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International Journal of Molecular... May 2018Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly... (Review)
Review
Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications.
Topics: Antineoplastic Agents; Genetic Heterogeneity; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neoplastic Stem Cells
PubMed: 29848954
DOI: 10.3390/ijms19061603 -
Nature Genetics Apr 2023Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing...
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Multiomics; Pleural Neoplasms; Lung Neoplasms; Biomarkers, Tumor
PubMed: 36928603
DOI: 10.1038/s41588-023-01321-1 -
Cancer Immunology Research Oct 2023Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation...
Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine-receptor expression in infiltrating T cells and results in a subpopulation of higher-intensity CAR-expressing T cells with high coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelin-expressing mesothelioma and mixed-mesothelin-expressing lung cancer-two thoracic cancers for which radiotherapy is part of the standard of care. Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich" cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells.
Topics: Humans; Mesothelin; Immunotherapy, Adoptive; GPI-Linked Proteins; Receptors, Antigen, T-Cell; Mesothelioma; Mesothelioma, Malignant; Receptors, Chemokine; Chemokines; Cell Line, Tumor
PubMed: 37540803
DOI: 10.1158/2326-6066.CIR-22-0840 -
Proceedings of the National Academy of... Jan 2023is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline mutations often develop mesothelioma, an aggressive malignancy...
is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline mutations and primary cells in which was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline mutations.
Topics: Humans; Heterozygote; Hypoxia-Inducible Factor 1, alpha Subunit; Mesothelioma; Mesothelioma, Malignant; Mutation; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 36656861
DOI: 10.1073/pnas.2217840120 -
European Respiratory Review : An... Dec 2022Thoracentesis and thoracoscopy are used to diagnose malignant pleural effusions (MPE). Data on how sensitivity varies with tumour type is limited. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Thoracentesis and thoracoscopy are used to diagnose malignant pleural effusions (MPE). Data on how sensitivity varies with tumour type is limited.
METHODS
Systematic review using PubMed was performed through August 2020 to determine the sensitivity of thoracentesis and thoracoscopy for MPE secondary to malignancy, by cancer type, and complication rates. Tests to identify sources of heterogeneity were performed. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and National Institutes of Health quality assessment tools. Publication bias was tested using funnel plots.
RESULTS
Meta-analyses for sensitivity of thoracentesis for MPE secondary to malignancy, mesothelioma and lung and breast cancer included 29, eight, 12 and nine studies, respectively. Pooled sensitivities were 0.643 (95% CI 0.592-0.692), 0.451 (95% CI 0.249-0.661), 0.738 (95% CI 0.659-0.836) and 0.820 (95% CI 0.700-0.917), respectively. For sensitivity of thoracoscopy for MPE secondary to malignancy and mesothelioma, 41 and 15 studies were included, respectively. Pooled sensitivities were 0.929 (95% CI 0.905-0.95) and 0.915 (95% CI 0.871-0.952), respectively. Pooled complication rates of thoracentesis and thoracoscopy were 0.041 (95% CI 0.025-0.051) and 0.040 (95% CI 0.029-0.052), respectively. Heterogeneity was significant for all meta-analyses. Funnel plots were asymmetric.
INTERPRETATION
Sensitivity of thoracentesis varied significantly per cancer type. Pooled complication rates were low. Awareness of how sensitivity of thoracentesis changes across cancers can improve decision-making when MPE is suspected.
Topics: Humans; Thoracentesis; Retrospective Studies; Pleural Effusion, Malignant; Mesothelioma; Mesothelioma, Malignant; Thoracoscopy
PubMed: 36543349
DOI: 10.1183/16000617.0053-2022 -
International Journal of Molecular... May 2023Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring... (Review)
Review
Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring systemic treatment. Chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care for approximately 20 years, without any relevant therapeutic advance until the introduction of immune checkpoint inhibitors. Nevertheless, the prognosis remains poor, with an average survival of only 18 months. Thanks to a better understanding of the molecular mechanisms underlying tumor biology, targeted therapy has become an essential therapeutic option in several solid malignancies. Unfortunately, most of the clinical trials evaluating potentially targeted drugs for MPM have failed. This review aims to present the main findings of the most promising targeted therapies in MPM, and to explore possible reasons leading to treatments failures. The ultimate goal is to determine whether there is still a place for continued preclinical/clinical research in this area.
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Lung Neoplasms; Pleural Neoplasms; Pemetrexed; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37298116
DOI: 10.3390/ijms24119165 -
Trends in Cancer Sep 2016Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our... (Review)
Review
Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches. Nevertheless, the clinical translation of these molecular findings has been slow and insufficient. In order to rapidly move translation from the bench to the bedside, we believe that cooperative research efforts have to be further endorsed and promoted at all levels.
Topics: Animals; Antineoplastic Agents; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Targeted Therapy; Translational Research, Biomedical
PubMed: 28603777
DOI: 10.1016/j.trecan.2016.07.004 -
Cancer Cytopathology Jul 2021Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition... (Review)
Review
Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1-associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.
Topics: Biomarkers, Tumor; Homozygote; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Mesothelioma, Malignant; Pleural Effusion; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 33465294
DOI: 10.1002/cncy.22398 -
Journal of Thoracic Oncology : Official... Mar 2022Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features...
INTRODUCTION
Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.
METHODS
Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and programmed death-ligand 1 were evaluated by immunohistochemistry (IHC) when tissue was available. Overall survival was stratified by selected genomic and IHC features.
RESULTS
A total of 50 consented patients with MPeM (45 epithelioid, 5 nonepithelioid) were studied exhibiting common alterations in BAP1 (60%; 30 of 50), NF2 (24%; 12 of 50) SETD2 (22%; 11 of 50), and TP53 (16%; 8 of 50). A total of 76% (38 of 50) of specimens were assessable for allele-specific copy number analysis; 8% (3 of 38) had GNH. IHC positivity rates were 93% (37 of 40) for mesothelin, 96% (46 of 48) for WT1, 50% (19 of 38) for programmed death-ligand 1, and 89% (34 of 38) for VISTA. BAP1 loss by IHC was observed in 76% (29 of 38), including five wild-type on NGS. Combining NGS and IHC for BAP1, overall survival was worse with alteration or loss compared with wild-type or retained in all patients (n = 37 versus 13, 43.8 versus 117.3 mo, p = 0.04) Three of 30 patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, and BAP1 E402∗.
CONCLUSIONS
MPeM has distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM, whereas BAP1, NF2, TP53, SETD2, and LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.
Topics: Humans; Mesothelioma; Mesothelioma, Malignant; Peritoneal Neoplasms
PubMed: 34648949
DOI: 10.1016/j.jtho.2021.09.012 -
Jornal Brasileiro de Pneumologia :... Nov 2022
Topics: Humans; Mesothelioma, Malignant; Pleural Neoplasms; Lung Neoplasms; Delivery of Health Care; Mesothelioma
PubMed: 36350958
DOI: 10.36416/1806-3756/e20220349