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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., Competing Interests: Declaration of interests KGB declares institutional grant funding from Rocket Medical and RS Oncology; lecture honoraria from Bristol-Myers Squibb; and the role of chief investigator of the PREDICT-Meso International Accelerator Network. PSA declares research funding from ATARA Biotherapeutics; patents, royalties, and intellectual property on therapies licensed to ATARA Biotherapeutics; and scientific advisory board membership and consulting fees from ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion Pharma, and Outpace Bio. PA declares equipment loans for courses from Novatech, Wolf, and Olympus. LD declares lecture honoraria from Bristol-Myers Squibb. YCGL declares receipt of equipment from Rocket Medical for use in clinical trials. ASM declares institutional grant funding from Novartis and Verily; consulting fees from Rising Tide and TRIPTYCH Health Partners; institutional payments or honoraria from Janssen, BeiGene, Chugai Pharmaceutical (Roche), Ideology Health (formerly Health Media), Antoni van Leeuwenhoek Kanker Instituut, AXIS Medical Education, Johnson & Johnson Global Services, Intellisphere, Answers in CME, University of Miami International Mesothelioma Symposium, and Immunocore; support for attending meetings from Shanghai Roche; membership of scientific advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Takeda Oncology, and Sanofi Genzyme; and study funding from Bristol-Myers Squibb. SJM is co-principal investigator of the Engineering and Physical Sciences Research Council Interdisciplinary Research Collaboration in Targeted Delivery for Hard-to-Treat Cancers; he declares consulting fees from DefiniGEN, and support for attending meetings from Alpha-1 Foundation, Federation of American Societies for Experimental Biology, and Mesothelioma UK. NM declares consulting fees from Rocket Medical UK, Cook Medical UK, and Becton Dickinson. VP declares grant funding from the Danish Comprehensive Cancer Center and no conflicts of interest within the scope of this Viewpoint. NMR declares consulting fees from Rocket Medical UK, Cook Medical UK, and LTI USA. MGZ declares institutional grant funding from Medimmune, Precog, GSK, Epizyme, Polaris, Sellas Life Sciences, Bristol-Myers Squibb, Millenium, Curis, and Atara; consulting fees from Curis, Ikena, Takeda, GSK, and Novocure; and honoraria from PER and Medscape. DS declares support including research funding and consulting fees from AstraZeneca, Boehringer Ingelheim, Exigo Management, Flame Biosciences, HitchBio, Intuitive Surgical, Janssen, Johnson & Johnson, Medscape, Olympus Corporation of the Americas (also known as Spiration), Sensei Biotherapeutics, Trizell, Trustees of the University of Pennsylvania, Verismo, and Wolters Kluwer Health. DAF declares institutional grants from Aldeyra, Astex Therapeutics, Bayer Oncology, Bergen Bio, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Lovance, MSD, Owkin, Roche Oncology, and RS Oncology; consulting fees from Cambridge Clinical Laboratories and RS Oncology; honoraria from MSD and Bristol-Myers Squibb; support for attending meetings from RS Oncology; and participation on data monitoring or advisory boards for AstraZeneca and RS Oncology. TP declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI., Methods: We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis., Results: We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases., Conclusions: We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies., Competing Interests: Competing interests: AM reports honoraria to his institution for participation in advisory boards from AbbVie, AstraZeneca, BeiGene, BMS, Genentech, Janssen; Travel support and honoraria from Shanghai Roche Pharmaceuticals, and is non-remunerated member of the Mesothelioma Applied Research Foundation and Friends of Patan Hospital Board of Directors., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies., (Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy., Methods: We used mate-pair (n = 22), RNA (n = 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome., Results: We observed that inter- or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival., Conclusions: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Mesothelioma has been considered a difficult pathologic diagnosis to achieve via image-guided core needle biopsy. The purpose of this study was to assess the diagnostic sensitivity of percutaneous image-guided biopsy for diagnosis of pleural mesothelioma., Materials and Methods: Retrospective review was performed to identify patients with a confirmed diagnosis of pleural mesothelioma and who underwent image-guided needle biopsy between January 1, 2002, and January 1, 2016. Thirty-two patients with pleural mesothelioma were identified and included for analysis in 33 image-guided biopsy procedures. Patient, procedural, and pathologic characteristics were recorded. Complications were characterized via standardized nomenclature [Common Terminology for Clinically Adverse Events (CTCAE)]., Results: Percutaneous image-guided biopsy was associated with an overall sensitivity of 81%. No CTCAE clinically significant complications were observed. No image-guided procedures were complicated by pneumothorax or necessitated chest tube placement. No patients had tumor seeding of the biopsy tract., Conclusion: Percutaneous image-guided biopsy can achieve high sensitivity for pathologic diagnosis of pleural mesothelioma with a low procedural complication rate, potentially obviating need for surgical biopsy.

