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To predict grade ≥ 2 radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (NSCLC) using multi-region radiomics analysis. Data from 77 patients with NSCLC who underwent definitive radiotherapy between 2008 and 2018 were analyzed. Radiomic feature extraction from the whole lung (whole-lung radiomics analysis) and imaging- and dosimetric-based segmentation (multi-region radiomics analysis) were performed. Patients with RP grade ≥ 2 or < 2 were classified. Predictors were selected with least absolute shrinkage and selection operator logistic regression and the model was built with neural network classifiers. A total of 49,383 radiomics features per patient image were extracted from the radiotherapy planning computed tomography. We identified 4 features and 13 radiomics features in the whole-lung and multi-region radiomics analysis for classification, respectively. The accuracy and area under the curve (AUC) without the synthetic minority over-sampling technique (SMOTE) were 60.8%, and 0.62 for whole-lung and 80.1%, and 0.84 for multi-region radiomics analysis. These were improved 1.7% for whole-lung and 2.1% for multi-region radiomics analysis with the SMOTE. The developed multi-region radiomics analysis can help predict grade ≥ 2 RP. The radiomics features in the median- and high-dose regions, and the local intensity roughness and variation were important factors in predicting grade ≥ 2 RP.

Preserved ratio impaired spirometry (PRISm) is defined by reduced FEV 1 with a preserved FEV 1 /FVC ratio; some individuals with PRISm can also have restrictive ventilatory abnormality. The aim of this study was to clarify clinical features of restrictive and non-restrictive PRISm. In total, 11,246 participants (mean, 49.1 years; range, 35–65 years) from five healthcare centres were included in this study. We evaluated baseline characteristics of participants with restrictive PRISm (FEV 1 /FVC ≥ 0.7, FEV 1  < 80% and FVC < 80%) and non-restrictive PRISm (FEV 1 /FVC ≥ 0.7, FEV 1  < 80% and FVC ≥ 80%), and airflow obstruction (FEV 1 /FVC < 0.7). We examined the longitudinal risk of developing airflow obstruction by comparing spirometry results at baseline and 5 years post-baseline among 2141 participants. Multivariate analysis demonstrated that a history of asthma or smoking could constitute an independent risk factor for non-restrictive PRISm, and that non-restrictive PRISm was independently associated with the risk of developing airflow obstruction. In contrast, female sex, advanced age, and high BMI, but not history of asthma or smoking, were risk factors for restrictive PRISm. Restrictive PRISm was not associated with the development of airflow obstruction. In conclusion, our results indicate that PRISm can be categorized according to the presence or absence of restrictive abnormality. Non-restrictive PRISm, which does not meet the conventional criteria of obstructive and restrictive ventilatory abnormalities, may be a precursor of chronic obstructive pulmonary disease and merits increased monitoring.

SummaryPurpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5 g/day for 14 days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.

Background: With global aging, especially in Asia, preventing pneumonia among seniors is vital. The necessity of introducing pneumococcal vaccines among the elderly has been highlighted, but there is a paucity of community-based real-world evidence on their effect. Sera Town in Hiroshima Prefecture, a super-aged community, launched a distinctive pneumococcal vaccination support project for elderly residents and conducted a 5-year follow-up survey. This study evaluates the effectiveness of this vaccination initiative.Methods: From October 2010 to March 2015, Sera Town recruited elderly residents for PPSV23 vaccination with partial cost subsidies. Participants were surveyed annually for 5 years post-vaccination to assess pneumonia incidence, calculated on a person-years basis. Using vital statistics from 2000 to 2016, we quantified changes in mortality rates associated with the vaccination support project through an interrupted-time-series analysis.Results: Of approximately 7,900 residents aged 65 and older, 3,422 (43%) participated in the project (median age: 84 years; range: 70–114 years; 56.7% female). Over 14,559 person-years of observation, 295 participants developed pneumonia. The post-vaccination incidence rate was 20.3 per 1,000 person-years (95% confidence interval [CI], 18.0–22.7). Interrupted time series analysis indicated a 25% reduction in Sera Town’s pneumonia mortality rate post-project, reversing an annual increase of 0.23 per 1,000 population pre-project to an annual decrease of 0.04 per 1,000 population post-project.Conclusion: This study provided real-world evidence on the association with PPSV23 vaccination on the general elderly through a community-based study. The results may be particularly useful for regions where PPSV23 serotypes are prevalent, offering insights for areas facing aging challenges.

Transforming growth factor-β (TGF-β) is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1) also has an established role. TGF-β is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-β in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-β-dependent epithelial-mesenchymal transition (EMT) and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-β induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-β-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-β-induced endogenous production of PAI-1 and TGF-β in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-β-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin. We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-β and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-β. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-β could be a promising therapeutic strategy for pulmonary fibrosis.

Asthma is a chronic inflammatory disease of airways, but an ideal biomarker that accurately reflects ongoing airway inflammation has not yet been established. The aim of this study was to examine the potential of sputum leucine-rich alpha-2 glycoprotein (LRG) as a new biomarker for airway inflammation in asthma. We obtained induced sputum samples from patients with asthma (N = 64) and healthy volunteers (N = 22) and measured LRG concentration by sandwich enzyme-linked immunosorbent assay (ELISA). Ovalbumin (OVA)-induced asthma model mice were used to investigate the mechanism of LRG production during airway inflammation. The LRG concentrations in the bronchoalveolar lavage fluid (BALF) obtained from mice were determined by ELISA and mouse lung sections were stained with anti-LRG antibody and periodic acid-Schiff (PAS) reagent. Sputum LRG concentrations were significantly higher in patients with asthma than in healthy volunteers (p = 0.00686). Consistent with patients' data, BALF LRG levels in asthma model mice were significantly higher than in control mice (p = 0.00013). Immunohistochemistry of lung sections from asthma model mice revealed that LRG was intensely expressed in a subpopulation of bronchial epithelial cells, which corresponded with PAS-positive mucus producing cells. These findings suggest that sputum LRG is a promising biomarker of local inflammation in asthma.

Postoperative acute exacerbation of interstitial lung disease (AE-ILD) can be fatal in patients with lung cancer concomitant with ILD. We aimed to elucidate the predictive potential of high-mobility group box 1 (HMGB1), which is associated with the development and severity of lung injury, for evaluating the risk of this complication. We included 152 patients with lung cancer and ILD who underwent radical surgery between January 2011 and August 2019. We evaluated the preoperative levels of serum HMGB1 and its predictive potential for postoperative AE-ILD. Postoperative AE-ILD developed in 17 patients. Serum levels of HMGB1 were significantly higher in patients with postoperative AE-ILD than in those without (median [interquartile range]: 5.39 [3.29–11.70] ng/mL vs. 3.55 [2.07–5.62] ng/mL). Univariate and multivariate logistic regression analyses revealed that higher HMGB1 levels were significantly associated with the development of postoperative AE-ILD in entire studied patients (n = 152). In the subgroup analysis, higher HMGB1 levels were associated with a significantly increased risk of this complication in patients who underwent lobectomy (n = 77) than in those who underwent sublobar resection (n = 75). Serum HMGB1 could be a promising marker for evaluating the risk of postoperative AE-ILD, specifically in patients who underwent lobectomy.