Lung cancer with comorbid interstitial pneumonia: Current situation and animal model development.

Interstitial pneumonia includes a range of disorders affecting the lung interstitium, significantly impacting life expectancy, especially during acute exacerbations. Concurrently, lung cancer remains a leading cause of cancer-related deaths worldwide. The coexistence of these two conditions presents a formidable challenge, complicating diagnosis, treatment, and prognosis. This review explores the critical issues associated with lung cancer comorbid with interstitial pneumonia, focusing on diagnostic challenges, prognosis, treatment complications, and the lack of effective research tools. Diagnosing lung cancer in patients with interstitial pneumonia is complicated due to overlapping imaging features and the risks associated with biopsies. The prognosis is poorer for patients with both conditions, as interstitial pneumonia promotes a more aggressive lung cancer phenotype. Standard treatment for interstitial pneumonia can inadvertently facilitate lung cancer progression, while anticancer therapies often exacerbate interstitial pneumonia. To address the lack of appropriate research tools, a novel murine model combining orthotopic lung cancer cell transplantation with bleomycin-induced interstitial pneumonia was developed to better understand their interaction. This new murine model successfully mimics the human condition, demonstrating increased tumor growth, metastasis, and alterations in the tumor microenvironment, including elevated tumor-associated macrophages, cancer-associated myofibroblasts, and regulatory T cells, alongside decreased cytotoxic T lymphocytes. Lung cancer comorbid with interstitial pneumonia represents a severe clinical challenge due to diagnostic difficulties and treatment-related complications. The novel murine model offers a valuable tool for future research to develop effective therapies. Dedicated efforts are needed to address this complex pathophysiology to improve patient outcomes.

Primary pulmonary extranodal NK/T-cell lymphoma diagnosed by thoracoscopic lung biopsy: A case report.

A 63-year-old Japanese female presented with fever. Computed tomography showed multiple nodules in both lungs. Corticosteroids and antibiotics were administered to treat suspected organizing and bacterial pneumonia, resulting in no improvement and respiratory failure worsened. Surgical lung biopsy revealed infiltration of CD3, CD56, Granzyme B, and EBV-encoded RNA-ISH-positive atypical lymphocytes. She was diagnosed with primary pulmonary extranodal NK/T-cell lymphoma (ENKL) and died two months after diagnosis with only a temporary effectiveness of chemotherapy. We should consider the possibility of ENKL and perform prompt and appropriate biopsy for early diagnosis in cases where empiric therapy is ineffective for suspected pneumonia.

A Case of Granulocyte-Colony-Stimulating Factor-Producing Non-Small Cell Lung Cancer under Steroid Treatment and with Poor Performance Status That Responded to Pembrolizumab.

Introduction: There have been only a few cases showing the efficacy of pembrolizumab on granulocyte-colony-stimulating factor (G-CSF)-producing non-small-cell lung cancer (NSCLC) with high programmed cell death ligand 1 (PD-L1) expression. Herein, we report the first case showing the efficacy of pembrolizumab for G-CSF-producing NSCLC with high PD-L1 expression, although the patient had factors indicative of poor pembrolizumab efficacy, such as poor performance status (PS) due to the tumor-induced inflammation and corticosteroids administration. Case Presentation: A 77-year-old woman was diagnosed with G-CSF-producing NSCLC-not otherwise specified, classified as clinical stage IVB, T2N3M1c. She had fever and her PS was 3, and her C-reactive protein (CRP) was 6.47 mg/dL due to inflammation by a G-CSF-producing tumor. Thus, we initiated the administration of dexamethasone (3.3 mg/day). Her fever abated the next day, and CRP dropped to 3.22 mg/dL after 4 days. Driver mutations were negative, and PD-L1, tumor proportion score, was highly expressed at 100%. Thus, pembrolizumab was started. Subsequently, the white blood cell count decreased, and the tumor shrank, indicating a partial response. After three cycles of pembrolizumab therapy, the anorexia improved, and she was discharged. The patient developed sclerosing cholangitis after discharge. Therefore, the pembrolizumab treatment was discontinued. The primary lesion was enlarged, indicating progressive disease. However, the patient and her family did not want additional treatment. Finally, her progression-free survival and overall survival were 6 and 7 months, respectively. Conclusion: Pembrolizumab may be effective against G-CSF-producing NSCLC with high PD-L1 expression. Corticosteroids seemed to inhibit inflammation induced by the tumor, and exert the efficacy of pembrolizumab.

