseases affecting 8 organs: (1) brain-cerebrovascular disorder, (2) eyes-diabetic retinopathy, (3) lungs-chronic obstructive pulmonary disease, (4) heart-ischemic heart disease, (5) liver-fatty liver, (6) kidneys-chronic kidney disease (diabetic kidney disease), (7) blood vessels-peripheral arterial disease, and (8) nerves-diabetic neuropathy., Conclusions: Providing enhanced mHealth education using novel digital technologies to visualize conventional health checkup data and lifestyle-related diseases is an innovative strategy. Future studies to evaluate the efficacy of the developed content are planned., (©Azusa Aida, Thomas Svensson, Akiko Kishi Svensson, Hirokazu Urushiyama, Kazuya Okushin, Gaku Oguri, Naoto Kubota, Kazuhiko Koike, Masaomi Nangaku, Takashi Kadowaki, Toshimasa Yamauchi, Ung-Il Chung. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 21.10.2020.)

Introduction: Patients with interstitial lung disease (ILD) are known to develop an acute exacerbation (AE) after surgery. Previous studies have evaluated the predictors of postoperative AE. However, it remains unclear whether the results of those studies can be generalised to patients with different types of ILD and/or extrapolated to those who undergo non-pulmonary surgery. This study aimed to elucidate the predictors of the development of AE after surgery with general anaesthesia in patients with ILD., Methods: We conducted a nested matched case-control study of 700 patients from an initial cohort of 50 840 patients. We excluded those who underwent solid organ or bone marrow transplantation. The cases were patients with ILD who developed AE within 30 days postoperatively, whereas the controls did not develop AE. Each case (n=28) was matched with four controls (n=112) for sex, year of surgery and multiple operations within 30 days. Furthermore, a multivariable conditional logistic regression analysis was used to identify significant predictors, as indicated by a p value of <0.05., Results: After adjusting for potential confounders, the multivariable conditional logistic regression analysis identified honeycombing on CT (OR 3.09; 95% CI 1.07 to 8.92), a per cent predicted FVC <80% (OR 4.21; 95% CI 1.46 to 12.2) and an ARISCAT score ≥45 (OR 6.14; 95% CI 2.10 to 18.0) significantly associated with the development of postoperative AE., Conclusions: We found that the three factors were independent predictors for the development of postoperative AE in patients with ILD. These predictors are advantageous because they can be readily evaluated before surgery by surgeons and anaesthesiologists even without consulting experienced pulmonologists., Competing Interests: Competing interests: KU reports grants from Nihon Kohden Corporation, grants from Nipro Medical Corporation, outside the submitted work. The other authors have no conflict of interest with any companies and/or organisations whose products or services may be discussed in this study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8 + , CD4 + , CD20 + , and FOXP3 + lymphocytes and CD163 + macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Localization of inflammatory stimuli may direct lung allografts to different phenotypes of chronic dysfunction, such as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). We hypothesized that airway stimulation with lipopolysaccharide (LPS) in rats leads to airway-centered inflammation similar to human BOS., Methods: Rat left lung transplantation was conducted (donor: Brown Norway, recipient: Lewis). Allotransplant recipients received cyclosporine A (CsA) until postoperative day 56 with airway instillation of LPS (Allo-LPS, n = 8), phosphate buffered saline (Allo-PBS, n = 5) from days 35 to 46 (3 times a wk), or no further treatment (n = 4). Some allotransplant recipients received CsA until day 14 and were immunosuppression free after day 15 until day 56. Bronchial and pleural fibrosis were semiquantified; alveolar fibrosis was evaluated with a histological scale., Results: The Allo-LPS group had significantly increased International Society for Heart and Lung Transplantation rejection grades (grade A, P = 0.005; grade B, P = 0.004), bronchial obstructive proportion (0.34 ± 0.04% [Allo-LPS] versus 0.11 ± 0.04% [Allo-PBS], P = 0.006), and airway resistance (3.05 ± 1.78 cm H2O·s/mL [Allo-LPS] versus 0.83 ± 0.58 cm H2O·s/mL [Allo-PBS], P = 0.007) compared with other groups. Allotransplant recipients that underwent a short course of CsA developed RAS-like fibrosis involving the airways, alveoli, and pleura., Conclusions: Airway instillation of LPS in allografts under immunosuppression resulted in BOS-like airway-centered inflammation and fibrosis distinct from RAS-like diffuse fibrosis, which was induced by a shortened course of immunosuppression. We propose novel animal models for BOS and RAS after lung transplantation.

