Pleural mesothelioma is an aggressive cancer often diagnosed late due to the lack of reliable non-invasive biomarkers. Early Contrast Enhancement (ECE) observed in Dynamic Contrast-Enhanced MRI (DCE-MRI) is a promising biomarker characterized by a peak in mean signal intensity within 270 seconds in pleural regions, achieving a malignancy classification accuracy of 0.83. However, it depends on manual ROI annotation, limiting clinical adoption. We present Meso-Regions, an automated pipeline that detects ECE-positive regions as 4D segmentation masks in DCE-MRI. The method integrates motion correction, pleural-region segmentation, automatic ROI placement, and patient-level classification based on temporal mean-intensity curves. Applied to 56 patient scans (20 for training and 36 for testing), the approach achieved a malignancy classification accuracy of 0.60, showing high concordance in malignant cases. False positives occurred mainly in benign subtypes with known progression risk, suggesting potential for early malignancy detection. Meso-Regions is explainable by design, generating 4D ECE-positive segmentation masks to assist clinical assessment of pleural mesothelioma.

BACKGROUND:CT scans are the current gold standard for disease monitoring for Pleural mesothelioma (PM), with radiology reported using the modified RECIST criteria. While mRECIST has its own challenges, attending for CT scans adds time and expense. A blood-based biomarker which tracks disease status could enable more responsive, community-based disease monitoring. This study evaluated the relationship between serial serum mesothelin (SM) levels and disease status. METHODS:Patients with PM were recruited from Assess-Meso, a multi-centre prospective cohort study of patients with mesothelioma, between 28/2/2019 and 31/12/2023. Logistic regression, adjusted for sex, age, histology, performance status, eGFR and treatment, was used to assess the relationship between serial SM and radiological disease status. Prespecified sub-group analyses stratified participants by initial SM and treatment status. RESULTS:156 patients had ≥ 2 SM measurements with paired CT scans. Rising SM was associated with disease progression in the coincident time period (Adj OR 1.11, 95 % CI 1.03-1.19) and the subsequent 6 months (Adj OR 1.13, 1.03-1.23), regardless of initial SM. A 25 % change in SM was the optimal threshold, with a 25 % rise associated with disease progression (Adj OR 2.68 (1.52-4.73)) with sensitivity and specificity of 48.7 % (43.1 %-54.4 %) and 75.7 % (70.8 %-80.5 %) respectively. For patients receiving treatment, falling SM predicted subsequent disease response (Adj OR 1.37, 1.16-1.61). CONCLUSIONS:Serial SM is a reliable response biomarker in PM, regardless of initial value and treatment status. These results support the use of SM in routine clinical care as an adjunct to CT scans, with several benefits over radiological monitoring.

Non-Specific Pleuritis (NSP) is a common diagnosis following thoracoscopy and encompasses a broad range of aetiologies with heterogeneous outcomes. In this article, we review pathophysiology, associated syndromes, and current best practice in follow-up. NSP typically runs a benign disease course; however, the biomechanical consequences of subsequent tissue re-modelling can be severe. A proportion of patients develop malignancy, notably pleural mesothelioma (PM), and clinicians currently lack the ability to stratify those at risk. Some may be harbouring occult malignancy with false-negative pleural biopsies. Alternatively, NSP may represent a true pre-PM precursor supported by the recent characterisation of mesothelioma-in-situ. Prospective surveillance of NSP patients could unlock the final biological milestone preceding PM evolution. Progress in this area would permit a more personalised patient stratification, whilst offering novel opportunities for translational research. The PREDICT-Meso International Accelerator Network has been established to focus on this goal.