Sex-related differences in efficacy of bone marrow-derived high aldehyde dehydrogenase activity cells against pulmonary fibrosis.

BACKGROUND: Although bone marrow-derived cells with high aldehyde dehydrogenase activity (ALDHbr) have shown therapeutic potential against various diseases in animal studies, clinical trials have failed to show concurrent findings. We aimed to clarify the optimal conditions for the efficacy of ALDHbr cells by using a murine bleomycin-induced pulmonary fibrosis model. METHODS: We intravenously transferred male or female donor C57BL/6 mice-derived ALDHbr cells into recipient C57BL/6 mice under various conditions, and used mCherry-expressing mice as a donor to trace the transferred ALDHbr cells. RESULTS: Pulmonary fibrosis improved significantly when (1) female-derived, not male-derived, and (2) lineage (Lin)-negative, not lineage-positive, ALDHbr cells were transferred during the (3) fibrotic, not inflammatory, phase. Consistent with the RNA-sequencing results, female-derived Lin-/ALDHbr cells were more resistant to oxidative stress than male-derived cells in vitro, and transferred female-derived Lin-/ALDHbr cells were more viable than male-derived cells in the fibrotic lung. The mechanism underlying the antifibrotic effects of Lin-/ALDHbr cells was strongly associated with reduction of oxidative stress. CONCLUSIONS: Our results indicated that Lin-/ALDHbr cell therapy could ameliorate pulmonary fibrosis by reducing oxidative stress and suggested that their efficacy was mediated by sex-related differences. Thus, sex-awareness strategies may be important for clinical application of bone marrow ALDHbr cells as a therapeutic tool.

Lipocalin-2 as a prognostic marker in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Lipocalin-2 (LCN2) is a secretory glycoprotein upregulated by oxidative stress; moreover, patients with idiopathic pulmonary fibrosis (IPF) have shown increased LCN2 levels in bronchoalveolar lavage fluid (BALF). This study aimed to determine whether circulatory LCN2 could be a systemic biomarker in patients with IPF and to investigate the role of LCN2 in a bleomycin-induced lung injury mouse model. METHODS: We measured serum LCN2 levels in 99 patients with stable IPF, 27 patients with acute exacerbation (AE) of IPF, 51 patients with chronic hypersensitivity pneumonitis, and 67 healthy controls. Further, LCN2 expression in lung tissue was evaluated in a bleomycin-induced lung injury mouse model, and the role of LCN2 was investigated using LCN2-knockout (LCN2 -/-) mice. RESULTS: Serum levels of LCN2 were significantly higher in patients with AE-IPF than in the other groups. The multivariate Cox proportional hazards model showed that elevated serum LCN2 level was an independent predictor of poor survival in patients with AE-IPF. In the bleomycin-induced lung injury mouse model, a higher dose of bleomycin resulted in higher LCN2 levels and shorter survival. Bleomycin-treated LCN2 -/- mice exhibited increased BALF cell and protein levels as well as hydroxyproline content. Moreover, compared with wild-type mice, LCN2-/- mice showed higher levels of circulatory 8-isoprostane as well as lower Nrf-2, GCLC, and NQO1 expression levels in lung tissue following bleomycin administration. CONCLUSIONS: Our findings demonstrate that serum LCN2 might be a potential prognostic marker of AE-IPF. Moreover, LCN2 expression levels may reflect the severity of lung injury, and LCN2 may be a protective factor against bleomycin-induced acute lung injury and oxidative stress.

High S100A9 level predicts poor survival, and the S100A9 inhibitor paquinimod is a candidate for treating idiopathic pulmonary fibrosis.