TAZ (transcriptional coactivator with PDZ-binding motif) and YAP (Yes-associated protein) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their roles during lung development remain unknown. We aimed to investigate YAP and TAZ functions using lung epithelium-specific Taz and Yap conditional knockout mice. We generated lung epithelium-specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Shh (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-β (transforming growth factor-β) stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. Our results provide a novel insight into the molecular mechanisms underlying lung development and contribute to a better understanding of the characteristics of TAZ and YAP.

Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II-induced polyarthritis and anti-cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H 2 ) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species-induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H 2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H 2 -rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8-hydroxy-2'-deoxyguanosine-positive cell numbers and tumour necrosis factor-α, BAX, transforming growth factor-β, interleukin-6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H 2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H 2 treatment and chronic interstitial pneumonia pathophysiology in humans. H 2 appears to protect against RA-ILD by alleviating oxidative stress., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.

Single crystals of (Na/Sr)-(Ga/Si) quaternary type-I clathrates, Na 8- y Sr y Ga x Si 46- x , were synthesized by evaporating Na from a mixture of Na-Sr-Ga-Si-Sn in a 6 : 0.5 : 1 : 2 : 1 molar ratio at 773 K for 12 h in an Ar atmosphere. Electron-probe microanalysis and single-crystal X-ray diffraction revealed that three crystals from the same product were Na 8- y Sr y Ga x Si 46- x with x and y values of 7.6, 2.96; 8.4, 3.80; and 9.1, 4.08. It was also shown that increasing the Sr and Ga contents increased the electrical resistivity of the crystal from 0.34 to 1.05 mΩ cm at 300 K., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts., Methods: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively., Results: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26., Conclusions: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Recent advances in bronchoscopy utilizing endobronchial ultrasound (EBUS) as well as lung cancer therapy may have driven physicians to perform diagnostic bronchoscopy (DB) for high-risk patients., Objectives: The aim of this study was to clarify the relationship between hospital volume (HV) and outcomes of DB., Methods: We collected data on inpatients with lung cancer who underwent DB from July 2010 to March 31, 2014. The annual HV of DB was classified as "very low" (≤50 cases/year), "low" (51-100 cases/year), "high" (101-300 cases/year), or "very high" (> 300 cases/year). The primary outcome was all-cause 7-day mortality after DB. Multivariable logistic regression fitted with a generalized estimation equation was performed to evaluate the association between HV and all-cause 7-day mortality after DB, adjusted for patient background factors., Results: We identified a total of 77,755 eligible patients in 954 hospitals. All-cause 7-day mortality was 0.5%. Compared with the low-volume group, 7-day mortality was significantly lower in the high-volume group (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.52-0.92, p = 0.010), and a similar trend was shown in the very-high-volume group (OR = 0.67; 95% CI: 0.43-1.05, p = 0.080). Radial EBUS with the guide sheath method and EBUS-guided transbronchial needle aspiration showed a significantly lower 7-day mortality., Conclusions: All-cause 7-day mortality was inversely associated with HV. The risk of DB in patients with lung cancer should be recognized, and the exploitation of EBUS may help reduce mortality after DB., (© 2018 S. Karger AG, Basel.)

