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Optimising response to immunotherapies in pleural mesothelioma: clinical data and alternative models for the evaluation of new strategies
http://thorax.bmj.com/cgi/content/short/81/8/806?rss=1
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.
| 2 | Rethinking pleural tuberculosis through the lens of cell-free DNA
http://thorax.bmj.com/cgi/content/short/81/8/721?rss=1
Tuberculous pleuritis (TBP) remains one of the most diagnostically challenging manifestations of tuberculosis.1 2 Despite its global prevalence, particularly in high-burden settings, confirmation of TBP is frequently elusive. Conventional microbiological techniques perform poorly in pleural fluid,3 4 where mycobacterial burden is low and organisms are often non-viable. Diagnostic confidence is therefore commonly inferred from surrogate markers such as adenosine deaminase (ADA), immunological assays5 6 or clinical response to therapy. The result is a persistent trade-off between diagnostic delay, empirical treatment and invasive pleural biopsy. In this issue of Thorax, Zhang and colleagues describe an approach that reframes this problem by leveraging modern molecular diagnostics to overcome paucicellularity in the pleural space.1 7 8 Rather than continuing to search for intact Mycobacterium tuberculosis (MTB) organisms or their genomic DNA (gDNA), the authors... | 48 |
| 3 | Inducible laryngeal obstruction/vocal cord obstruction: still happening under our noses
http://thorax.bmj.com/cgi/content/short/81/8/733?rss=1
Inducible laryngeal obstruction (ILO) is an enigmatic condition with considerable impact on clinical practice. Historically, this condition has been known by several names, most notably vocal cord dysfunction (VCD) coined by Christopher and colleagues in 1983.1 However, it has been proposed to replace this terminology by the umbrella term ‘ILO’ and the term ILO will therefore be used throughout the manuscript. The prevalence of ILO in a general population has not been reported. However, it often acts as an asthma mimic, with a pooled prevalence in adults with asthma of approximately 25%.2 Progress in chronic cough3 and severe asthma has reignited interest in ILO as a key treatable trait that could be impeding remission and contributing to ‘difficult-to-treat asthma’.4 Approximately 10 years ago, we published a paper in Thorax entitled: ‘Middle airway obstruction: it is happening under our noses’ to draw... | 52 |
| 4 | Aligning management of chronic cough in asthma with BTS/NICE/SIGN guidance
http://thorax.bmj.com/cgi/content/short/81/8/736?rss=1
We welcome the recently updated British Thoracic Society (BTS)/National Institute for Health and Care Excellence (NICE)/Scottish Intercollegiate Guidelines Network (SIGN) approach to asthma treatment1 which provides simple, clear guidance to clinicians, based on robust evidence. Going further than Global Initiative for Asthma (GINA) guidance,2 the use of short-acting beta agonists and inhaled corticosteroid (ICS) monotherapy is no longer recommended. Initial treatment is with a combined inhaled corticosteroid/formoterol inhaler either as required for mild symptoms (as-needed therapy (AIR)) or a regular dose supplemented by as required use if symptoms are more persistent (maintenance and reliever therapy (MART)). For individuals presenting with chronic cough, we propose a pragmatic approach for clinicians, to ensure consistent and safe asthma treatment for individuals, aligning with the new guidelines. Chronic cough in adults, defined as >8 weeks (note >4 weeks in children), is an important and troublesome symptom that is a... | 32 |
| 5 | Running away from the smoke, the role of physical activity in tobacco dependency treatment
http://thorax.bmj.com/cgi/content/short/81/8/729?rss=1
The tobacco epidemic is far from over. Tobacco smoking still causes an estimated eight million deaths a year and is the largest preventative healthcare issue we face worldwide.1 Tobacco smoking is responsible for a multitude of chronic diseases and cancers, and a main factor driving health inequalities,2 making smoking cessation a vital intervention across physical, mental and social health.3 Smoking cessation programmes traditionally combine behavioural support with pharmacological tools to reduce withdrawal symptoms, including alternative sources of nicotine such as dual nicotine replacement therapy and nicotine analogues like varenicline or cytisine, delivered in an outpatient setting.4 However, researchers have investigated novel deviations from this model, via embedding services into clinical lung cancer screening, using digital tools and physical activity interventions.5 6 Physical activity has been proposed as a tool in cessation due to potential impacts in helping... | 31 |
| 6 | What constitutes meaningful gain in skeletal muscle strength in COPD?