BACKGROUND: S100A9 is a damage-associated molecular pattern protein that may play an important role in the inflammatory response and fibrotic processes. Paquinimod is an immunomodulatory compound that prevents S100A9 activity. Its safety and pharmacokinetics have been confirmed in human clinical trials. In this study, we investigated the effects of paquinimod in preventing the development of lung fibrosis in vivo and examined the prognostic values of circulatory and lung S100A9 levels in patients with idiopathic pulmonary fibrosis (IPF). METHODS: The expression and localisation of S100A9 and the preventive effect of S100A9 inhibition on fibrosis development were investigated in a mouse model of bleomycin-induced pulmonary fibrosis. In this retrospective cohort study, the S100A9 levels in the serum and bronchoalveolar lavage fluid (BALF) samples from 76 and 55 patients with IPF, respectively, were examined for associations with patient survival. RESULTS: S100A9 expression was increased in the mouse lungs, especially in the inflammatory cells and fibrotic interstitium, after bleomycin administration. Treatment with paquinimod ameliorated fibrotic pathological changes and significantly reduced hydroxyproline content in the lung tissues of mice with bleomycin-induced pulmonary fibrosis. Additionally, we found that paquinimod reduced the number of lymphocytes and neutrophils in BALF and suppressed endothelial-mesenchymal transition in vivo. Kaplan-Meier curve analysis and univariate and multivariate Cox hazard proportion analyses revealed that high levels of S100A9 in the serum and BALF were significantly associated with poor prognoses in patients with IPF (Kaplan-Meier curve analysis: p=0.037 (serum) and 0.019 (BALF); multivariate Cox hazard proportion analysis: HR=3.88, 95% CI=1.06 to 14.21, p=0.041 (serum); HR=2.73, 95% CI=1.05 to 7.10, p=0.039 (BALF)). CONCLUSIONS: The present results indicate that increased S100A9 expression is associated with IPF progression and that the S100A9 inhibitor paquinimod is a potential treatment for IPF.

Hypoxia-inducible factor 1α modulates interstitial pneumonia-mediated lung cancer progression.

BACKGROUND: The prognosis of patients with lung cancer accompanied by interstitial pneumonia is poorer than that of patients with lung cancer but without interstitial pneumonia. Moreover, the available therapeutic interventions for lung cancer patients with interstitial pneumonia are limited. Therefore, a new treatment strategy for these patients is required. The aim of the present study was to investigate the pathophysiological relationship between interstitial pneumonia and lung cancer and explore potential therapeutic agents. METHODS: A novel hybrid murine model of lung cancer with interstitial pneumonia was established via bleomycin-induced pulmonary fibrosis followed by orthotopic lung cancer cell transplantation into the lungs. Changes in tumor progression, lung fibrosis, RNA expression, cytokine levels, and tumor microenvironment in the lung cancer with interstitial pneumonia model were investigated, and therapeutic agents were examined. Additionally, clinical data and samples from patients with lung cancer accompanied by interstitial pneumonia were analyzed to explore the potential clinical significance of the findings. RESULTS: In the lung cancer with interstitial pneumonia model, accelerated tumor growth was observed based on an altered tumor microenvironment. RNA sequencing analysis revealed upregulation of the hypoxia-inducible factor 1 signaling pathway. These findings were consistent with those obtained for human samples. Moreover, we explored whether ascorbic acid could be an alternative treatment for lung cancer with interstitial pneumonia to avoid the disadvantages of hypoxia-inducible factor 1 inhibitors. Ascorbic acid successfully downregulated the hypoxia-inducible factor 1 signaling pathway and inhibited tumor progression and lung fibrosis. CONCLUSIONS: The hypoxia-inducible factor 1 pathway is critical in lung cancer with interstitial pneumonia and could be a therapeutic target for mitigating interstitial pneumonia-mediated lung cancer progression.

Usefulness of Quantification and Serial Monitoring of Fine Crackles for Early Detection of Treatment-related Lung Injury: A Report of Two Cases.

Early detection and appropriate management of treatment-related interstitial lung disease (ILD) are important in cancer treatment. We established an algorithm for quantifying fine crackles using machine learning and reported that the fine crackle quantitative value (FCQV) calculated by this algorithm was more sensitive than chest radiography for detecting interstitial changes. Using this algorithm, we periodically analyzed respiratory sounds in two patients with lung cancer who developed treatment-related ILDs and found that the FCQV was elevated before the diagnosis of ILD. These cases may indicate the usefulness of the FCQV in the early diagnosis of treatment-related ILDs.