Single crystals of a Na-Ga-Si clathrate, Na 8 Ga 5.70 Si 40.30 , of size 2.9 mm were grown via the evaporation of Na from a Na-Ga-Si melt with the molar ratio of Na : Ga : Si = 4 : 1 : 2 at 773 K for 21 h under an Ar atmosphere. The crystal structure was analyzed using X-ray diffraction with the model of the type-I clathrate (cubic, a = 10.3266(2) Å, space group Pm 3̄ n , no. 223). By adding Sn to a Na-Ga-Si melt (Na : Ga : Si : Sn = 6 : 1 : 2 : 1), single crystals of Na 8 Ga x Si 46- x ( x = 4.94-5.52, a = 10.3020(2)-10.3210(3) Å), with the maximum size of 3.7 mm, were obtained via Na evaporation at 723-873 K. The electrical resistivities of Na 8 Ga 5.70 Si 40.30 and Na 8 Ga 4.94 Si 41.06 were 1.40 and 0.72 mΩ cm, respectively, at 300 K, and metallic temperature dependences of the resistivities were observed. In the Si L 2,3 soft X-ray emission spectrum of Na 8 Ga 5.70 Si 40.30 , a weak peak originating from the lowest conduction band in the undoped Si 46 was observed at an emission energy of 98 eV., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Adjuvant chemotherapy with vinorelbine plus cisplatin (VNR/CDDP) is a standard regimen for treatment of postoperative stage II-IIIA non-small cell lung cancer (NSCLC). However, oral fluorouracil offers a feasible alternative adjuvant chemotherapeutic regimen. We compared the prognoses of patients with NSCLC treated with adjuvant chemotherapy with either VNR/CDDP or oral fluorouracil., Methods: We identified patients with stage II-IIIA NSCLC who underwent lung surgery followed by adjuvant chemotherapy with VNR/CDDP (n = 384) or oral fluorouracil (n = 268) between July 2010 and March 2015, using the national Japanese inpatient and outpatient Diagnosis Procedure Combination database. We compared recurrence-free survival between the groups by multivariable Cox regression analysis for one-to-one propensity score-matched patients and by instrumental variable analysis., Results: Younger patients and patients with positive N2 nodes were more likely to receive VNR/CDDP, while older patients and those with T3N0 classification were more likely to receive oral fluorouracil. Among 172 pairs of propensity-matched patients, time to adjuvant chemotherapy was shorter for oral fluorouracil compared with VNR/CDDP. Oral fluorouracil was also significantly associated with improved recurrence-free survival compared with VNR/CDDP, according to multivariable Cox regression analysis (hazard ratio, 0.41; 95% confidence interval, 0.26-0.64). Instrumental variable analysis showed a similar relationship (hazard ratio, 0.19; 95% confidence interval, 0.038-0.92)., Conclusions: On a large nationwide cohort, adjuvant chemotherapy with oral fluorouracil prolonged recurrence-free survival in patients with postoperative stage II-IIIA NSCLC, compared with VNR/CDDP. Oral fluorouracil may thus be a useful alternative to VNR/CDDP for the adjuvant treatment of these patients., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Irinotecan hydrochloride (CPT-11) is used to treat a wide spectrum of malignant tumors. Hangeshashin-to (Japanese herbal medicine TJ-14) is reportedly effective in preventing and controlling diarrhea associated with CPT-11. However, the effect of TJ-14 on tolerability of chemotherapy with CPT-11 has not been fully investigated. We used the Japanese Diagnosis Procedure Combination inpatient database to retrospectively identify patients who had received CPT-11 on their first admission with and without TJ-14. Patients who did receive TJ-14 ( N = 7092) received CPT-11 more often and in larger doses than those who did not receive TJ-14 ( N = 82,019). The incidence rate ratio of CPT-11 administration was 1.34 for frequency (95% confidence interval [CI], 1.31⁻1.38; p < 0.001), and 1.16 for total dose (95% CI, 1.14⁻1.19; p < 0.001) according to stabilized inverse probability treatment weighting using propensity scores. Instrumental variable analysis showed similar trends. In-hospital mortality was significantly lower in patients who received TJ-14 than in those who did not. Odds ratios of in-hospital death in patients receiving TJ-14 was 0.81 (95% CI, 0.71⁻0.93; p = 0.002) according to stabilized inverse probability treatment weighting using propensity scores and 0.42 (95% CI, 0.22⁻0.81; p = 0.009) according to instrumental variable analysis. Our findings indicate that TJ-14 improve the tolerability of CPT-11.

