Explore the vast range of titles available.

Background The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non‐small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP. Methods In this retrospective cohort study, CIP severity, CIP‐related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients’ medical charts. Results All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP‐related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre‐existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression‐free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5–2.0 vs. 3.5 months, 95% CI 2.0–5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5–13 vs. 12.7 months, 95% CI 8.0–21.0 months, P = 0.011). Conclusion CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre‐existing ILD, should be carefully assessed.

Nontuberculous mycobacterial pulmonary disease (NTM-PD), mainly caused by Mycobacterium avium complex (MAC), and pulmonary tuberculosis (TB) are emerging health problems worldwide. However, because their clinical features are often similar, it remains difficult to differentiate NTM-PD from TB when the diagnosis cannot be made by sputum culture. To investigate potential serum biomarkers, we conducted non-targeted proteome analysis on serum extracellular vesicles (EVs) collected from 10 patients with MAC pulmonary disease (MAC-PD), 7 patients with TB, and 10 healthy controls. A total of 2614 proteins were identified in the discovery cohort. The EV protein signature from patients with NTM-PD and TB reflected infectious diseases and inflammatory response pathways. Among the identified proteins, the expression of Na+/H+ exchanger regulatory factor 2 (NHERF2) was significantly elevated in patients with MAC-PD compared with healthy controls and patients with TB. Moreover, upregulation of NHERF2 was confirmed by immunoblotting of serum EVs and immunohistochemistry of lungs with mycobacterial infection. Our findings highlight that NHERF2 in serum EVs might be a potential biomarker for distinguishing MAC-PD from TB, possibly reflecting the pathogenesis of MAC-PD.

The defining biology that distinguishes neutrophil extracellular traps (NETs) from other forms of cell death is unresolved, and techniques which unambiguously identify NETs remain elusive. Raman scattering measurement provides a holistic overview of cell molecular composition based on characteristic bond vibrations in components such as lipids and proteins. We collected Raman spectra from NETs and freeze/thaw necrotic cells using a custom built high-throughput platform which is able to rapidly measure spectra from single cells. Principal component analysis of Raman spectra from NETs clearly distinguished them from necrotic cells despite their similar morphology, demonstrating their fundamental molecular differences. In contrast, classical techniques used for NET analysis, immunofluorescence microscopy, extracellular DNA, and ELISA, could not differentiate these cells. Additionally, machine learning analysis of Raman spectra indicated subtle differences in lipopolysaccharide (LPS)-induced as opposed to phorbol myristate acetate (PMA)-induced NETs, demonstrating the molecular composition of NETs varies depending on the stimulant used. This study demonstrates the benefits of Raman microscopy in discriminating NETs from other types of cell death and by their pathway of induction.

Background Interstitial lung disease (ILD), represented by idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), shows poor prognosis due to progressive fibrosis. Early therapeutic intervention is required to enhance the efficacy of antifibrotic drugs, highlighting the importance of early detection of ILD progression. Although candidate biomarkers for predicting ILD progression have been recently reported through omics analyses, clinically measurable biomarkers remain unestablished. This study aimed to identify clinically measurable biomarkers that could predict the degree of ILD progression. Methods The serum levels of 13 candidate biomarkers were prospectively measured by chemiluminescent enzyme immunoassay and the utilities for predicting ILD progression were compared in the discovery cohort (total 252 patients). Moreover, we evaluated the utility of the identified biomarker in another independent cohort (154 patients with non-IPF-ILD) and examined the dynamics of the biomarker by immunoblotting and single-cell RNA sequencing (scRNA-seq) using samples of patients and a mouse model. Results In the discovery cohort, C-C motif chemokine ligand (CCL)17 could reliably predict ILD progression, particularly in patients with ILD other than IPF, and showed significant associations with mortality (hazard ratio [HR] 3.70; 95% confidence interval [CI] 1.19–11.49; P  = 0.015; cut-off value = 418 pg/mL). Consistently, in the validation cohort, the CCL17 high group showed significantly higher mortality (HR: 2.15; 95% CI 0.99–4.69; P  = 0.049), and CCL17 was identified as an independent prognostic factor from corticosteroid or immunosuppressive agents use and ILD-gender-age-physiology index. Similar to the results of serum studies, CCL17 levels in the lungs of patients with PPF and model mice were higher than those in controls. They were positively correlated with CCL17 levels in the serum, suggesting that the increased serum CCL17 levels could reflect an increase in CCL17 levels in lung tissues. The scRNA-seq analysis of lung tissues from model mice suggested that the levels of CCL17 derived primarily from conventional dendritic cells and macrophages increased, especially during the profibrotic phase. Conclusions We identified serum CCL17 as a clinically measurable biomarker for predicting non-IPF-ILD progression. Serum CCL17 could enable the stratification of patients at risk of non-IPF-ILD progression, leading to appropriate early therapeutic intervention. Graphical abstract

