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Journal of Thoracic Oncology : Official... May 2018Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication,... (Review)
Review
Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.
Topics: Humans; Immunotherapy; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant
PubMed: 29524617
DOI: 10.1016/j.jtho.2018.02.021 -
International Journal of Molecular... Jul 2018Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular... (Review)
Review
Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by and seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation.
Topics: Animals; Animals, Genetically Modified; Carcinogenesis; Epithelium; Humans; Lung; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mutation; Neoplasms, Experimental; Rats
PubMed: 30060470
DOI: 10.3390/ijms19082191 -
The American Journal of Pathology May 1950
Topics: Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neoplasms; Pleura; Pleural Neoplasms
PubMed: 15410857
DOI: No ID Found -
Journal of the American Society of... 2022Serous effusion is often the first sign of mesothelioma. Diagnosis based on cytologic material from the effusions remains controversial and complementary biopsy is...
INTRODUCTION
Serous effusion is often the first sign of mesothelioma. Diagnosis based on cytologic material from the effusions remains controversial and complementary biopsy is usually required. However, obtaining representative tissue sample may be challenging, while obtaining cytologic material is a minimally invasive procedure, providing potential for an earlier diagnosis. Loss of BRCA1-associated protein (BAP1), combined with loss of methylthionadenosine phosphorylase (MTAP) detected by immunohistochemistry, have shown to be reliable markers in the diagnosis of mesothelioma on histologic sections. Here we evaluate the value of these biomarkers in cytologic specimens.
MATERIALS AND METHODS
The BAP1 and MTAP expression in specimens of 162 mesothelioma patients (156 pleural, 6 peritoneal)-71 cytologic, 91 histologic (44 epithelioid, 31 biphasic, 16 sarcomatoid)-and 20 patients with reactive mesothelial proliferations were investigated.
RESULTS
The loss of BAP1 and/or MTAP was highly sensitive and specific in differentiating mesothelioma from reactive mesothelial proliferations, with no significant difference between pleural effusions and biopsies, specificity of 100% in both and a sensitivity of 78.9% and 80.2%, respectively (P = 0.3). There was a 100% concordance of the expression of BAP1 and MTAP in cytologic and corresponding histopathologic samples. Loss of BAP1 and/or MTAP in histologic sections discriminated sarcomatoid, biphasic, and epithelioid mesothelioma from reactive mesothelial proliferations with a sensitivity of 81.2%, 83.9%, and 77.3% respectively.
CONCLUSION
Loss of expression of BAP1 and/or MTAP differentiated mesothelioma from reactive mesothelial proliferations with excellent specificity and high sensitivity in cytologic samples, comparable to histopathologic sections.
Topics: Humans; Ubiquitin Thiolesterase; Tumor Suppressor Proteins; Lung Neoplasms; Biomarkers, Tumor; Mesothelioma; Mesothelioma, Malignant; Biopsy; Sarcoma; Phosphorylases
PubMed: 35945149
DOI: 10.1016/j.jasc.2022.07.003 -
JAMA Network Open Aug 2023Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely...
IMPORTANCE
Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.
OBJECTIVE
To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.
DESIGN, SETTING, AND PARTICIPANTS
A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.
MAIN OUTCOMES AND MEASURES
The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.
RESULTS
Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.
CONCLUSIONS AND RELEVANCE
In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.
Topics: Humans; Male; Middle Aged; Female; Genetic Predisposition to Disease; Mesothelioma; Mesothelioma, Malignant; High-Throughput Nucleotide Sequencing; Genomics; Adaptor Proteins, Signal Transducing; DNA Helicases
PubMed: 37556141
DOI: 10.1001/jamanetworkopen.2023.27351 -
BioMed Research International 2022Mesothelioma (MESO) is a mesothelial originate neoplasm with high morbidity and mortality. Despite advancement in technology, early diagnosis still lacks effectivity and...
Mesothelioma (MESO) is a mesothelial originate neoplasm with high morbidity and mortality. Despite advancement in technology, early diagnosis still lacks effectivity and is full of pitfalls. Approaches of cancer diagnosis and therapy utilizing immune biomarkers and transcription factors (TFs) have attracted more and more attention. But the molecular mechanism of these features in MESO bone metastasis has not been thoroughly studied. Utilizing high-throughput genome sequencing data and lists of specific gene subsets, we performed several data mining algorithm. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to identify downstream immune cells. Potential pathways involved in MESO bone metastasis were identified using Gene Oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Cox regression analysis. Ultimately, a model to help early diagnosis and to predict prognosis was constructed based on differentially expressed immune-related genes between bone metastatic and nonmetastatic MESO groups. In conclusion, immune-related gene SDC2, regulated by TFs TCF7L1 and POLR3D, had an important role on immune cell function and infiltration, providing novel biomarkers and therapeutic targets for metastatic MESO.
