Treatment Strategies for Non-Small-Cell Lung Cancer with Comorbid Respiratory Disease; Interstitial Pneumonia, Chronic Obstructive Pulmonary Disease, and Tuberculosis.

Non-small cell lung cancer (NSCLC) patients are often complicated by other respiratory diseases, including interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB), and the management of which can be problematic. NSCLC patients with IP sometimes develop fatal acute exacerbation induced by pharmacotherapy, and the establishment of a safe treatment strategy is desirable. For advanced NSCLC with IP, carboplatin plus nanoparticle albumin-bound paclitaxel is a relatively safe and effective first-line treatment option. Although the safety of immune checkpoint inhibitors (ICIs) for these populations remains controversial, ICIs have the potential to provide long-term survival. The severity of COPD is an important prognostic factor in NSCLC patients. Although COPD complications do not necessarily limit treatment options, it is important to select drugs with fewer side effects on the heart and blood vessels as well as the lungs. Active TB is complicated by 2-5% of NSCLC cases during their disease course. Since pharmacotherapy, especially ICIs, reportedly induces the development of TB, the possibility of developing TB should always be kept in mind during NSCLC treatment. To date, there is no coherent review article on NSCLC with these pulmonary complications. This review article summarizes the current evidence and discusses future prospects for treatment strategies for NSCLC patients complicated with IP, severe COPD, and TB.

Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

The effect of nintedanib on health-related quality of life in Japanese patients with progressive fibrosing interstitial lung diseases: A subset analysis of the INBUILD trial.

BACKGROUND: In previous Japanese subgroup/subset analyses of the global INBUILD trial, nintedanib reduced the annual rate of forced vital capacity (FVC) decline and the risk of disease progression in patients with progressive fibrosing interstitial lung diseases (PF-ILDs). This exploratory subset analysis assessed the effect of nintedanib on symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs, including those with usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT). METHODS: This analysis included Japanese patients who received at least one dose of study treatment in the randomized, double-blind, placebo-controlled INBUILD trial. The Living with Pulmonary Fibrosis (L-PF) questionnaire was used to assess pulmonary fibrosis symptoms and impacts (higher scores indicated greater impairment) at baseline and weeks 12-52. RESULTS: In total, 108 Japanese patients (nintedanib: n = 52; placebo: n = 56) were included; 84 patients had UIP-like fibrotic pattern on HRCT. In the total Japanese subgroup and in those with UIP-like fibrotic pattern, numerically greater increases in L-PF total, symptoms total, symptoms fatigue domain, and impacts scores were observed in the placebo group than in the nintedanib group at all timepoints, starting from week 12. A numerically greater increase in the symptoms dyspnea domain score was observed with placebo versus nintedanib starting from week 36. Throughout the study, the symptoms cough domain score increased in the placebo group but decreased in the nintedanib group. CONCLUSIONS: Our findings demonstrate that nintedanib has the potential to reduce the worsening of symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs.

Compatible with fibrotic hypersensitivity pneumonitis on high-resolution computed tomography: from the ATS/JRS/ALAT 2020 hypersensitivity pneumonitis guidelines.

Background: In compatible with fibrotic hypersensitivity pneumonitis (HP) of the computed tomography (CT) classification using the American Thoracic Society (ATS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) HP guidelines, the lung fibrosis pattern was classified as either a usual interstitial pneumonia (UIP) pattern or a diffuse ground-glass opacity (GGO) pattern with subtle fibrosis. We investigated whether patients with the same imaging classification had different disease progression. We also attempted to reclassify these patients using the CHEST HP guidelines. Methods: Patients with fibrotic HP who had compatible CT pattern in the ATS/JRS/ALAT classification were investigated retrospectively. Results: With 62 patients in the UIP pattern group and 25 patients in the diffuse GGO pattern group, 87 patients with fibrotic HP had compatible pattern on CT. Annual forced vital capacity changes in the UIP pattern group and diffuse GGO pattern group were -2.7% and +3.3% (P=0.004), respectively. The 5-year survival rates in the UIP pattern group and diffuse GGO pattern group were 86% and 100% (P=0.02). In UIP pattern group in the ATS/JRS/ALAT classification, 27% patients were classified as typical fibrotic HP pattern in the CHEST guidelines. In the diffuse GGO pattern group, 52% patients were classified as typical pattern of fibrotic HP. In the CHEST guidelines, more patients in the GGO pattern were classified as typical pattern compared with those in the UIP pattern (P=0.02). Conclusions: The two patterns in compatible with fibrotic HP of CT classification using the ATS/JRS/ALAT HP guidelines had different disease progression. Typical patterns were more frequent in the CHEST guidelines than the ATS/JRS/ALAT guidelines.