Background Hypereosinophilic syndrome is a group of disorders characterized by organ dysfunction caused by hypereosinophilia, which frequently leads to thromboembolic complications with potentially fatal outcomes. Interleukin-5, a key cytokine that promotes the differentiation and activation of eosinophils, has been identified as a therapeutic target. Anti-interleukin-5 antibody therapy has demonstrated efficacy in reducing eosinophil counts and enabling steroid dose tapering in patients with hypereosinophilic syndrome. This report describes the case of a patient with severe thromboembolism associated with hypereosinophilic syndrome during the acute phase who was successfully treated with benralizumab, an anti-interleukin-5 receptor alpha antibody. Case presentation A 22-year-old woman presented with a persistent cough and was diagnosed with eosinophilic pneumonia and portal vein thrombosis. Although eosinophilic pneumonia improved with corticosteroid therapy, thrombotic complications worsened despite additional anticoagulant treatment. The administration of benralizumab led to marked improvement in thrombosis, resulting in clinical recovery. Conclusions This case suggests that the early administration of anti-interleukin-5 receptor antibody therapy may be a valuable treatment option for refractory thrombosis.

The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration. To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls. Furthermore, single-cell RNA sequencing of peripheral blood mononuclear cells collected from 10 patients with COVID-19 and 5 healthy controls was performed. Among the 3046 extracellular vesicle proteins that were identified, expression of MACROH2A1 was significantly elevated in refractory cases compared to non-refractory cases; moreover, its expression was increased according to disease severity. In single-cell RNA sequencing of peripheral blood mononuclear cells, the expression of MACROH2A1 was localized to monocytes and elevated in critical cases. Consistently, single-nucleus RNA sequencing of lung tissues revealed that MACROH2A1 was highly expressed in monocytes and macrophages and was significantly elevated in fatal COVID-19. Moreover, molecular network analysis showed that pathways such as \"estrogen signaling pathway,\" \"p160 steroid receptor coactivator (SRC) signaling pathway,\" and \"transcriptional regulation by STAT\" were enriched in the transcriptome of monocytes in the peripheral blood mononuclear cells and lungs, and they were also commonly enriched in extracellular vesicle proteomics. Our findings highlight that MACROH2A1 in extracellular vesicles is a potential biomarker of refractory COVID-19 and may reflect the pathogenesis of COVID-19 in monocytes.

The current study reports the type of salvage chemotherapy following osimertinib and its treatment efficacy in patients with non-small-cell lung carcinoma (NSCLC) who acquire resistance to osimertinib. In this retrospective cohort study, data from the medical charts of 40 patients with NSCLC treated with osimertinib were obtained, primarily focusing on 14 undergoing salvage chemotherapy including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) or cytotoxic agents immediately following osimertinib. The treatment efficacy of salvage chemotherapy was evaluated. Five and nine patients received EGFR-TKI and cytotoxic agents following osimertinib, respectively. The overall response rate to EGFR-TKI treatment following osimertinib tended to be lower than that for cytotoxic agents (0% vs. 44.4%). The median progression-free-survival was significantly poorer in patients receiving EGFR-TKI treatment than in those receiving cytotoxic agents. Cytotoxic agent administration should be considered more frequently than EGFR-TKIs for patients with NSCLC resistant to osimertinib.

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

BackgroundRadial endobronchial ultrasonography (R-EBUS) has been used in conjunction with transbronchial lung cryobiopsy (TBLC) to diagnose diffuse parenchymal lung disease (DPLD) and to decrease the risk of bleeding complications. The diagnostic utility of different R-EBUS signs, however, remains unknown.ObjectivesThis study aimed to determine whether different R-EBUS signs could be used to more accurately diagnose DPLD and whether bronchial bleeding could be prevented with use of R-EBUS during TBLC.MethodEighty-seven patients with DPLD were included in this multicentre prospective study, with 49 patients undergoing R-EBUS. R-EBUS signals were characterised as displaying either dense or blizzard signs. Pathological confidence of specimens obtained from TBLC was compared between patients with dense versus blizzard signs, and severity of bronchial bleeding was determined based on whether R-EBUS was performed or not.ResultsAll patients with dense signs on R-EBUS showed consolidation on high-resolution CT (HRCT) imaging. Pathological confidence of lung specimens was significantly higher in patients with dense signs versus those with blizzard signs (p<0.01) and versus those who did not undergo R-EBUS (p<0.05). Patients who underwent TBLC with R-EBUS were more likely to experience no or mild bronchial bleeding than patients who did not undergo R-EBUS (p<0.01), with shorter procedure times (p<0.01).ConclusionsThe dense R-EBUS sign corresponded with consolidation on HRCT. High-quality lung specimens may be obtainable when the dense sign is observed on R-EBUS, and R-EBUS combined with TBLC may reduce risk of bronchial bleeding and shorten procedure times.

To assess the relationship of treatment effects between immune checkpoint inhibitor (ICI) and salvage chemotherapy, with the safety profile of salvage chemotherapy. 18 patients with advanced NSCLC treated using salvage chemotherapy following ICI treatment were retrospectively included. We assessed the overall response rate to and adverse events of salvage chemotherapy. The overall response rate to salvage chemotherapy was 33.3% and that of ICI responders was significantly higher than that of ICI nonresponders (66.7 vs 16.7%, respectively, p = 0.03). The incidence rate of adverse events to salvage chemotherapy was 55.6%. The efficacy of salvage chemotherapy was similar to that preceding ICI. Moreover, the safety of salvage chemotherapy was good.