http://thorax.bmj.com/cgi/content/short/81/8/731?rss=1
Low muscle mass and strength is a common systemic consequence of chronic obstructive pulmonary disease (COPD) and an important determinant of clinical outcomes.1–3 Quadriceps muscle strength, in particular, predicts transplant-free survival in COPD independent of the severity of airflow obstruction.3 While it may be assumed that low muscle strength is an inevitable feature of advanced disease, this is far from reality. Rather, it represents dysfunction of the largest organ system by mass in the human body and is often present in the absence of severe disease.4 Crucially, unlike many disease manifestations, skeletal muscle is highly modifiable, potently affected by both therapeutic (eg, resistance training) and habitual (eg, daily physical activity) patterns of mechanical tension. For individuals with COPD, progressive resistance exercise targeting the upper and lower limbs forms a key component of therapeutic interventions such as pulmonary rehabilitation (PR),... | 29 |
| 7 | An asthma-related anxiety intervention appropriate for the shift to digitalised care
http://thorax.bmj.com/cgi/content/short/81/8/727?rss=1
Asthma can cause immediate disabling symptoms such as wheezing and breathlessness. These symptoms, combined with the implications of living with a potentially fatal condition even when symptoms are well controlled, can also cause anxiety for many patients—with recent meta-analytical estimates from over 50 000 patients reporting a pooled prevalence of anxiety symptoms in 32% of people with asthma.1 As well as the impact of asthma on anxiety, anxiety symptoms can further worsen pulmonary symptoms experienced by patients.2 Recent clinical guidelines have recognised scientific consensus of the role that psychological and behavioural factors play in worsening asthma outcomes.3 Cognitive (eg, perception of breathlessness, interoception), affective (eg, chronic and acute stress) and behavioural factors (eg, poor medication adherence, avoidance behaviours) can all contribute to worse asthma outcomes—including anxiety-related catastrophic interpretation of symptom experiences, that can lead to a vicious worsening spiral of physical symptoms and anxiety in... | 30 |
| 8 | Getting more than early detection from lung cancer screening
http://thorax.bmj.com/cgi/content/short/81/8/725?rss=1
Lung cancer (LC) remains the deadliest cancer in the world and LC screening programmes continue to expand across healthcare systems to improve outcomes by earlier detection.1 Following results from screening trials, multiple countries have implemented their versions of LC screening programmes or have expanded their screening eligibility criteria.2–5 By design, these programmes aim to identify individuals at the highest risk of developing LC. The main prescreening eligibility assessment criteria are age and smoking status.1 In the UK, between one-third and 50% of participants attending ‘lung health checks’ for LC screening are actively smoking.6 To aid smoking cessation, most programmes rely on a brief advice plus onward referral approach: smokers receive short advice during the lung health check, then are asked to engage later with separate stop-smoking services.6 However, given the high number of... | 27 |
| 9 | Unraveling lung function trajectories and social determinants of health: the quest continues
http://thorax.bmj.com/cgi/content/short/81/8/723?rss=1
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and COPD prevalence is expected to increase for decades to come.1 2 Worldwide, it is estimated that as many as 480 million people have COPD.2 Tobacco use contributes to most cases of COPD, but there are extensive data to show that social determinants of health (SDOH) contribute to lung function impairment and COPD.3 SDOH are the conditions to which people are born, raised, live and work in. These conditions include factors such as education access and attainment, socioeconomic status (SES), access to healthcare and food, and employment. Exposures like poor air quality, undernutrition and occupational hazards can impair lung function from a young age and make individuals more susceptible to respiratory diseases like asthma and COPD.4 5 Minoritised groups are disproportionately represented in those with... | 29 |