An association between chemotherapy and venous thromboembolic events (VTEs) in patients with cancer is well established, with cisplatin (CDDP) being one of the most well-studied risk factors. However, whether CDDP is more strongly associated with occurrence of VTEs than carboplatin (CBDCA) or nedaplatin (CDGP) is controversial. Our purposes were to characterize patients with lung cancer and in-hospital VTEs, identify risk factors associated with VTEs, and compare the risks associated with CDDP-based versus CBDCA/CDGP-based chemotherapy. We retrospectively identified patients with lung cancer who underwent platinum-based chemotherapy from April 2012 to March 2015 from a national inpatient database in Japan. We used multivariable logistic regression analysis to analyze associations between various factors, including chemotherapy regimens and VTE. Of 235 104 eligible patients, 675 (0.29%) had VTEs after receiving platinum-based chemotherapy while hospitalized. Multivariable analysis showed that age, activity of daily living index, and invasive medical procedures were significant risk factors for the occurrence of VTE. Furthermore, CDDP-based chemotherapy was associated with a higher rate of VTE than CBDCA/CDGP-based chemotherapy (adjusted odds ratio: 1.35; 95% confidence interval: 1.08-1.68; P<0.01). In conclusion, CDDP-based chemotherapy is a stronger risk factor for VTEs than CBDCA/CDGP-based chemotherapy in patients with lung cancer.

A malignant tumor can cause hypercoagulation and it also often coexists with thrombosis. Cisplatin-based chemotherapy can also induce adverse vascular effects, including arterial thrombosis. We herein report a case of acute arterial thrombosis in a patient undergoing postoperative adjuvant cisplatin-based chemotherapy for completely resected lung cancer. The patient complained of acute leg pain after chemotherapy, and computed tomography revealed multiple thrombi from the thoracic to popliteal arteries. Arterial thrombosis during adjuvant chemotherapy is extremely rare; however, careful clinical observation of patients receiving cisplatin-based chemotherapy is important, because arterial thrombosis, even in the absence of the primary malignant tumor, is possible.

Background: Asthma is a chronic airway inflammatory disease characterized by airway remodeling, in which the bronchial smooth muscle (BSM) cells play an important role. Periostin, a biomarker that reflects Th2-driven inflammatory diseases such as asthma, may play an important role in the asthmatic airway. Although periostin is mainly produced in airway epithelial cells and fibroblasts after interleukin (IL)-13 stimulation, whether BSM cells produce periostin remains unclear. Therefore, we investigated periostin production in BSM cells and the mechanisms involved., Methods: Human BSM cells were cultured, and the effect of IL-13 stimulation on periostin production was evaluated using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). We evaluated the phosphorylation of signal transducer and activator of transcription factor 6 (STAT6), extracellular signal-regulated kinase (ERK)1/2, and Akt after IL-13 stimulation. Furthermore, using ELISA, we evaluated the influence of several phosphorylation inhibitors on periostin production., Results: Periostin mRNA expression increased in a dose- and time-dependent manner after IL-13 stimulation; periostin production was induced 24 and 48 h after stimulation. IL-13 stimulation induced the phosphorylation of STAT6, ERK1/2, and Akt. IL-13-induced periostin production was attenuated by inhibiting STAT6 phosphorylation and strongly suppressed by inhibiting mitogen-activated protein kinase kinase 1/2 phosphorylation or phosphatidylinositol 3-kinase (PI3K) phosphorylation., Conclusions: BSM cells produced periostin after IL-13 stimulation, via the JAK/STAT6, ERK1/2, and PI3K/Akt pathways. Understanding the mechanism of periostin production in BSM cells may help to clarify asthma pathogenesis., (© 2018 S. Karger AG, Basel.)