BACKGROUND: We describe the occurrence of second primary lung cancers (SPLCs) and their determinant in Sweden. METHODS: Nation-wide cancer registry from years 1961 to 2021 identified a total of 853 SPLCs. RESULTS: The in...BACKGROUND: We describe the occurrence of second primary lung cancers (SPLCs) and their determinant in Sweden. METHODS: Nation-wide cancer registry from years 1961 to 2021 identified a total of 853 SPLCs. RESULTS: The incidence of SPLCs increased almost linearly from 1980 onwards, equally for women and men and approximately equally after the four main histological types. SPLC included adenocarcinoma 63.9%, squamous cell carcinoma (SCC) 19.4%, small cell carcinoma 9.6% and large cell carcinoma 9.1%. The female cumulative probability (CumP) of SPLC after first adenocarcinoma in 10 years reached 0.019, after SCC 0.015 and after small and large cell carcinoma 0.008. The respective CumP for men was 0.013, 0.012, 0.002 and 0.005. While adenocarcinoma was often followed by second adenocarcinoma, after first non-adenocarcinoma SPLCs presented in diverse histologies. Relative risk of SPLC compared with first lung cancer was overall 3.59, higher for women (4.16) than for men (2.99) and approximately equally high after adenocarcinoma and SCC. In patients diagnosed before age 55 years, the relative risk was 6.68 for all, but after female adenocarcinoma it was 9.95 compared with 6.77 for males. The highest relative risks, up to 20-fold, were found after early onset female adenocarcinoma diagnosed after defined T stages. CONCLUSIONS: Although SPLCs are still rare, their number is increasing rapidly and the relative risks compared with first lung cancer are substantial, qualifying selected groups of high-risk patients, such as patients with early onset adenocarcinoma for early detection by CT screening when/if such tests become available.
RATIONALE: Residual sleep apnoea-defined by an Apnoea-Hypopnoea Index ≥10 events/hour-affects~20% of obstructive sleep apnoea patients treated with positive airway pressure therapy and poses a major clinical challenge. V...RATIONALE: Residual sleep apnoea-defined by an Apnoea-Hypopnoea Index ≥10 events/hour-affects~20% of obstructive sleep apnoea patients treated with positive airway pressure therapy and poses a major clinical challenge. Ventilatory control instability is a plausible cause of residual sleep apnoea. Elevated loop gain (LG), a measure of ventilatory instability, may be a risk factor, but this has not been rigorously tested. OBJECTIVE: To assess whether high LG at baseline is associated with residual sleep apnoea on positive airway pressure therapy in two large, randomised control trials: Apnoea Positive Pressure Long-Term Efficacy Study (APPLES) and Randomised Intervention with CPAP in Coronary Artery Disease and OSA (RICCADSA). METHODS: LG was estimated from baseline polysomnography using a validated method. Residual sleep apnoea was defined using polysomnography on positive airway pressure at 2 months (APPLES) or device downloads at 3 months (RICCADSA). Logistic regression estimated the odds of residual sleep apnoea with high LG (highest quartile), adjusting for confounders. A sensitivity analysis was performed using linear regression, where both the exposure and outcome were defined continuously. MEASUREMENTS AND MAIN RESULTS: In the unadjusted analysis, high LG was associated with threefold odds of residual sleep apnoea in both samples. After adjustment, elevated odds persisted in both APPLES (2.17 (1.24-3.78)) and RICCADSA (3.31 (1.33-8.24)). Associations remained after accounting for measures of central sleep apnoea. Linear regression confirmed the association of LG and residual Apnoea-Hypopnoea Index. CONCLUSIONS: High LG is a significant risk factor for residual sleep apnoea on positive airway pressure therapy. Ventilatory control instability identified at baseline may warrant closer monitoring or the initiation of adjunctive therapies aimed at reducing LG and improving the therapeutic response.
Rehman U, Ahn Y, Yerushalmi E
… +12 more, Abdelwahab M, Eynon-Lewis N, Liu J, Sutton L, Holsinger FC, Capasso R, Côté ML, Cheong RCT, Kotecha B, Ohayon MM, Hafner M, Lechner M
This study estimates the prevalence and workplace productivity burden of obstructive sleep apnoea (OSA) syndrome in the UK and USA, using self-reported breathing pauses and excessive daytime sleepiness as a proxy. The pr...This study estimates the prevalence and workplace productivity burden of obstructive sleep apnoea (OSA) syndrome in the UK and USA, using self-reported breathing pauses and excessive daytime sleepiness as a proxy. The prevalence of OSA syndrome was 22.8% in the USA and 19.5% in the UK. Annual productivity losses were estimated at US$180.2 billion in the USA and £4.22 billion in the UK. In the UK and USA, individual-level productivity losses exceeded the cost of continuous positive airway pressure (CPAP) treatment, suggesting that improved identification, access to treatment and adherence could yield significant economic benefits in both countries.