Topics: Bone Neoplasms; Humans; Mesothelioma; Prognosis; Transcription Factors
PubMed: 35127947
DOI: 10.1155/2022/9940566 -
Frontiers in Bioscience (Landmark... Jan 2011Malignant pleural mesothelioma (MPM), arises from the mesothelial cells, is difficult to be diagnosed at an early stage, and is refractory to conventional chemotherapy... (Review)
Review
Malignant pleural mesothelioma (MPM), arises from the mesothelial cells, is difficult to be diagnosed at an early stage, and is refractory to conventional chemotherapy and radiotherapy. Therefore, the establishment of novel effective therapies is necessary to improve the prognosis for many patients with this disease. Recent studies have demonstrated that angiogenesis plays a significant role in MPM progression, suggesting the importance of tumor vessels as therapeutic targets. To explore molecular pathogenesis and evaluate the efficacy of vascular targeting therapy in MPM, we developed orthotopic implantation SCID mouse models of MPM. We found that selective VEGF inhibitors were effective only in the treatment of high-VEGF-producing MPM models. On the other hand, multiple kinase inhibitor E7080, with inhibitory activity against various angiogenic cytokine receptors, suppressed the progression and prolonged survival of both high-VEGF-producing and low-VEGF-producing MPM models. Further understanding of the functional characteristics of tumor angiogenesis may be essential to improve targeting therapies in MPM. In this review, we introduce current status of clinical strategies and novel therapeutic approaches against angiogenesis in MPM.
Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cell Line, Tumor; Disease Models, Animal; Humans; Mesothelioma; Mice; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic; Phenylurea Compounds; Piperidines; Pleural Effusion, Malignant; Pleural Neoplasms; Quinazolines; Quinolines; Thoracic Cavity; Vascular Endothelial Growth Factors
PubMed: 21196199
DOI: 10.2741/3716 -
Nihon Eiseigaku Zasshi. Japanese... May 2011Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are... (Review)
Review
Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.
Topics: Animals; Asbestosis; Humans; Mesothelioma; Pleural Neoplasms
PubMed: 21701088
DOI: 10.1265/jjh.66.562 -
International Journal of Molecular... Dec 2022Malignant mesothelioma (MM) is a devastating cancer of mesothelial cells, caused by asbestos exposure. Limited knowledge regarding the detection of asbestos exposure and... (Review)
Review
Malignant mesothelioma (MM) is a devastating cancer of mesothelial cells, caused by asbestos exposure. Limited knowledge regarding the detection of asbestos exposure and the early diagnosis of MM, as well as a lack of successful treatment options for this deadly cancer, project an immediate need to understand the mechanism(s) of MM development. With the recent discovery of nano-vesicles, namely exosomes, and their enormous potential to contain signature molecules representative of different diseases, as well as to communicate with distant targets, we were encouraged to explore their role(s) in MM biology. In this review, we summarize what we know so far about exosomes and MM based on our own studies and on published literature from other groups in the field. We expect that the information contained in this review will help advance the field of MM forward by revealing the mechanisms of MM development and survival. Based on this knowledge, future therapeutic strategies for MM can potentially be developed. We also hope that the outcome of our studies presented here may help in the detection of MM.
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Lung Neoplasms; Asbestos; Exosomes
PubMed: 36499762
DOI: 10.3390/ijms232315438 -
Cancer Epidemiology, Biomarkers &... Dec 2020Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm, which can be treated successfully only if correctly diagnosed and treated in early stages. The... (Review)
Review
Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm, which can be treated successfully only if correctly diagnosed and treated in early stages. The asbestos-exposed population serves as a high-risk group that could benefit from sensitive and specific blood- or tissue-based biomarkers. This review details the recent work with biomarker development in MPM and the contributions of the NCI Early Detection Research Network Biomarker Developmental Laboratory of NYU Langone Medical Center. The literature of the last 20 years was reviewed to comment on the most promising of the blood- and tissue-based biomarkers. Proteomic, genomic, and epigenomic platforms as well as novel studies such as "breath testing" are covered. Soluble mesothelin-related proteins (SMRP) have been characterized extensively and constitute an FDA-approved biomarker in plasma with diagnostic, monitoring, and prognostic value in MPM. Osteopontin is found to be a valuable prognostic biomarker for MPM, while its utility in diagnosis is slightly lower. Other biomarkers, such as calretinin, fibulin 3, and High-Mobility Group Box 1 (HMGB1), remain under study and need international validation trials with large cohorts of cases and controls to demonstrate any utility. The EDRN has played a key role in the development and testing of MPM biomarkers by enlisting collaborations all over the world. A comprehensive understanding of previously investigated biomarkers and their utility in screening and early diagnosis of MPM will provide guidance for further future research.
Topics: Biomarkers, Tumor; Early Detection of Cancer; Female; Humans; Male; Mesothelioma
PubMed: 32699075
DOI: 10.1158/1055-9965.EPI-20-0083