Exhaled Nitric Oxide and Olfactory Dysfunction in Patients with Asthma: Association with Chronic Rhinosinusitis.

Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction (12% and 9%, respectively). Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.

Nestin and Notch3 collaboratively regulate angiogenesis, collagen production, and endothelial-mesenchymal transition in lung endothelial cells.

BACKGROUND: Nestin, an intermediate filament protein, participates in various pathophysiological processes, including wound healing, angiogenesis, endothelial-mesenchymal transition (EndoMT), and fibrosis. However, the pathophysiological roles of lung nestin-expressing cells remain unclear due to conflicting reports. The objective of this study is to elucidate the characteristics and functions of lung nestin-expressing cells. METHODS: We conducted a series of in vitro and in vivo experiments using endothelial cell line MS1 and nestin-GFP mice. This animal model allows for nestin-expressing cell detection without the use of anti-nestin antibodies. RESULTS: Lung nestin-expressing cells occurred in approximately 0.2% of CD45- cells and was co-expressed with epithelial, endothelial, and mesenchymal cell-surface markers. Importantly, virtually all nestin-expressing cells co-expressed CD31. When compared to lung nestin-nonexpressing endothelial cells, nestin-expressing endothelial cells showed robust angiogenesis with frequent co-expression of PDGFRß and VEGFR2. During TGFß-mediated EndoMT, the elevation of Nes mRNA expression preceded that of Col1a1 mRNA, and nestin gene silencing using nestin siRNA resulted in further upregulation of Col1a1 mRNA expression. Furthermore, Notch3 expression was regulated by nestin in vitro and in vivo; nestin siRNA resulted in reduced Notch3 expression accompanied with enhanced EndoMT. Contrary to previous reports, neither Nes mRNA expression nor nestin-expressing cells were increased during pulmonary fibrosis. CONCLUSIONS: Our study showed that (1) lung nestin-expressing cells are an endothelial lineage but are distinct from nestin-nonexpressing endothelial cells; (2) nestin regulates Notch3 and they act collaboratively to regulate angiogenesis, collagen production, and EndoMT; and (3) nestin plays novel roles in lung angiogenesis and fibrosis. Video Abstract.

Intestinal overgrowth of Candida albicans exacerbates bleomycin-induced pulmonary fibrosis in mice with dysbiosis.

Increasing evidence indicates an interaction between the intestinal microbiota and diseases in distal organs. However, the relationship between pulmonary fibrosis and the intestinal microbiota, especially intestinal fungal microbiota, is poorly understood. Thus, this study aimed to determine the effects of changes in the intestinal fungal microbiota on the pathogenesis of pulmonary fibrosis. Mice with intestinal overgrowth of Candida albicans, which was established by oral administration of antibiotics plus C. albicans, showed accelerated bleomycin-induced pulmonary fibrosis relative to the control mice (i.e. without C. albicans treatment). In addition, the mice with intestinal overgrowth of C. albicans showed enhanced Th17-type immunity, and treatment with IL-17A-neutralizing antibody alleviated pulmonary fibrosis in these mice but not in the control mice. This result indicates that IL-17A is involved in the pathogenesis of C. albicans-exacerbated pulmonary fibrosis. Even before bleomycin treatment, the expression of Rorc, the master regulator of Th17, was already upregulated in the pulmonary lymphocytes of the mice with intestinal overgrowth of C. albicans. Subsequent administration of bleomycin triggered these Th17-skewed lymphocytes to produce IL-17A, which enhanced endothelial-mesenchymal transition. These results suggest that intestinal overgrowth of C. albicans exacerbates pulmonary fibrosis via IL-17A-mediated endothelial-mesenchymal transition. Thus, it might be a potential therapeutic target in pulmonary fibrosis. This study may serve as a basis for using intestinal fungal microbiota as novel therapeutic targets in pulmonary fibrosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Clinical characteristics of extrapulmonary nontuberculous mycobacteria infections in comparison with pulmonary infections: A single-center, retrospective study in Japan.