KRASG12C Inhibitor as a Treatment Option for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

Successful pembrolizumab treatment for microsatellite instability-high thymoma: A case report.

Microsatellite instability (MSI) is a valuable biomarker for immune checkpoint inhibitors. We report the first case of MSI-high thymoma successfully treated with pembrolizumab. This patient had pleural dissemination and was treated with two cytotoxic chemotherapy regimens including carboplatin and paclitaxel combination therapy and pemetrexed, which did not have the desired effect. Because MSI status was high by using the surgical specimen, pembrolizumab was administered as 3rd line chemotherapy. After three courses, the pleural lesions dramatically shrunk, which confirmed a partial response. Although MSI-high thymoma is rare, our results suggest the necessity to evaluate MSI status in patients with thymoma.

Drug-related pneumonitis caused by amikacin liposome inhalation suspension: One pathologically proven case and single-center experience.

Amikacin liposome inhalation suspension (ALIS) is known to cause drug-related pneumonitis, which has been described as "hypersensitivity pneumonitis (HP)". However, its clinical and pathological characteristics have never been reported. We retrospectively evaluated 18 patients treated with ALIS. Three (16.7%) patients developed HP-pattern pneumonitis on high-resolution computed tomography. Serum eosinophil counts were elevated up to above 1000/µL in these three patients, which decreased with ALIS discontinuation only. Of note, the specimen obtained by transbronchial lung cryobiopsy in one patient revealed a mild degree of lymphocyte and eosinophil infiltration. Rather, the findings of acute lung injury such as an edematous thickening of the alveolar walls, and an accumulation of foamy degenerative macrophages in the alveolar lumina was prominent. A pulmonary alveolar proteinosis reaction was also observed. HP-pattern pneumonitis due to ALIS may pathologically correspond to acute lung injury and a pulmonary alveolar proteinosis reaction despite increasing serum eosinophil counts.

Hypersensitivity pneumonitis with Paecilomyces as suspected inciting antigen.

A 73-year-old man visited our hospital for persistent cough. Chest high-resolution CT (HRCT) showed infiltration shadows in lower lobes and diffuse ground glass opacities in the upper lobes. Blood tests showed elevated white blood cell, C-reactive protein, surfactant protein D, and Krebs von den Lungen-6 levels. After an antigen avoidance test, his HRCT and blood test findings improved; we diagnosed him with hypersensitivity pneumonitis (HP). A culture of the rotting interior walls within his home revealed Paecilomyces, which we believe caused his HP. Given the few patients with Paecilomyces-induced HP, systematic approach was important to identify the inciting antigen.

The Molecular Landscape of Gastric Cancers for Novel Targeted Therapies from Real-World Genomic Profiling.