Introduction Malignant Pleural Mesothelioma (MPM) is commonly associated with high symptom burden, cancer cachexia and poor health related quality of life (HRQOL). Uptake of systemic anticancer treatment is low, often due to reduced physical fitness associated with a diagnosis of MPM and advanced age at diagnosis. There is evidence to support exercise therapy in other cancers, including lung cancer, but there is limited evidence for the role of exercise therapy in MPM. EXTRA Meso feasibility study is a randomised feasibility trial of exercise therapy versus standard care in patients with a diagnosis of MPM. Methods and Analysis Patients with a diagnosis of mesothelioma, with performance status 0 to 2, clinical frailty score less than 5 will be randomised 1:1 between exercise intervention, where the patient is provided with a personalised exercise and wellbeing programme, after being assessed by a physiotherapist or qualified exercise professional with specific cancer training, or standard care (routine clinical follow up). The primary objective is to determine whether sufficient numbers of patients, defined as 40 patients over 12 months, can be recruited and randomised to justify a subsequent phase III trial examining the role of exercise therapy in maintaining or improving HRQOL in patients with MPM. Recruitment will take place across 2 UK mesothelioma centres (Glasgow and Manchester). Secondary objectives include assessment of barriers to recruitment and retention, and the safety and tolerability of the intervention and study assessments. Ethics and Dissemination Protocol approved by West Midlands South Birmingham Research Ethics Committee (Ref 23/WM/0186). Trial registration ISRCTN24557328 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN24557328 ### Funding Statement This study was funded by Mesothelioma UK (grant award number GR22/02) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: West Midlands South Birmingham Research Ethics Committee gave ethical approval for this work (Reference 23/WM/0186). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

BACKGROUND:Lung cancer remains the leading cause of cancer death worldwide, with early diagnosis linked to improved survival. Artificial intelligence (AI) holds promise for augmenting radiologists' workflows in chest X-ray (CXR) interpretation, particularly for detecting thoracic malignancies. However, clinical implementation of this technology relies on robust and standardised reference standard methodology at the patient-level. PURPOSE:This systematic review aims to describe reference standard methodology in the clinical evaluation of CXR algorithms for lung cancer detection. MATERIALS AND METHODS:Searches targeted studies on AI CXR analysis across MEDLINE, Embase, CENTRAL, and trial registries. 2 reviewers independently screened titles and abstracts, with disagreements resolved by a 3rd reviewer. Studies lacking external validation in real-world cohorts were excluded. Bias was assessed using a modified QUADAS-2 tool, and data synthesis followed SWiM guidelines. RESULTS:1,679 papers were screened with 46 papers included for full paper review. 24 different AI solutions were evaluated across a broad range of research questions. We identified significant heterogeneity in reference standard methodology, including variations in target abnormalities, reference standard modality, expert panel composition, and arbitration techniques. 25 % of reference standard parameters were inadequately reported. 66 % of included studies demonstrated high risk of bias in at least one domain. DISCUSSION:To our knowledge, this is the first systematic description of patient-level reference standard methodology in CXR AI analysis of thoracic malignancy. To facilitate translational progress in this field, researchers undertaking evaluations of diagnostic algorithms at the patient-level should ensure that reference standards are aligned with clinical workflows and adhere to reporting guidelines. Limitations include a lack of prospective studies.

Defining preclinical models is of utmost importance for pleural mesothelioma (PM) to improve prognosis and predict therapeutic response. Using cells isolated from pleural fluid (PF) and diagnostic pleural biopsy (PB), we generated PM patient-derived organoids (PM-PDOs) and reactive-mesothelial (RM) patient-derived organoids (RM-PDOs) aiming at assessing the proportion of successful cultures both from PF and PB. We also compared the architectural and immune-histochemical features of PM-PDOs with those of parental tissues and evaluated the PM-PDOs response to chemoimmunotherapy. We obtained 11 successful PM-PDOs from 15 PF/PB (73.3%). The rate of success was higher in epithelioid PM (88.8%) compared with biphasic PM (40.0%) (P = 0.175), and when using PF (60.0%) compared with PB (20.0%) (P = 0.001). We also obtained 3 RM effective cultures from 6 asbestos-exposed patients (50%) with nonspecific pleuritis. Transcriptome analysis identified gene expression profile in PM-PDOs, which differentiate from RM-PDOs. PM-PDOs successfully maintained the histological architecture and molecular markers of their parental tumor tissues. The macrophagic component (CD68+ and CD163+) was an important component in RM-PDOs and was present in all three PM histotypes. Epithelioid PM-PDOs showed resistance to both Cis/PeMtx and pembrolizumab plus peripheral blood mononuclear cells (PBMCs), whereas both biphasic and sarcomatoid subtypes were sensitive to immunotherapy. Notably, immunotherapy induced an upregulation of PD-L1 expression and activated the STAT3/NF-κB signaling pathway, suggesting a mechanism of immune evasion. PF offers a valuable source of cancer and stromal cells to generate PDO, reinforcing its clinical utility for patients who cannot undergo invasive procedures.NEW & NOTEWORTHY Using cells isolated from pleural effusion and pleural biopsy, we established an efficient 3-D culture system for generating PM and reactive mesothelial (RM) patient-derived organoids. PM-PDOs expressed a specific gene profile, preserved the histological architecture, showing markers of the parental tumor tissues and recapitulated the tumor microenvironment (e.g., macrophages and tumor lymphocytes), which is an important factor influencing responses to therapy. This approach will be useful for drug screening, contributing to a more accurate selection of therapeutic options.