INTRODUCTION: The prevalence of nontuberculous mycobacteria (NTM) infections is increasing worldwide. Although NTM can affect extrapulmonary organs, studies on the clinical characteristics of extrapulmonary NTM are rare. METHODS: We retrospectively analyzed patients who were newly diagnosed with NTM infections at Hiroshima University Hospital between 2001 and 2021 to investigate species distribution, infected sites, and risk factors of extrapulmonary NTM compared to pulmonary NTM. RESULTS: Of the 261 NTM infections, 9.6% and 90.4% had extrapulmonary and pulmonary NTM, respectively. The mean ages of patients with extrapulmonary and pulmonary NTM were 53.4 and 69.3 years, 64.0% and 42.8% were male, 36.0% and 9.3% received corticosteroids, 20.0% and 0% had acquired immune deficiency syndrome (AIDS), and 56.0% and 16.1% had any immunosuppressive conditions, respectively. Younger age, corticosteroid use, and AIDS were associated with extrapulmonary NTM. In pulmonary NTM, Mycobacterium avium complex (MAC) accounted for 86.4% of NTM species, followed by M. abscessus complex (4.2%), whereas in extrapulmonary NTM, M. abscessus complex, MAC, M. chelonae, and M. fortuitum accounted for 36.0%, 28.0%, 12.0%, and 8.0%, respectively. Compared to pulmonary NTM, extrapulmonary NTM were significantly more likely to be rapid-growing mycobacteria (RGM) (56.0% vs. 5.5%). The most common sites of infection were the skin and soft tissues (44.0%), followed by the blood (20.0%), tenosynovium, and lymph nodes (12.0%). CONCLUSION: Younger age and immunosuppressive conditions are associated with extrapulmonary NTM, with a higher prevalence of RGM in extrapulmonary NTM than in pulmonary NTM. These results provide a better understanding of extrapulmonary NTM.

Serum and bronchoalveolar lavage fluid levels of soluble B7H3 in patients with interstitial lung diseases.

BACKGROUND: The B7 family member B7H3/CD276 was recently reported to be involved in the pathophysiology of idiopathic pulmonary fibrosis (IPF). However, the association of B7H3 with prognosis in patients with fibrosing interstitial lung diseases (ILDs), including IPF, remains unclear. This study was investigated to determine the potential of soluble B7H3 (sB7H3) as a biomarker to predict prognosis in patients with fibrosing ILDs. METHODS: Patients with ILDs from various categories who underwent bronchoalveolar lavage (BAL) were included in the study. The relationship between sB7H3 levels in serum or BAL fluid (BALF) and clinical variables at the time of ILD diagnosis was studied retrospectively. All patients who met the fibrosing ILD criteria were followed for 5 years. RESULTS: We found that coexisting malignancy affected the serum, but not the BALF, sB7H3 levels. There was no significant correlation between serum and BALF levels of sB7H3 in 49 ILD patients without malignancy (11 with sarcoidosis, 5 with drug-induced ILD, 22 with IPF, and 11 with ILD associated with systemic sclerosis). We also found that the BALF levels, but not serum levels, of sB7H3 at the time of ILD diagnosis had independent prognostic potential on 5-year survival in patients with fibrosing ILDs. Of note, patients with a higher level of BALF sB7H3 at diagnosis (≥0.100 ng/mL) showed significantly shorter survival than those with lower levels. CONCLUSIONS: This study suggests that BALF sB7H3 could be a novel prognostic biomarker in a broad range of fibrosing ILD patients.

Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial-Mesenchymal Transition.