BACKGROUND: Panel-based comprehensive genomic profiling is used in clinical practice worldwide; however, large real-world datasets of patients with advanced gastric cancer are not well known. OBJECTIVE: We investigated what differences exist in clinically relevant alterations for molecularly defined or age-stratified subgroups. METHODS: This was a collaborative biomarker study of a real-world dataset from comprehensive genomic profiling testing (Foundation Medicine, Inc.). Hybrid capture was carried out on at least 324 cancer-related genes and select introns from 31 genes frequently rearranged in cancer. Overall, 4634 patients were available for analyses and were stratified by age (≥ 40/< 40 years), microsatellite instability status, tumor mutational burden status (high 10 ≥ /low < 10 Muts/Mb), Epstein-Barr virus status, and select gene alterations. We analyzed the frequency of alterations with a chi-square test with Yate's correction. RESULTS: Genes with frequent alterations included TP53 (60.1%), ARID1A (19.6%), CDKN2A (18.2%), KRAS (16.6%), and CDH1 (15.8%). Differences in comprehensive genomic profiling were observed according to molecularly defined or age-stratified subgroups. Druggable genomic alterations were detected in 31.4% of patients; ATM (4.4%), BRAF V600E (0.4%), BRCA1 (1.5%), BRCA2 (2.9%), ERBB2 amplification (9.2%), IDH1 (0.2%), KRAS G12C (0.7%), microsatellite instability-high (4.8%), NTRK1/2/3 fusion (0.13%), PIK3CA mutation (11.4%), and tumor mutational burden-high (9.4%). CDH1 alterations and MET amplification were significantly more frequent in patients aged < 40 years (27.7 and 6.2%) than in those aged ≥ 40 years (14.7 and 4.0%). CONCLUSIONS: Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

Myocardial Injury by COVID-19 Infection Assessed by Cardiovascular Magnetic Resonance Imaging　- A Prospective Multicenter Study.

BACKGROUND: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR).Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis. CONCLUSIONS: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

Favorable treatment response of bevacizumab-combined chemotherapy for advanced or recurrent invasive mucinous adenocarcinoma of the lung: A retrospective observational study.

Invasive mucinous adenocarcinoma (IMA) of the lung is a rare variant of adenocarcinoma characterized by abundant intracytoplasmic mucin within the tumor. Although IMA has poor sensitivity to conventional chemotherapy regimens used for non-small cell lung cancer, we observed a better response to the bevacizumab (BEV) regimen. In this retrospective study, we aimed to investigate the response to BEV-combined regimens in patients with IMA. Among 16 consecutive patients diagnosed with IMA between January 2016 and December 2020 at our institution and treated with systemic chemotherapy, seven patients were treated with BEV-combined regimens. The overall response rate to BEV-combined regimens was 85.7%, with six patients showing a partial response. The median progression-free survival was 6.1 months. One patient experienced respiratory failure, which was improved after administration of BEV-combined regimen. BEV-combined systemic therapy may have a favorable effect on advanced or recurrent IMA of the lung.

Spontaneous regression of acute fibrinous organizing pneumonia induced by COVID-19 vaccination: A case report.

A 42-year-old woman visited our hospital with complaints of fever, muscle pain, and dyspnea one week after receiving the coronavirus disease 2019 (COVID-19) vaccine. Chest high-resolution computed tomography showed a patchy consolidation and ground-glass attenuation in the both lungs, consistent with acute interstitial pneumonia. Transbronchial lung cryobiopsy revealed organizing pneumonia with marked intra-alveolar fibrin, and pathologically diagnosed as acute fibrinous organizing pneumonia (AFOP). Other causative diseases such as dermatomyositis was clinically ruled out, and COVID-19 vaccine-induced AFOP was diagnosed. Physician should check the history of COVID-19 vaccination when encountering a case of AFOP with an unknown cause.

Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Bilateral Pneumothorax after a Transbronchial Lung Cryobiopsy for Interstitial Lung Disease.

We herein report a case of bilateral pneumothorax after a unilateral transbronchial lung cryobiopsy (TBLC). A 73-year-old man with no history of cardiothoracic surgery underwent a TBLC for the reevaluation of interstitial lung disease. Five hours later, he developed bilateral pneumothorax, pneumomediastinum, and subcutaneous emphysema. He underwent bilateral chest drainage and was discharged 18 days later. The lung biopsy specimens obtained from the TBLC contained visceral pleura and bronchial cartilage, suggesting bronchial injury as the cause of the bilateral pneumothorax.

Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19.

