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The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC) might depend on the presence of emphysema, but this association is not established. We aimed to investigate if quantitively and automatically measuring emphysema can predict the effect of ICIs. We retrospectively analyzed 56 patients with NSCLC who underwent immunotherapy at our hospital. We used the Goddard scoring system (GS) to evaluate the severity of emphysema on baseline CT scans using three-dimensional image analysis software. The emphysema group (GS ≥ 1) showed better progression-free survival (PFS) than the non-emphysema group (GS = 0) (6.5 vs. 2.3 months, respectively, p < 0.01). Multivariate analyses revealed that good performance status, GS of ≥ 1, and high expression of PD-L1 were independently associated with better PFS, while smoking status was not. In conclusion, quantitative evaluation of emphysema can be an objective parameter for predicting the therapeutic effects of ICIs in patients with NSCLC. Our findings can be used to generate hypotheses for future studies.

Background Nivolumab has promising efficacy for the treatment of non‐small cell lung cancer (NSCLC). Various predictive factors for nivolumab response in those with NSCLC have been reported, including performance status (PS). The objective of this retrospective study was to determine the predictive factors for nivolumab response in those with NSCLC with good PS and those with poor PS. Methods We retrospectively collected pretreatment clinical data of 296 consecutive patients with NSCLC treated with nivolumab. We investigated the relationship between progression‐free survival (PFS) and patient characteristics and analyzed predictive factors associated with good PS (PS 0‐1) or poor PS (PS 2‐4). Results The median age of patients was 70 years; 206 patients were male, and 224 were classified as having good PS (PS 0‐1). The median PFS was 3.0 months, 3.7 months, and 1.2 months for all patients, patients with good PS, and patients with poor PS respectively. Multivariate analysis showed that never smoking (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.15‐2.75), high C‐reactive protein (CRP) (HR, 1.39; 95% CI, 1.00‐1.93), liver metastasis (HR, 1.95; 95% CI, 1.24‐3.07), pleural effusion (HR, 1.45; 95% CI, 1.06‐2.00), and steroid use (HR, 2.85; 95% CI, 1.65‐4.94) were associated with significantly shorter PFS in patients with good PS. A high advanced lung cancer inflammation index (ALI) was significantly associated with longer PFS in patients with poor PS (HR, 0.24; 95% CI, 0.08‐0.79). Conclusions In patients with NSCLC treated with nivolumab, the factors found to be predictive of shorter PFS in patients with good PS were never smoking, high CRP, liver metastasis, pleural effusion, and steroid administration, whereas high ALI was predictive of longer PFS in patients with poor PS. PS was associated with PFS in patients with NSCLC receiving nivolumab treatment. Never smoking, high CRP, liver metastasis, pleural effusion, and steroid use at the commencement of nivolumab treatment were predictive of worse PFS in patients with NSCLC who received nivolumab treatment with good PS, and a high ALI was predictive of better PFS in patients with poor PS.

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.

Coronavirus disease 2019 (COVID‐19) can cause severe lymphopenia and respiratory failure requiring prolonged invasive mechanical ventilation (MV). COVID‐19 patients with severe lymphopenia or respiratory failure are at risk of developing secondary infections. Here, we present the needle autopsy findings of a critically ill patient with COVID‐19 who required reintubation and prolonged MV, and eventually died of secondary cytomegalovirus (CMV) pneumonia. This case highlights the potential risk of long‐term steroid use and the need for routine monitoring for CMV infection in critically ill patients with COVID‐19. Here, we present the needle autopsy findings of a critically ill patient with coronavirus disease 2019 (COVID‐19) who required reintubation and prolonged mechanical ventilation, and eventually died of secondary cytomegalovirus (CMV) pneumonia. This case highlights the potential risk of long‐term steroid use and the need for routine monitoring for CMV in critically ill patients with COVID‐19.

Background Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non‐small cell lung cancer (NSCLC). However, factors associated with long‐term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long‐term survival in NSCLC patients treated with nivolumab, using real‐world data. Methods We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG‐PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long‐term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong‐term survivors and long‐term survivors and performed univariate and multivariate analyses of factors associated with long‐term survival. Results Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG‐PS ≤1 were included in the study. Young age, ECOG‐PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil‐to‐lymphocyte ratio (NLR) change (ΔNLR) <1 were significantly associated with long‐term survival. Long‐term survivors had significantly higher response and disease control rates than nonlong‐term survivors. Multivariate analysis showed that ΔNLR <1 was significantly associated with long‐term survival. Further, OS was significantly different between the PS 0 and PS 1 groups (median OS: 32.0 months vs. 10.6 months) and the nonincreasing NLR and increasing NLR groups (median OS: 20.8 months vs. 5.7 months). Conclusions ΔNLR <1 was a significant long‐term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with ECOG‐PS ≤1 treated with nivolumab. We evaluated the differences between nonlong‐term survivors and long‐term survivors and performed univariate and multivariate analyses of factors associated with long‐term survival. ΔNLR <1 was a significant long‐term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab.

Combined small cell lung cancer (c‐SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non‐small cell carcinoma (NSCLC). Standard chemotherapy for patients with c‐SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c‐SCLC. However, little is known about anaplastic lymphoma kinase (ALK) rearrangement in c‐SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK‐positive c‐SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR‐ or ALK‐positive c‐SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component. Key points Significant findings of the study • This is the first report describing the treatment course comprising immunochemotherapy and ALK‐TKI in a patient with c‐SCLC harboring ALK rearrangement. What this study adds • Our case and literature review suggest that although ALK mutation is rare in patients with c‐SCLC, its identification and treatment with ALK‐TKIs may contribute to clinical benefits. Standard chemotherapy for patients with c‐SCLC has not yet been established. Here, we report a young female patient successfully treated with alectinib for ALK‐positive c‐SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma.

This is the first report of COVID‐19 in a human T‐cell lymphotropic virus type‐1 (HTLV‐1) carrier. HTLV‐1 infection can cause immune dysfunction even in asymptomatic carriers. This case highlights the need for guidance on management of COVID‐19‐HTLV‐1 coinfection, specifically on the appropriate use of corticosteroid treatment while considering secondary infection. HTLV‐1 infection can cause immune dysfunction even in asymptomatic carriers. There is a need for guidance on how to manage COVID‐19 in patients with HTLV‐1 infection, and especially optimized steroid treatment while considering secondary infection.

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.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1 – 5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene ( DOCK2 ), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis ( n  = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target. A genome-wide association study highlights a variant in DOCK2 , which is common in East Asian populations but rare in Europeans, as a host genetic risk factor for severe COVID-19.