Most epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Plasminogen activator inhibitor-1 (PAI-1) was reported to be involved in chemotherapeutic or radiotherapeutic resistance. The purpose of the present study was to investigate whether PAI-1 is involved in osimertinib tolerance and whether it could be a therapeutic target for overcoming this tolerance. We showed that the PAI-1 mRNA expression levels and mesenchymal gene expression levels were significantly higher in drug-tolerant EGFR-mutated NSCLC cells than in control cells after 7 days of in vitro osimertinib treatment. Additionally, an RNA microarray analysis revealed upregulation of the integrin-induced EMT pathway in osimertinib-tolerant cells. Furthermore, we observed that PAI-1 inhibitors suppressed proliferation and the degree of epithelial-mesenchymal transition (EMT) in tolerant cells. Finally, in a subcutaneous tumor model, we showed that combining osimertinib with a PAI-1 inhibitor prevented the regrowth of tumors comprising EGFR-mutated cancer cells. The present study is the first to show PAI-1 to be involved in tolerance to osimertinib via EMT.

Preserved ratio impaired spirometry with or without restrictive spirometric abnormality.

Preserved ratio impaired spirometry (PRISm) is defined by reduced FEV1 with a preserved FEV1/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 (FEV1/FVC ≥ 0.7, FEV1 < 80% and FVC < 80%) and non-restrictive PRISm (FEV1/FVC ≥ 0.7, FEV1 < 80% and FVC ≥ 80%), and airflow obstruction (FEV1/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.

Predictive value of serum high-mobility group box 1 levels for checkpoint inhibitor pneumonitis.

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor pneumonitis (CIP), caused by the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high-mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. METHODS: Blood samples, prospectively stored before anti-PD-1/PD-L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non-small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti-PD-1/PD-L1 therapy. RESULTS: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut-off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut-off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. CONCLUSION: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients.

Association Between Patient Preference for Inhaler Medications and Asthma Outcomes.

Purpose: Asthma guidelines recommend considering the patient preference to optimize medication choices. Patient preference for inhaler medication may affect asthma outcomes, but evidence regarding this is lacking. This study investigated the associations between patient preference for inhaler medications and asthma outcomes. Patients and Methods: A multicenter questionnaire survey was conducted among 351 adult patients with asthma treated with regular inhaled corticosteroids. Agreement between patients' preferences and current medication was evaluated using two questions: matched preference was defined as patients answering that the current inhaler medication was the most preferred treatment and they were satisfied with it. Mismatched preference was defined as when patients reported that the current inhaler medication was not the most preferred treatment and/or they were not satisfied with it. We investigated the factors associated with patient preference for asthma inhaler medications. Results: In total, 269 (76.6%) patients were classified into the matched preference group and 82 (23.4%) patients into the mismatched preference group. Multivariate analyses showed that matched preference was independently associated with higher asthma control test scores (P<0.001), fewer exacerbations (P=0.009), less regular oral corticosteroid use (P=0.009), and better inhaler adherence (P=0.006) than the mismatched preference group. In subgroup analysis, younger age was associated with matched preference in patients using dry powder inhalers but not in those using pressurized metered dose inhalers. Conclusion: The use of preference-matched inhaler medication was associated with better asthma outcomes. Evaluation of patients' preference for inhaler medication might provide useful information for individualized treatment with asthma inhaler medications.

Predictive role of circulatory levels of high-mobility group box 1 for radiation pneumonitis in patients with non-small cell lung cancer treated with definitive thoracic radiotherapy.

BACKGROUND: High-mobility group box 1 (HMGB1) is a pro-inflammatory protein associated with the pathophysiology of lung injury and lung tumorigenesis. Here, we investigated the predictive potential of serum HMGB1 levels for radiation pneumonitis in patients with lung cancer. METHODS: This was a retrospective biomarker study of 73 patients with non-small cell lung cancer treated with definitive thoracic radiotherapy between August 2007 and January 2021. We measured HMGB1 levels in serum stored before treatment, and analyzed its association with the development of grade ≥ 2 or grade ≥ 3 radiation pneumonitis. Additionally, baseline characteristics affecting HMGB1 levels were identified. RESULTS: Of the 73 patients, 21 (28.8%) and 6 (8.2%) patients experienced grade 2 and ≥ 3 radiation pneumonitis, respectively. Univariate and multivariate logistic regression analyses revealed that higher baseline levels of serum HMGB1 were significantly associated with a higher risk of grade ≥ 3, but not grade ≥ 2, radiation pneumonitis. The incidence of grade ≥ 3 radiation pneumonitis was higher in patients with HMGB1 levels ≥ 6.2 ng/mL than in those with levels < 6.2 ng/mL (25.0% vs. 3.5%, p = 0.019). Baseline serum levels of HMGB1 were independently and positively associated with gross tumor volume. CONCLUSIONS: Higher serum HMGB1 levels were significantly associated with the risk of grade ≥ 3 radiation pneumonitis in patients with lung cancer, and therefore, HMGB1 could be a potential blood biomarker for predicting severe radiation pneumonitis.