Influenza A virus (IAV)-induced exacerbations are a major contributor to morbidity in chronic obstructive pulmonary disease (COPD), yet the epithelial mechanisms that govern these events remain unknown. We profiled the r...Influenza A virus (IAV)-induced exacerbations are a major contributor to morbidity in chronic obstructive pulmonary disease (COPD), yet the epithelial mechanisms that govern these events remain unknown. We profiled the response to IAV infection of differentiated airway epithelial cells from healthy donors and individuals with COPD at single-cell resolution. The analysis revealed infection-driven shifts across multiple epithelial compartments and distinct alterations in cell-cell communication in COPD, associated with an increased CXCL11 expression. Functional assays demonstrated that CXCL11 augments mucus-associated gene and protein expression, particularly MUC5AC, increases mucus secretion and viscosity and is associated with reduction of virus-related immune pathways. This highlights CXCL11 as a contributor to both mucus hypersecretion and impaired antiviral epithelial responses in COPD exacerbations.
BACKGROUND: The global burden of bacterial respiratory infections, now among the leading causes of mortality worldwide, has been exacerbated by the rise of antimicrobial resistance. This has highlighted significant gaps...BACKGROUND: The global burden of bacterial respiratory infections, now among the leading causes of mortality worldwide, has been exacerbated by the rise of antimicrobial resistance. This has highlighted significant gaps in current management strategies, underscoring the need for deeper insights into bacterial pathogenesis. METHODS: This review assesses the utility of various experimental models for achieving human relevance and explores recent innovations in human airway organoid (HAO) technology for modelling bacterial infections. RESULTS: Human airway organoid models offer a promising solution by merging the biological relevance of animal models with the versatility of cell cultures. Over the last decade, advancements in HAO technology have revolutionised our understanding of infection pathogenesis and expanded the scope of infection biology. CONCLUSIONS: We highlight the transformative discoveries made using HAOs and their potential to enhance healthcare management for bacterial respiratory infections.
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Most single-cell studies rely on end-stage explant lungs, leaving early disease mechanisms poor...INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Most single-cell studies rely on end-stage explant lungs, leaving early disease mechanisms poorly understood. Profiling earlier stages may reveal distinct cellular phenotypes that could be pharmacologically targeted. Recent evidence also implicates airway epithelial cells in IPF disease development and progression. METHODS: To investigate early-stage IPF mechanisms, we profiled the airway mucosa of newly diagnosed, treatment-naïve patients using single-cell RNA-sequencing of air-liquid interface cultures. We further assessed the transcriptional and functional responses of these cells to antifibrotic drugs (nintedanib and pirfenidone) and a Src kinase inhibitor (saracatinib). RESULTS: Profiling of 129 986 transcriptomes identified primed fibroblasts ( , ), dysregulated basal cells ( , , ), and proinflammatory airway epithelial cells (SAA, CXCL, CCL). Integrative analyses with explant-derived IPF atlases revealed different basal and fibroblast phenotypes spanning tissue regions and disease stages. In vitro, bronchial epithelial cells stimulated fibroblast proliferation and activation, and fibroblasts remained sensitive to TGF-β. While all three drugs attenuated many IPF signatures, saracatinib most effectively suppressed fibroblast activation and epithelial proliferation. CONCLUSIONS: This study defines epithelial-mesenchymal programmes of the airway mucosa at an early, diagnostic stage of IPF and demonstrates distinct drug responses at single-cell resolution. By linking airway-derived phenotypes to antifibrotic efficacy, our findings highlight the therapeutic potential of saracatinib and may inform future treatment strategies.
BACKGROUND: Pleural mesothelioma (PM) is a rare tumour, usually associated with previous asbestos exposure. Standard frontline, pemetrexed/platinum-based chemotherapy has been challenged since 2020 by dual immunotherapy,...BACKGROUND: Pleural mesothelioma (PM) is a rare tumour, usually associated with previous asbestos exposure. Standard frontline, pemetrexed/platinum-based chemotherapy has been challenged since 2020 by dual immunotherapy, that is, anti-programmed cell death-1 (anti-PD-1) + anti-cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors and recently by combination of chemotherapy + anti-PD-1. However, PM prognosis remains globally poor, without validated curative treatment to date. METHODS: We reviewed alternative pre-clinical models and clinical data for the evaluation of new treatments and strategies to optimize response to immunotherapies in pleural mesothelioma. RESULTS: Various innovative immunotherapies alone or combined with standard treatments and/or targeted therapies are currently assessed by clinical trials. The evaluation of these new strategies deserves relevant preclinical models, requiring the use of human models in addition to or even instead of mouse models. These models recapitulate, at least partially, heterogeneity of the tumours and offer new perspectives for the development and evaluation of immunotherapies. However, like all models, they exhibit advantages and disadvantages needing to be identified in order to use them to answer a well-defined biological question. CONCLUSIONS: Along with ongoing trials testing innovative immunotherapies and strategies in pleural mesothelioma, original pre-clinical models are required to optimize these strategies and discover new ones for our patients.