INTRODUCTION: Favipiravir terminates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Accordingly, early administration of favipiravir to SARS-CoV-2-infected coronavirus disease 2019 (COVID-19) patients may be expected to suppress disease progression. METHODS: A randomized double-blind placebo-controlled trial was conducted to demonstrate efficacy of favipiravir in reducing disease progression in patients with mild COVID-19. The participants were unvaccinated patients with comorbidities and at risk of progression to severe disease. Patients were enrolled within 72 h of disease onset and randomized to receive either favipiravir (1800 mg/dose on Day 1 followed by 800 mg/dose) or matching placebo twice daily for 10 days. The primary endpoint was the proportion of patients requiring oxygen therapy within 28 days of randomization. RESULTS: The trial was discontinued after enrolling 84 patients due to slower than anticipated enrollment caused by rapid uptake of SARS-CoV-2-vaccines and the emergence of the Omicron variant. Results from the 84 patients demonstrated no significant difference in all clinical outcomes. In post-hoc analyses, favipiravir treatment showed higher efficacy in patients within 48 h of onset. No deaths or severe adverse events were documented in the favipiravir group. Plasma concentrations of favipiravir from Day 2 onward were maintained above 40 µg/mL. CONCLUSIONS: Conducting clinical trials for pathogens like SARS-CoV-2 that rapidly accumulate mutations leading to altered disease characteristics carries significant risks unless it can be done in a short period. Therefore, it would be important to prepare the comprehensive clinical trial platform that can appropriately and promptly evaluate drugs even under a pandemic.

Concordance between transbronchial lung cryobiopsy and surgical lung biopsy in patients with idiopathic multicentric Castleman disease: A report of four cases.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease often associated with pulmonary involvement. Recently, transbronchial lung cryobiopsy (TBLC) has been reported to be useful for the diagnosis of diffuse interstitial lung disease. However, there have been no reports of pathological assessment of TBLC for iMCD. METHOD: To clarify the efficacy of TBLC in the diagnosis of iMCD, we retrospectively reviewed four iMCD patients who had undergone both TBLC and surgical lung biopsy (SLB). RESULTS: The median age was 44 years; 2 males and 2 females. Two or three TBLC specimens were taken from each patient. All patients had no complications other than minimal bleeding. The size of the TBLC specimens was approximately 5-6 × 3-4 mm, and the alveolar region, and centrilobular and perilobular areas were adequately sampled. As with SLB, the extent of lung lesions and inflammatory cell infiltration could be sufficiently evaluated by TBLC. The presence of lymphoid follicles could also be assessed by TBLC; however, the germinal centers with lymphoid follicles were difficult to evaluate. The TBLC specimens could also be evaluated for immunostaining, especially IgG4 immunostaining, to rule out IgG4-related lung disease. Pulmonary pathological grading showed a high concordance rate between major pathological findings of TBLC and SLB. The pathologist's confidence level of TBLC for the diagnosis of iMCD was high in all cases. CONCLUSIONS: TBLC exhibits a high concordance rate with SLB in the pathological evaluation of iMCD, which may be useful for the diagnosis of iMCD.

Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer's disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.

Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis.

Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the bleomycin-induced PF mouse model has improved our understanding of exogenous factor-induced fibrosis, the mechanism governing endogenous factor-induced fibrosis remains unknown. Here, we find that Ifngr1-/-Rag2-/- mice, which lack the critical suppression factor for group 2 innate lymphoid cells (ILC2), develop PF spontaneously. The onset phase of fibrosis includes ILC2 subpopulations with a high Il1rl1 (IL-33 receptor) expression, and fibrosis does not develop in ILC-deficient or IL-33-deficient mice. Although ILC2s are normally localized near bronchioles and blood vessels, ILC2s are increased in fibrotic areas along with IL-33 positive fibroblasts during fibrosis. Co-culture analysis shows that activated-ILC2s directly induce collagen production from fibroblasts. Furthermore, increased IL1RL1 and decreased IFNGR1 expressions are confirmed in ILC2s from individuals with idiopathic PF, highlighting the applicability of Ifngr1-/-Rag2-/- mice as a mouse model for fibrosis research.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib.

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.