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Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax. Prospective single-arm trials have shown that the median survival of patients who have completed high-dose hemithoracic radiotherapy after extrapleural pneumonectomy could reach 23·9–39·4 months independent of the chemotherapeutic response, suggesting that IMRT could potentially have an intrinsic benefit to this subset of patients. These observations have led to a change in practice, with the introduction of adjuvant pleural IMRT after pleurectomy-decortication and the development of induction-accelerated hemithoracic IMRT followed by extrapleural pneumonectomy. This Review focuses on recent observations on the role of radiotherapy in the treatment of malignant pleural mesothelioma, with particular emphasis on the results of clinical trials that evaluate the role of high-dose hemithoracic radiotherapy.

The existence of an in situ phase of malignant mesothelioma has long been postulated but until recently has been impossible to prove. Here we describe ten patients with mesothelioma in situ, defined by a single layer of surface mesothelial cells showing loss of BAP1 nuclear immunostaining, no evidence of tumor by imaging and/or by direct examination of the pleura/peritoneum, and no invasive mesothelioma developing for at least 1 year. Nine cases were pleural and one peritoneal. Most patients were biopsied for repeated effusions of unknown etiology; in two patients mesothelioma in situ was found incidentally in lung cancer resections. In addition to surface mesothelium with BAP1 loss, one case had a surface papillary proliferation with BAP1 loss, and two cases had a small (few millimeter) nodule with BAP1 loss. CDKN2A was deleted by FISH in one of eight cases. Methylthioadenosine phosphorylase showed partial loss in the surface mesothelium by immunohistochemistry in three cases. Invasive malignant mesothelioma developed in seven patients with time between biopsy and invasive disease from 12 to 92 (median 60) months. Invasive mesothelioma has not developed in the other three patients at 12, 57, and 120 months, but the latter patient, who has pleural plaques, still has repeated pleural effusions, probably representing a so-called “benign asbestos effusion.” We conclude that mesothelioma in situ, as diagnosed using the criteria outlined above, is associated with a high risk of developing invasive mesothelioma, but typically over a relatively protracted time, so that curable interventions maybe possible.

Malignant mesothelioma (MESO) is a highly aggressive cancer with poor prognosis. Epithelial–mesenchymal transition (EMT) is a critical process in malignancies involved in tumor angiogenesis, progression, invasion and metastasis, immunosuppressive microenvironment and therapy resistance. However, there is a lack of specific biomarkers to identify EMT in MESO. Biphasic MESO with dual phenotypes could be an optimal model to study EMT process. Using a powerful EMTome to investigate EMT gene signature, we identified a panel of EMT genes COL5A2, ITGAV, SPARC and ACTA2 in MESO. In combination with TCGA database, Timer2.0 and other resources, we observed that overexpression of these emerging genes is positively correlated with immunosuppressive infiltration, and an unfavorable factor to patient survival in MESO. The expression of these genes was confirmed in our patients and human cell lines. Our findings suggest that these genes may be novel targets for therapeutics and prognosis in MESO and other types of cancers.

Many donor lungs do not meet current criteria for transplantation. In this study, ex vivo lung perfusion and ventilation allowed the successful transplantation of lungs that might otherwise have been considered unsuitable as transplants. Lung transplantation is lifesaving for patients with end-stage lung diseases. However, the number of patients waiting for a lung transplant greatly exceeds the number of available donors. On average, only 15% of lungs from multiorgan donors are used for transplantation 1 ; the rest are considered unsuitable owing to the lung injury that occurs after brain death and to complications associated with treatment in the intensive care unit (ICU) (e.g., barotrauma and pulmonary edema). Although nonstandard donor lungs (i.e., lungs with suboptimal gas-exchange function or infiltrates visible on chest radiographs) 2 have been used successfully, 3 , 4 increased primary graft dysfunction — an . . .