Characteristic computed tomography features in mesenchymal-epithelial transition exon14 skipping-positive non-small cell lung cancer.

BACKGROUND: Mesenchymal-epithelial transition exon14 (METex14) skipping is one of the therapeutic driver oncogene mutations in non-small cell lung cancer (NSCLC), and can be treated with tepotinib and capmatinib. There is only one report on computed tomography (CT) findings of METex14 skipping-positive NSCLC, which shows that the primary tumor tends to have a large mass in the upper lobe, and extrathoracic metastases are common. This study examined the CT findings of METex14 skipping-positive NSCLC, focusing on the features of the margins and internal structures. METHODS: We consecutively included patients with METex14 skipping-positive NSCLC who were diagnosed between January 2018 and December 2020 at four independent institutions. We retrospectively reviewed the patient demographics and CT findings for tumor margins (invasion into surrounding tissue, lobulation, pleural indentation, spicula, and ground-glass opacity) and internal structures (air bronchograms, cavitation and internal low-density area). RESULTS: Fifteen patients with METex14 skipping-positive NSCLC were identified. Almost half of the patients were men (7/15; 46.7%), and their median age was 75.0 years. More than half were either current or former smokers (9/15; 60.0%). A vast majority of histological subtypes were adenocarcinoma (10/15; 66.7%), followed by pleomorphic carcinoma (3/15; 20.0%) and squamous cell carcinoma (2/15; 13.3%). With regard to CT findings, most primary tumors presented as masses larger than 30 mm (12/15; 80.0%) and were located in the upper lobes (12/15; 80.0%). Invasion into surrounding tissue and presence of internal low-density areas were observed in 60.0% (9/15) and 66.7% (10/15) of the primary tumors, respectively. Additionally, their frequencies increased to 72.7% (8/11) and 90.9% (10/11) in stage III/IV cases, respectively. In lymph node metastasis, internal low-density areas were observed in 8/10 cases (80.0%). Although these two CT features were rarely observed in distant metastases at diagnosis, they became apparent with progression of the metastatic tumor size. CONCLUSIONS: METex14 skipping-positive NSCLC tumors tend to invade surrounding tissue and possess internal low-density areas. These CT findings might be characteristic of METex14 skipping-positive NSCLC.

Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation.

The receptor for advanced glycation end product (RAGE) is a transmembrane receptor highly expressed in type 1 pneumocytes of healthy lungs. RAGE is considered to play a homeostatic role in the lung, as RAGE knockout mice develop lung fibrosis as they age. In contrast, RAGE can bind numerous ligands, including high-mobility group box 1 (HMGB1). These interactions initiate pro-inflammatory signaling associated with the pathogenesis of lung injury and interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF). ILD is a broad category of diffuse parenchymal lung disease characterized by various extents of lung fibrosis and inflammation, and IPF is a common and progressive ILD of unknown cause. The prognosis of patients with IPF is poor, and acute exacerbation of IPF (AE-IPF) is one of the main causes of death. Recent reports indicate that acute exacerbations can occur in other ILDs (AE-ILD). Notably, ILD is frequently observed in patients with lung cancer, and AE-ILD after surgical procedures or the initiation of chemotherapy for concomitant lung cancer are clinically important due to their association with increased mortality. In this review, we summarize the associations of RAGE/soluble RAGE (sRAGE)/RAGE ligands with the pathogenesis and clinical course of ILD, including IPF and AE-IPF. Additionally, the potential use of sRAGE and RAGE ligands as predictive markers of AE-IPF and cancer treatment-triggered AE-ILD is also discussed.