c-Met is a receptor tyrosine kinase shown to be overexpressed in malignant pleural mesothelioma (MPM). Whereas MET mutations have been identified in 3%-16% of MPMs, MET amplification has recently been reported in a single epithelioid MPM. We studied c-Met expression and MET amplification in a large MPM cohort and correlated results with morphologic and clinical features. We report the first case of MET amplification in sarcomatoid MPM. MPMs from surgical pathology files (1989-2014) were reviewed. c-Met immunohistochemistry was performed. Staining intensity and distribution were multiplied (H-score). Staining localization (cytoplasmic and/or membranous) was noted. Fluorescence in situ hybridization was performed using probes for MET and centromere 7. One hundred forty-nine patients (median age, 68.0years; interquartile range, 61-75) had epithelioid (n=97), biphasic (n=18), or sarcomatoid (n=34) MPM. Median follow-up was 10.1months (range, 0.1-222.5). One hundred thirty patients died of disease; 2 were alive with disease. c-Met was expressed in 147 MPMs. c-Met staining intensity, distribution, and H-score differed among the histologic subtypes (P=.015; P=.0001, and P=.0005, respectively), but none were predictive of survival. Epithelioid subtype had greater c-Met expression. MET amplification was identified in 1 sarcomatoid MPM and MET duplication in 1 epithelioid MPM; both had poor outcomes. Chromosome 7 aneusomy was observed in 54 of 144 (37.5%) MPMs and associated with decreased overall survival in sarcomatoid MPMs (hazard ratio=2.81; 95% confidence interval, 1.21-6.51; P=.01). In conclusion, c-Met is expressed in MPM, with significant differences in expression among histologic subtypes. MET amplification is a rare event in MPM, making it an unlikely common pathogenesis for c-Met expression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Rationale: Malignant pleural mesothelioma is an almost universally fatal malignancy primarily related to asbestos exposure. Based on the differences in immunologic markers and gene expression between histologic subtypes of mesothelioma, and our clinical impression that response rates vary by histology, we decided to examine the reported response rates of mesothelioma subtypes., Objectives: Our objective was to compare the response rates of sarcomatoid mesotheliomas to the overall response rates in published clinical trials., Methods: We searched PubMed for "mesothelioma" with the clinical trials filter selected. We included articles published between January 1, 2000 and March 20, 2014 in which subjects received first or second line systemic therapy for malignant pleural mesothelioma. Studies investigating multi-modality therapy including surgery were excluded. Response rates [including 95% confidence intervals (95% CI)] were estimated for the entire patient cohort and then separately for subjects with sarcomatoid tumors., Measurements and Main Results: We reviewed 544 publications of which 41 trials met our inclusion criteria. Eleven of these trials did not include patients with sarcomatoid mesothelioma (27% of eligible studies). The remaining 30 publications included 1475 subjects, 1011 with epithelioid tumors (68.5%), 203 with biphasic tumors (13.8%), 137 with sarcomatoid tumors (9.3%) and 124 with unknown subtypes (8.4%). In total, there were 323 responses (21.9%, complete and partial responses, 95% CI: 16.3, 28.8) to systemic therapy across all histological subtypes. In patients with sarcomatoid tumors (n=137) 19 responses were observed. This accounted for 5.9% of all responses and yields a 13.9% (95% CI: 8.6, 21.6) response rate for patients with sarcomatoid tumors. Multiple biases likely affected this systematic review., Conclusion: Response rates for different histological subtypes of malignant pleural mesothelioma are infrequently reported. Partial and complete responses to systemic therapies appear to be less common among patients with sarcomatoid tumors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: B7 homolog 1 (B7-H1; aka programmed cell death 1 ligand 1) is a negative costimulatory molecule that is associated with poor prognosis in many tumor types. Given the poor prognosis and the limited treatments available for mesothelioma, we decided to examine B7-H1 expression and its association with survival in patients with mesothelioma., Methods: Expression of B7-H1 was determined in 106 patients using a mouse monoclonal antihuman B7-H1 (clone 5H1-A3) antibody with immunohistochemistry. Positive expression was defined as ≥5% positively stained cells. Clinicopathologic features and survival were compared between B7-H1-positive and B7-H1-negative groups., Results: Malignant mesotheliomas of 42 patients (40%) expressed B7-H1. Patients with B7-H1-postive tumors were less likely to be offered or undergo therapeutic surgery (p = 0.03). All sarcomatoid mesotheliomas except one desmoplastic subtype expressed B7-H1. Survival was significantly decreased for patients whose tumors expressed B7-H1 (5 months median, 2-9.5 months interquartile range) compared with those whose tumors did not (14.5 months, 9.25-19 months; p < 0.0001). In a multivariate model, B7-H1 expression and sarcomatoid mesothelioma remained significantly associated with worse survival (risk ratio 1.71, 95% confidence interval 1.03-2.78 [p = 0.04] and risk ratio 2.18, 1.08-4.23 [p = 0.03], respectively)., Conclusions: B7-H1 is expressed in a substantial proportion of malignant pleural mesotheliomas and is associated with poor survival. Almost all malignant pleural mesotheliomas with sarcomatoid differentiation expressed B7-H1. The expression of B7-H1 may have important therapeutic implications for the management of malignant pleural mesothelioma.