| 10 | Arthrographis kalrae presenting as an enlarging solitary pulmonary nodule
http://thorax.bmj.com/cgi/content/short/81/8/794?rss=1
A 53-year-old male manual labourer presented for evaluation of a solitary nodule in the left lower lobe. The lesion had initially been detected incidentally during a health check-up 7 years earlier and had enlarged over the preceding 2 months. The patient reported an intermittent productive cough with mucoid, blood-streaked sputum. He did not smoke and had received empirical four-drug antituberculosis therapy 1 year earlier for an unconfirmed left lower lobe pulmonary opacity, without substantial symptomatic or radiological improvement. Chest CT revealed an enlarging subpleural nodule with increasing solid components in the left lower lobe, without mediastinal lymphadenopathy, raising concern for an early-stage primary lung malignancy (figure 1A). Given the diagnostic uncertainty, video-assisted thoracoscopic surgery (VATS) wedge resection was performed. Intraoperative exploration identified a firm, 15 mm nodule without pleural indentation or effusion (figure 1B). Histopathological examination showed chronic inflammation, circumscribed abscess formation, fibrosis and reactive atypia of... | 31 |
| 11 | Enhanced diagnosis of tuberculous pleurisy using a multiplex droplet digital PCR assay targeting circulating mycobacterial DNA
http://thorax.bmj.com/cgi/content/short/81/8/738?rss=1
Background
Tuberculous pleurisy (TBP) is a leading aetiology of exudative pleural effusion in tuberculosis (TB)-endemic regions and poses significant diagnostic challenges due to its paucibacillary nature of Mycobacterium tuberculosis (MTB) in pleural fluid. This study aims to characterise MTB-derived cell-free DNA (cfDNA) in pleural effusion and to develop an optimised molecular assay to improve TBP diagnostic accuracy.
Methods
We quantified MTB cfDNA/genomic DNA (gDNA) concentrations and characterised cfDNA fragment profiles in pleural effusion specimens using ddPCR. A multiplex droplet digital PCR (ddPCR) assay was developed, targeting two insertion sequences (IS6110 and IS1081) using ultra-short amplicons (49–59 bp) to enhance detection efficiency. Diagnostic performance was prospectively evaluated in 356 consecutive adults with radiologically confirmed pleural effusion, using composite microbiological criteria as the reference standard.
Results
MTB cfDNA exhibited significantly higher detection rates than gDNA in definite TBP cases (p=0.0006), with dominant fragment lengths of 60–80 bp. The multiplex ddPCR assay demonstrated a limit of detection of 0.2 genome equivalents per reaction. Among microbiologically confirmed TBP cases (n=69), the assay achieved a sensitivity of 94.2%, significantly outperforming Xpert MTB/RIF (52.0%, p
Conclusions
Our findings establish MTB cfDNA as the predominant nucleic acid form in tuberculous pleural effusion. The optimised multiplex ddPCR platform, leveraging multicopy targets and fragment-length-adapted amplification, achieves improved diagnostic sensitivity without compromising specificity in a high-prevalence TB setting. This approach may help address key limitations of TBP diagnostics and shows promise for clinical implementation. | 32 |
| 12 | Intratumour, anatomical and temporal heterogeneity in mesothelioma
http://thorax.bmj.com/cgi/content/short/81/8/796?rss=1
Background
Pleural mesothelioma (PM) is characterised by marked heterogeneity, both clinically in terms of survival and response to treatment, and in terms of histology and molecular status. Development of novel therapies, stratified treatment pathways and a better understanding of resistance mechanisms are urgently needed. This requires an in-depth understanding of the multiple sources of heterogeneity affecting tumour cells and the tumour microenvironment.