The prognosis of pleural mesothelioma (PM) is poor and conventional chemotherapy regimens have shown limited antitumor activity. Recent use of immune checkpoint inhibitors (ICIs) has shown promise, with CheckMate-743 trial establishing nivolumab plus ipilimumab as first line treatment in unresectable PM. Nevertheless, real-world applicability as well as differential benefit of immunotherapy according to histologic are areas of active debate. In addition, increased incidence of immune-related adverse events (IRAEs) and high discontinuation rates highlight the need for careful patient selection. While ICIs represent a significant advancement in PM treatment, ongoing research is necessary to refine their use, potentially through biomarker-informed approaches, and manage associated toxicities. This review highlights the evolving landscape of immunotherapy and associated controversies in PM.

Early community treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may reduce severe coronavirus disease (COVID-19) incidence. We evaluated clinical effectiveness, safety, and SARS-CoV-2 mutagenicity of favipiravir, an oral viral RNA polymerase inhibitor. We performed an open-label, community-based, randomized Phase III trial, recruiting non-hospitalized adults with mild COVID-19 (WHO ordinal severity score [OSS] ≤ 3). Positive cases were invited to web-based self-screening within 24 h using public health data. Exclusion criteria included symptoms for >7 days, pregnancy/breastfeeding, severe renal/liver disease, gout, and licensed antiviral eligibility. Participants were randomized 1:1 to 10 days favipiravir (Day 1: 3,600 mg; days 2-10: 1,600 mg) or no additional treatment. The primary endpoint was worst recorded OSS up to and including Day 15 (intention-to-treat). The target recruitment was 302. Secondary endpoints included adverse event (AE) rate to Day 60, time-to-viral clearance (TTVC), time-to-symptom resolution (TTSR), and SARS-CoV-2 sequencing variant rate (≥5% frequency) at Day 15 (registration ISRCTN: 31062548; EudraCT: 2020-001904-41). A total of 68,788 adults were invited, and 302 (0.4%) were subsequently randomized between December 2020 and July 2022 (favipiravir [n = 152]: standard care [n = 150]). Mean (SD) age was 47.2 (13.2), and 230/302 (76%) were vaccinated. Severe outcomes were infrequent, with no intensive care unit admissions/deaths. There was no difference in the primary endpoint: odds ratio 1.18 (95% confidence interval [CI] 0.63-2.20), TTSR (HR 1.03 [95% CI 0.81-1.31]), or TTVC (HR 1.13 [95% CI 0.65-1.97]). Favipiravir was well tolerated with few AEs but was associated with increased variant frequency, including C-to-U mutations. Community administration of favipiravir for mild COVID-19 was not associated with clinical benefits or safety concerns but was associated with SARS-CoV-2 mutagenicity.CLINICAL TRIALSThis study is registered with ISRCTN as 31062548 and with EU-CTR as 2020-001904-41.

Background/Objectives: The precise staging of non-small cell lung cancer (NSCLC) determines its initial treatment and provides more accurate prognostic information for patients. The aim of this cohort study was to determine pre- and post-operative mediastinal nodal staging agreement and its effect on 2-year survival. Methods: A retrospective multi-centre cohort study was performed, using prospectively collected and pre-defined data from weekly lung cancer multidisciplinary team (MDT) meetings in 11 hospitals. Consecutive patients who underwent surgical resection of NSCLC between 2015 and 2017 were eligible. Pre-operative under-staging was defined as a lower pre-operative than post-operative nodal stage, and pre-operative over-staging as a higher pre-operative than post-operative nodal stage. Disparities between pre-operative nodal staging established at MDT and post-surgical nodal staging were determined and associations with subsequent lung cancer-specific 2-year mortality were identified using univariate and multivariate regression. Results: A total of 973 patients fulfilled the eligibility criteria. Concordant pre- and post-operative nodal staging was observed in 783/973 (80%), 123/973 (13%) were under-staged pre-operatively and 67/973 (7%) were over-staged. In 173 patients with clinical N1 or N2 disease (in whom invasive mediastinal staging was indicated), staging EBUS was performed in 55/173 (32%). In these patients, younger age and use of staging EBUS were independent predictors of concordant pre- and post-operative staging. In all patients, pre-operative under-staging was independently associated with increased lung cancer-specific 2-year mortality. There was no increased mortality associated with pre-operative nodal over-staging. Conclusions: Invasive mediastinal staging with EBUS was independently associated with more accurate pre-operative staging. Pre-operative nodal under-staging was associated with increased lung cancer-specific mortality. Nodal staging accuracy in potentially curable NSCLC is of fundamental importance to ensure patients receive the correct first-line treatment and to improve survival.