Husta BC, Cheng GZ, Batra H
… +12 more, Reisenauer JS, Bartek WM, Kalchiem-Dekel O, Zouk A, Patel N, Chawla M, Eapen GA, Jimenez CA, Lee RP, Bott MJ, Oh S, Casal RF
BACKGROUND: The use of 3D imaging with navigation bronchoscopy has increased with the introduction of mobile cone-beam CT (mCBCT). Shape-sensing robotic-assisted bronchoscopy (ssRAB) integrated with mCBCT has been introd...BACKGROUND: The use of 3D imaging with navigation bronchoscopy has increased with the introduction of mobile cone-beam CT (mCBCT). Shape-sensing robotic-assisted bronchoscopy (ssRAB) integrated with mCBCT has been introduced to correct for CT to body divergence (CT-BD) during the biopsy of peripheral pulmonary nodules (PPNs). METHODS: Prospective observational multicentre study, enrolling patients with a PPN of ≤20 mm suspicious for malignancy, assessing tool-in-lesion (TIL), diagnostic yield, sensitivity for malignancy and incidence of pneumothorax or airway bleeding. Non-malignant index biopsies were followed for 12 months. Descriptive statistics are reported for all variables along with 95% CI for primary endpoints. RESULTS: 155 consecutive patients were enrolled at six centres. Median nodule size was 14.0 mm (IQR 11.0-17.0), with 54.8% of nodules (85/155) in the upper lobes, 25.8% (40/155) with CT bronchus sign present and median distance to the nearest pleural surface of 8.2 mm (IQR 1.8-20.0). TIL was achieved in 154/155 (99.4%, 95% CI 96.5 to 100.0) procedures. A median of two (IQR 1-3) mCBCT spins were performed, with median dose area product of 25.7 Gy · cm (IQR 11.0-46.7). Diagnostic yield per the American Thoracic Society/American College of Chest Physicians (ATC/ACCP) definition was 89.0% (n=138/155; 95% CI 83.0 to 93.5) and sensitivity for malignancy was 91.5% (95% CI 86.4 to 96.5). No pneumothorax (0%, 95% CI 0.0 to 2.4) and two Nashville Grade three bleeding events were reported (1.3%, 95% CI 0.2 to 4.6). INTERPRETATION: The first prospective multicentre study of integrated ssRAB and mCBCT for small peripheral nodules resulted in diagnostic outcomes similar to those reported for transthoracic biopsy with a more favourable safety profile. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT05562895.
Pollock J, Huang JTJ, Shuttleworth M
… +19 more, Long MB, Richardson H, Alferes de Lima D, Kuzmanova E, Clarke C, Shteinberg M, Aliberti S, Haworth C, Chotirmall SH, Polverino E, Goeminne PC, Loebinger M, Lorent N, Ringshausen FC, Sibila O, Rodriguez-Suarez E, McCrae C, Shoemark A, Chalmers JD
OBJECTIVES: Eosinophilic bronchiectasis is defined by a blood eosinophil count (BEC) ≥300 cells/µL, but blood eosinophils imperfectly reflect airway eosinophilic inflammation. Here, we investigated the relationship betwe...OBJECTIVES: Eosinophilic bronchiectasis is defined by a blood eosinophil count (BEC) ≥300 cells/µL, but blood eosinophils imperfectly reflect airway eosinophilic inflammation. Here, we investigated the relationship between eosinophilic airway inflammation, blood eosinophils and clinical severity in bronchiectasis and explored the phenotype associated with eosinophilic bronchiectasis. METHODS: Sputum from 180 patients with stable CT-confirmed bronchiectasis was utilised to investigate airway levels of eosinophil proteins (eosinophil peroxidase (EPX), eosinophil derived-neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein (MBP) and Galectin-10 (Gal-10)) using a novel stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. To profile eosinophilic bronchiectasis, a nested analysis of patients with BEC <150 cells/µL (n=52) and ≥300 cells/µL (n=49) was conducted. RESULTS: Sputum concentrations of Gal-10, ECP and EDN were weakly but significantly associated with radiological severity, FEV and sputum culture positivity for . Airway eosinophil protein concentrations did not associate with exacerbation frequency. Total eosinophil protein concentration moderately correlated with BECs (r=0.33 95% CI 0.14 to 0.49, p=0.0007). Nested analysis revealed increased sputum PCR-positivity for (26.7% vs 7.7%, p=0.033) and an increased frequency of patients showing signs of sensitisation (defined as -specific IgE titres >0.35 kUA/L, 24.5% vs 3.8%) in eosinophilic bronchiectasis. Sputum inflammatory biomarkers and clinical parameters did not differ between groups. CONCLUSIONS: LC-MS/MS can detect eosinophilic inflammation within bronchiectasis sputum. Weak associations between elevated airway eosinophil proteins, bronchiectasis severity and infection were observed. Direct measurement of eosinophilic airway inflammation provides additional information in addition to BECs. Eosinophilic bronchiectasis associated with infection and sensitisation.