Methods and results
This review, which synthesises the key studies available in the literature, provides a detailed description of the current state of the art regarding heterogeneity in PM. After an overview of the general molecular landscape and a summary of heterogeneity between patients (intertumour heterogeneity), we review sources of variation within an individual patient’s tumour (intratumour heterogeneity). This section covers both the local heterogeneity classically reported in other tumours and the anatomical heterogeneity, which is more profound in PM given the large pleural surface area over which the disease develops and progresses. We also synthesise the available data on changes that develop over time (temporal heterogeneity). The various cellular and molecular sources of heterogeneity are also highlighted throughout each section, including histological variations, genomic and non-genomic molecular changes and variations in tumour, stromal and immune compartments.
Conclusions
The solid understanding of intertumour heterogeneity recently achieved has highlighted diverse molecular and cellular landscapes. However, this knowledge has yet to be effectively translated into clinical practice (eg, diagnostic classification, treatment allocation, trial design). Further research is needed for a better comprehension of intratumour heterogeneity, including characterisation of local tumour-immune-stromal interactions, including those based on anatomical position on the pleural surface. Efforts should also include dissection of intratumour heterogeneity in patients treated by immunotherapy, development of preclinical models that adequately capture heterogeneity and the investigation of clonality and tumour evolution over time. | 36 |
| 13 | Disparities in lung function trajectories among tobacco-exposed individuals
http://thorax.bmj.com/cgi/content/short/81/8/749?rss=1
Background
The relationship of social determinants of health (SDOH), environmental exposures and medical history to lung function trajectories is underexplored. A better understanding of these relationships could inform preventive strategies for lung health.
Methods
We analysed data from COPDGene, a US longitudinal, observational study. Participants were tobacco-exposed (≥10 pack-years of smoking) non-Hispanic Black and non-Hispanic White adults aged 45–80 years. We analysed 2990 males and 2945 females, using Bayesian trajectory modelling on post-bronchodilator forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). We applied multinomial logistic regression to assess the association of SDOH, environmental exposures and medical history with lung function trajectories.
Measurements and main results
Six trajectories were identified within each sex. Non-Hispanic Black race was more prevalent in trajectories characterised by lower FEV1 and FVC values (ie, lower lung function trajectories) compared with non-Hispanic White adults. In adjusted models, non-Hispanic Black race, residence in the Southeastern USA, lifetime asthma and a father with COPD were associated with significantly higher odds of the lowest trajectory (ie, trajectory six vs the reference trajectory) for both sexes. Higher income and private insurance showed inverse associations with lower lung function trajectories. The Social Vulnerability Index socioeconomic theme (based on census-level poverty, unemployment, income and educational attainment) was associated with the lowest trajectory in males.
Conclusions
Significant disparities in lung function trajectories exist between non-Hispanic Black adults and non-Hispanic White adults. Individual- and community-level factors are associated with lower lung function trajectory in people exposed to tobacco. | 37 |
| 14 | Journal club
http://thorax.bmj.com/cgi/content/short/81/8/818?rss=1
Rapid results, Lingering questions: PCR in antibiotic stewardship Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are a significant cause of morbidity and mortality among patients in the intensive care unit (ICU). Early antibiotic therapy improves patient outcomes, but delays in pathogen identification results in suboptimal antimicrobial stewardship. Rapid molecular diagnostics can identify pathogens with increased speed and sensitivity, but evidence demonstrating clinical benefit has been limited. Enne et al (Intensive Care Med 2025;51:272) conducted the INHALE WP3 trial, a randomised, multicenter trial assessing the clinical utility of rapid PCR test compared with standard of care. Among 554 patients hospitalised for HAP or VAP across 14 ICUs in the United Kingdom, 277 patients were each randomised to the rapid PCR group and standard of care. Rapid PCR substantially improved the time for pathogen identification, with results available in under 2 hours compared with approximately 74 hours for routine cultures.... | 39 |
| 15 | Guidelines adherence: from quality indicator to prognostic relevance
http://thorax.bmj.com/cgi/content/short/81/8/719?rss=1