Pleural Mesothelioma (PM) may be presaged by benign pleural inflammation, typically labelled non-specific pleuritis (NSP). NSP is common and presents a clinical challenge given divergent rates of subsequent PM in previous studies. Greater clarity on cohorts at highest risk would inform clinical decision-making and ongoing precision PM prevention research.

Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients’ quality of life, and is thus a challenge for the daily practice in respiratory medicine. Advances in the genetic knowledge of thoracic tumours' mutational landscape, and the development of targeted therapies and immune checkpoint inhibitors, have led to a paradigm shift in the treatment of lung cancer and pleural mesothelioma. During the 2023 European Respiratory Society Congress in Milan, Italy, experts from all over the world presented their high-quality research and reviewed best clinical practices. Lung cancer screening, management of early stages of lung cancer, application of artificial intelligence and biomarkers were discussed and they will be summarised here.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

TPS8124 Background: Tumor cells generate elevated levels of reactive oxygen species (ROS), leading to increased expression and activity of critical ROS scavenging pathways. Peroxiredoxin 3 (PRX3) is the principal peroxide scavenging enzyme in mitochondria. RSO–021 is a novel small molecule PRX3 inhibitor that inactivates PRX3 through direct covalent adduction of active site cysteine residues, in turn inducing oxidative stress that is incompatible with tumor cell survival. Preclinical studies of RSO-021 show that it selectively inhibits mitochondrial PRX3 in vitro and is highly effective in a variety of tumor models, including mesothelioma and many solid tumors. RSO-021 has completed phase 1 evaluation in patients with advanced mesothelioma or solid tumors with predominant pleural disease and malignant pleural effusions. The phase 1 data supported weekly intrapleural dosing of RSO-021 at the 90 mg dose level, with acceptable safety and early signals of efficacy. Some patients were able to receive >30 weeks of treatment. Pre- and post-dose primary prophylaxis for local inflammatory reactions to intrapleural injection was instituted during dose escalation, using corticosteroids, NSAIDS and paracetamol. It also became clear that RSO-021 should not be administered to patients with a dry pleural tap, due to risk of extravasation. Methods: The objectives of this open-label, multi-center, 4-arm phase 2 study (MITOPE) are to confirm the efficacy, safety, tolerability, and pharmacology of weekly intrapleural RSO-021 administration. Exploratory endpoints include target engagement as well as biomarkers of response and inflammation. The study explores 2 different RSO-021 doses (90 mg/wk and 45 mg/wk) per FDA Project Optimus, both as monotherapy and in combination with IV paclitaxel 175 mg/m2 every 3 weeks at until progression or limiting toxicity. Each arm at each dose has a 2-stage Simon design (12-21 patients) requiring 1 response to trigger stage 2 (null/target response rate 3%/20% and type I/type II error 0.05/0.8) for a maximum of 168 patients in the trial. Three of the 4 study arms are investigating the antitumor activity of RSO-021 monotherapy (arms 1-3) and the fourth is assessing the paclitaxel combination. Eligibility (by arm) requires: newly diagnosed treatment-naïve mesothelioma with pleural effusion; mesothelioma with pleural effusion that progressed on ≥1 standard of care (SoC) regimen; solid tumor with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen; and breast, epithelial ovarian or non-small cell lung cancer with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen. The first patient was treated in 4Q2023 and the trial is actively recruiting to all 4 arms at 9 UK sites. Additional sites are planned. Clinical trial information: NCT05278975 .