Plasma levels of fibulin-3 reliably distinguish patients with pleural mesothelioma from patients with other types of pleural effusions and asbestos-exposed persons. Despite advances in chemotherapy, radiation therapy, and surgical management for malignant pleural mesothelioma, the median survival remains 12 months. 1 Early detection is limited by the long latency period, an inability of imaging to detect the disease at an early stage even when it is used as a screening strategy, and the lack of sensitive and specific blood-based markers. 2 Moreover, in patients with undiagnosed pleural effusion, the ability to diagnose mesothelioma is delayed by failure to include the disease in the differential diagnosis and by the lack of noninvasive mesothelioma-specific blood-based markers. Soluble mesothelin-related protein, the most extensively studied blood-based mesothelioma . . .

Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as “mesothelioma”, LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.

Neoadjuvant chemoimmunotherapy (chemo-IO) has fundamentally reshaped the treatment paradigm for resectable non-small cell lung cancer (NSCLC), challenging long-held surgical boundaries and redefining what constitutes “resectable” disease. Trials such as CheckMate-816, KEYNOTE-671, and AEGEAN have demonstrated that integrating immune checkpoint blockade with chemotherapy yields unprecedented rates of pathological response and event-free survival, positioning chemo-IO as the new global standard for stage IB–IIIA NSCLC. Yet these advances bring new complexities; how do we define resectability in an era of immunotherapeutic downstaging, and how should multidisciplinary teams adapt to evolving biology? Traditional radiological and anatomic criteria now sit alongside immune-mediated regression and circulating tumor DNA (ctDNA) kinetics as measures of treatment success. ctDNA clearance and pathological response serve as powerful surrogates for long-term survival, with ongoing studies such as MERMAID-1/2 exploring their potential to guide adjuvant therapy and spare overtreatment. The modern challenge lies in integrating these biomarkers into surgical decision-making and developing standardized, biology-informed resectability frameworks. Future progress will depend on close collaboration between surgeons, oncologists, and translational scientists to expand surgical candidacy safely and define the next generation of curative strategies in lung cancer.

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive cancer with median survival of 18 months. Due to the lack of proper tumour targets, no cellular immunotherapy is currently available for MPM. New non-ablative radiation and surgery combination therapy programs for MPM are underway at the Princess Margaret Cancer Centre in Toronto. As part of a comprehensive multiomics study of tumor microenvironment, we implemented a computational method for discovery and prioritization of endogenous retroviral protein (ERV) particles as novel antigen-specific targets in MPM.MethodsWe performed ERV gene-discovery based on identification of protein-coding open-reading frames with viral or bacterial origins.1 An extended human reference genome was constructed with novel open-reading frames and single-cell RNAseq sequencing (10Xgenomics Inc.) reads of tumor samples were aligned and gene-count tables were computed. ERVs with less than ten aligned reads or present in only one patient were removed from the analysis. ERVs with transcripts overlapping GTEx Consortium database (10K samples, 56 tissues) were removed to ensure no remaining ERV was constitutively expressed in normal tissues. The ERVs were further annotated with experimentally validated T and B cell epitopes in the Immune Epitope Database (IEDB).2 BLAST searches performed to identify humongous epitope of ERVs in human pathogen. A select set of identified transcripts were validated with PCR.ResultsSingle-cell RNAseq expression of tumor microenvironment of 19 MPM patients was analyzed. All patients expressed two ERVs annotated in the human reference genome (ERV3–1, ERVK3–1) with another four (ERVFRD-1, ERVH48–1, ERVMER34–1, ERVW-1) expressed in at least 5 patients. We identified 400 ERVs not curated in the human reference genome with lengths of 95–3935 amino acids (1520.9525 +- 1069). From this, 224 contained at least one T-cell epitope (with presentation at MHC class-I and class-II) or B epitope (antibody binding) record in IEDB. 135 ERVs had at least one epitope with 100% homology in human pathogens. We further measured the expression (in terms of TPM) of identified genes in 2708 publicly available cell lines of 14 cancers. All 400 ERVs were shared with at least one and some with all 14 other cancers.ConclusionsWe identified several ERV proteins present in MPM tumors that are prominently encoded in intronic regions of but not curated in the human reference genome. Annotation of these proteins with homologues epitopes of human pathogen and IEDB epitopes provide opportunities for prioritization of these novel targets for T-cell therapies or antibody drugs.ReferencesNakagawa S, Takahashi MU. gEVE: a genome-based endogenous viral element database provides comprehensive viral protein-coding sequences in mammalian genomes. Database, 2016; 2016 :1–8. https://doi.org/10.1093/database/baw087Vita R, Mahajan S, Overton JA, Dhanda SK, Martini S, Cantrell JR, Wheeler DK, Sette A, Peters B. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Research, 2019; 47 (D1):D339-D343. https://doi.org/10.1093/nar/gky1006