The treatment of chronic obstructive pulmonary disease (COPD) has been guided for decades by robust clinical practice guidelines (CPGs), such as NICE1 and GesEPOC,2 as well as international recommendations such as GOLD,3 which provide clinicians with clear recommendations for diagnosis, risk stratification and pharmacological management. Yet, as the study by Yin and colleagues published in this issue in Thorax4 demonstrates, the translation of these recommendations into real-world clinical practice remains strikingly incomplete. Despite widespread dissemination of CPGs and the growing availability of effective inhaled therapies, adherence to guideline-based care continues to be disappointingly low.5 The present work reveals three crucial and inter-related insights. First, adherence to CPGs in COPD pharmacotherapy remains suboptimal, characterised by both overuse and underuse of inhaled medication. Overuse—most notably of inhaled corticosteroids (ICS)—persists in low-risk patients without clear indications, exposing them to unnecessary side effects... | 57 |
| 16 | [Personal View] The role of sweat chloride in determining CFTR protein restoration in people with cystic fibrosis
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(26)00159-1/fulltext?rss=yes
Sweat chloride concentrations are elevated in people with cystic fibrosis due to the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial cell membrane ion channel. For many people with cystic fibrosis with responsive variants and drug access, treatment with CFTR modulators increases CFTR function, reduces sweat chloride concentrations, and improves lung health and quality of life. In clinical trials, average sweat chloride reduction is correlated with clinical efficacy across different modulators and study populations. | 150 |
| 17 | [Position Paper] Reproductive health guidance for the cystic fibrosis community: a Cystic Fibrosis Foundation Position Paper
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(26)00120-7/fulltext?rss=yes
The Cystic Fibrosis Foundation organised a multidisciplinary committee to develop this Position Paper to outline current knowledge and best practices in reproductive health care for individuals with cystic fibrosis. Working groups reviewed the literature and provided relevant guidance on reproductive health services, fertility, contraception, preconception and pregnancy, and cystic fibrosis transmembrane conductance regulator (CFTR) modulator exposure in utero and during lactation. Findings included: (1) reproductive health-care provision should be standardised, and education should begin at cystic fibrosis diagnosis and revisited annually; (2) contraception is safe overall, but underutilised in those with cystic fibrosis compared with the general population; (3) fertility might be improving with CFTR modulators for females with cystic fibrosis, but not for males with cystic fibrosis—assisted reproductive technologies are still required for males to achieve biological parenthood; (4) pregnancy requires close monitoring and unique screening for diabetes; and (5) CFTR modulator exposure in utero has implications for infant monitoring and cystic fibrosis screening results in newborns. | 151 |
| 18 | 🔴 Noninvasive Respiratory Support for Adult Patients with Acute Respiratory Failure
: 2026 ATS Guidelines
Updates in Medicine
July 2026 #medicalguidelines
@Updates_in_Medicine | 283 |
| 19 | [Correspondence] COPA syndrome: a monogenic mimic of rheumatoid arthritis-associated ILD that warrants inclusion in future consensus statements
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(26)00220-1/fulltext?rss=yes
We read with great interest the expert consensus statement by Joshua J Solomon and colleagues on the screening, diagnosis, and management of rheumatoid arthritis-associated interstitial lung disease (ILD).1 Their Position Paper addresses genetic risk factors, including variants shared with idiopathic pulmonary fibrosis such as the MUC5B promoter polymorphism and rare variants in TERT, RTEL1, PARN, and SFTPC. We highlight an unmentioned monogenic condition: COPA (coatomer subunit α) syndrome. | 381 |
| 20 | [Comment] Beyond eosinophils: redefining asthma exacerbations in the biologic era
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(26)00194-3/fulltext?rss=yes
The introduction of biologic therapies for severe asthma has transformed clinical practice. Among these agents, benralizumab occupies a unique position. By targeting the interleukin-5 receptor α, benralizumab induces near-complete depletion of circulating eosinophils and substantially reduces exacerbation risk.1 Yet, even among patients with excellent biological responses, exacerbations continue to occur. Why these events persist remains an important unanswered question in severe asthma. In this issue of The Lancet Respiratory Medicine, Jennifer Logan and colleagues report findings from the BenRex study,2 a prospective, multicentre cohort specifically designed to characterise exacerbations occurring during benralizumab treatment. | 389 |
