bims-mesote 2026-09-20 papers

Issue of 2026–09–20
three papers selected by
Laura Mannarino, Humanitas Research

Lung Cancer. 2026 Sep 15. pii: S0169-5002(26)00685-9. [Epub ahead of print]221 109624

Discordance in pleural mesothelioma response classification and modelling of impact on clinical trials.

Gordon W Cowell, Joshua Roche, Colin Noble, David B Stobo, Andrew Papanastasiou, Andrew C Kidd, Selina Tsim, Kevin G Blyth.

INTRODUCTION: Agreement between radiologists regarding treatment response in Pleural Mesothelioma (PM) is acknowledged to be poor, but downstream effects in clinical trials have not been quantified.
METHODS: We performed a mixed methods study, composed of a multicentre, retrospective cohort study and in silico modelling. CT images and data were retrieved from 4 UK centres regarding chemotherapy-treated patients. Expert radiologists classified response using modified Response Evaluation Criteria In Solid Tumours (mRECIST) v1.1, generating discordance rate (%) and agreement. In silico modelling simulated two-arm trials of an active therapy with intended 80% power and confidence intervals for four endpoints (objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS)) covering 95% of the true effect. Actual power and endpoint coverage were modelled against mRECIST misclassification rate (a single reporter equivalent of discordance rate). Consecutive simulations varied misclassification rate from 0 to 100% in 1% increments, each repeated 10,000 times.
RESULTS: 172 cases were included. Discordance rate was 35% (60/172), kappa = 0.456. In silico modelling demonstrated reduced power and endpoint precision with increasing misclassification. At 17% misclassification, corresponding to the observed 35% discordance, power dropped from 80% to 39% for ORR, 54% for DCR, 64% for PFS and 64% for OS, with endpoint coverage reduced to 85%, 90%, 92% and 92%, respectively. 50/60 (83%) discordances reflected interpretation or measurement differences intrinsic to mRECIST. Discordance was not associated with tumour volume.
CONCLUSIONS: Inconsistent response classification is common in PM and substantially reduces statistical power and endpoint precision in clinical trials.

Keywords: In silico modelling; Pleural mesothelioma; Radiology; Response assessment; Simulation study

DOI: https://doi.org/10.1016/j.lungcan.2026.109624

JTO Clin Res Rep. 2026 Oct;7(10): 101049

BAP1 Loss in Pleural Mesothelioma Is Associated With Reduced Soluble CCL2 in Patient Effusion, Abrogated CCL2-Mediated Monocyte Recruitment In Vitro.

Alistair Nash, Ebony Rouse, Tina Firth, Ian M Dick, Vanessa S Fear, Catherine A Forbes, Amber Louw, Y C Gary Lee, Alec J Redwood, Bruce W Robinson, Jenette Creaney.

Objectives: Pleural mesothelioma is an incurable cancer of the cell layer lining the chest wall and lung. Patients frequently present with pleural effusion, which is often drained for symptom relief and enables minimally invasive sampling of the tumour environment, including immune cells and related soluble factors. Most of the mesothelioma tumours exhibit loss of BRCA1-associated protein 1 (BAP1), a multifunctional tumour suppressor protein. Here, we aim to elucidate the effect of BAP1 loss on the mesothelioma microenvironment through profiling soluble factors within pleural effusion.
Methods: A custom panel of 22 soluble factors was measured by Luminex assay and enzyme-linked immunosorbent assay in an initial cohort of 40 patients with known BAP1 status. Validation was performed by enzyme-linked immunosorbent assay in an independent cohort of 100 cases. Secretion of soluble factors and chemoattraction of monocytes were characterised using a CRISPR-mediated BAP1 deletion model in a mesothelioma and a lung cancer cell line. Immune cell infiltration, estimated by CIBERSORT, was further explored in the Cancer Genome Atlas -MESO cohort.
Results: Soluble C-C motif chemokine ligand 2 (CCL2) was approximately 55% to 60% lower in pleural effusion from BAP1-loss cases in both independent cohorts. Deletion of BAP1 reduced CCL2 secretion in vitro and abolished CCL2-mediated chemoattraction of monocytes in both mesothelioma and lung cancer cell lines. In the Cancer Genome Atlas -MESO cohort, BAP1-mutant tumours exhibited a reduction in estimated macrophage content.
Conclusion: Loss of BAP1 impairs CCL2 secretion into pleural effusions, potentially influencing monocyte recruitment into the tumour microenvironment.

Keywords: BAP1; CCL2; Effusion; Mesothelioma; Monocytes; Pleural

DOI: https://doi.org/10.1016/j.jtocrr.2026.101049

Int J Mol Sci. 2026 Sep 02. pii: 7859. [Epub ahead of print]27(17):

Damage-Associated Molecular Patterns in Mesothelioma: Drivers of Inflammation and Therapeutic Targets.

Annamaria Molinario, Francesca Caprioglio, Angela A Rilievo, Marco E Bianchi, Rosanna Mezzapelle.

Mesothelioma is a rare and aggressive malignancy arising from mesothelial cells. Despite recent advances in systemic therapies, overall survival remains limited, underscoring the need for a deeper mechanistic understanding of disease pathogenesis and novel therapeutic strategies. In mesothelioma, chronic tissue injury induced by asbestos fibers leads to sustained activation of innate immune pathways and chronic inflammation that actively promote tumorigenesis. The release of Damage-Associated Molecular Patterns (DAMPs)-endogenous molecules that signal cellular stress and damage-contributes to establishing a self-sustaining inflammatory circuit within the pleural microenvironment that promotes tumor initiation and progression and immune evasion. Among DAMPs, High-Mobility Group Box 1 (HMGB1) has emerged as a key regulator of mesothelioma pathogenesis. Several studies demonstrated that mesothelial cells actively secrete HMGB1 in response to asbestos exposure, driving macrophage recruitment, cytokine production, and chronic inflammation. Beyond HMGB1, additional DAMPs-including IL-33, extracellular ATP, cell-free nucleic acids, heat shock proteins, and calreticulin-contribute to inflammasome activation, stromal remodeling, and immune dysregulation. Recent evidence suggests that DAMP signaling in mesothelioma is dysregulated, resulting in chronic inflammation coupled with ineffective antitumor immunity. This review provides a comprehensive synthesis of DAMP biology in mesothelioma, highlighting the emerging therapeutic opportunities targeting DAMP-associated pathways.

Keywords: damage associated molecular patterns; inflammation; mesothelioma

DOI: https://doi.org/10.3390/ijms27177859