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high‐resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1‐asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Background: Given advancements in adjuvant treatments for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-targeted therapies, it is important to consider postoperative targeted therapies for other early-stage oncogene-addicted NSCLC. Exploring baseline outcomes for early-stage NSCLC with these rare mutations is crucial. Objectives: This study aims to assess relapse-free survival (RFS) and overall survival (OS) in patients with resected early-stage NSCLC with rare targetable driver mutations. Methods: This retrospective single-center study identified stage I–III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue-based molecular profiling identified mutations in KRASG12C, EGFR Exon20, Erb-B2 receptor tyrosine kinase 2 (ERBB2), ALK, ROS1, B-Raf proto-oncogene (BRAF) V600E, mesenchymal–epithelial transition factor (MET) exon14 skipping, and rearranged during transfection (RET). Baseline patient and tumor characteristics, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRASG12C cohort was used as the reference for survival comparisons. Results: Among 225 patients, mutations included the following: KRASG12C (n = 101, 45%), MET exon 14 skipping (n = 26, 12%), EGFR Exon 20 (n = 25, 11%), ERBB2 (n = 25, 11%), ALK fusion (n = 16, 7%), ROS1 fusion (n = 14, 6%), BRAF V600E mutation (n = 13, 6%), and RET fusion (n = 5, 2%). Five-year survival probabilities were 76% for stage I, 60% for stage II, and 58% for stage III. RFS was shorter across most mutation subgroups compared to KRASG12C, with ROS1 mutations showing significantly poorer RFS (HR 2.70, p = 0.019). By contrast, all mutation subgroups were associated with better OS than KRASG12C. The incidence of brain metastasis was highest in ERBB2 (22% at 5 years). TP53 co-mutation was associated with significantly worse OS (HR 2.35, p = 0.008). Conclusion: While RFS was poorer for most mutations compared to KRASG12C, OS generally was better, suggesting a potential role for postoperative targeted therapies. These findings warrant further investigation through prospective studies and clinical trials to optimize adjuvant treatment strategies for patients with early-stage NSCLC harboring rare driver mutations. Plain language summary Outcomes of patients with resected early-stage lung cancer with rare targetable driver mutations Early-stage non-small cell lung cancer (NSCLC) is often treated with surgery and sometimes chemotherapy after surgery. Recent advancement with discovery of mutations that drive cancer has led to improvement of outcomes in NSCLC with targeted therapies. Certain mutations in NSCLC are rare and how these mutations impact outcomes after surgery in early-stage NSCLC is less clear. Our study focused on patients with early-stage NSCLC who had surgery and specific rare mutations including EGFR Exon20 insertion, KRAS G12C, ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, and ERBB2 mutations. We want to understand how presence of these mutations affects the chance of cancer returning (relapse-free survival) and overall survival after surgery. We found that most mutations had higher risk of cancer returning (relapse-free survival) compared to patients with KRAS mutation and ROS1 had highest risk of cancer returning in our study. However, for overall survival all mutations were linked to better overall survival than KRAS mutation. ERBB2 mutation had highest risk to develop brain metastasis when the cancer returns. Those with additional TP53 mutation, another genetic change had worse overall survival outcome. These results provide more evidence regarding the outcome of these patients with rare mutations in early-stage NSCLC. There might be a benefit of using targeted therapies early in the diagnosis of early-stage NSCLC. We hope our results help to inform potential studies in the future to show benefit of using targeted therapies after surgery in early-stage NSCLC.