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Modern Pathology : An Official Journal... Jan 2022Mesothelial tumors are classified into benign or preinvasive tumors, and mesotheliomas. The benign or preinvasive group includes adenomatoid tumors, well-differentiated... (Review)
Review
Mesothelial tumors are classified into benign or preinvasive tumors, and mesotheliomas. The benign or preinvasive group includes adenomatoid tumors, well-differentiated papillary mesothelial tumors, and mesothelioma in situ. Malignant tumors are mesotheliomas and can be localized or diffuse. Histological classification of invasive mesotheliomas into three major subtypes-epithelioid, sarcomatoid, and biphasic is prognostically important. It also plays a significant role in the treatment decisions of patients diagnosed with this deadly disease. Grading and subtyping of epithelioid mesotheliomas have been one of the major changes in the recent WHO classification of pleural tumors. Mesothelioma in situ has emerged as a precisely defined clinico-pathologic entity that for diagnosis requires demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH. The use of these two biomarkers improves the diagnostic sensitivity of effusion specimens and limited tissue samples and is valuable in establishing the diagnosis of epithelioid mesothelioma. In this review, recent changes in the histologic classification of pleural mesothelioma, importance of ancillary diagnostic studies, and molecular characteristics of mesotheliomas are discussed.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Genes, p16; Humans; Mesothelioma, Malignant; Pleura; Pleural Neoplasms; Prognosis; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 34465883
DOI: 10.1038/s41379-021-00895-7 -
Journal of Clinical Oncology : Official... Feb 2022Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes... (Review)
Review
Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell- and Tissue-Based Therapy; Chemotherapy, Adjuvant; Humans; Immunotherapy; Mesothelioma, Malignant; Pleural Neoplasms; Radiation Dosage; Radiotherapy, Adjuvant; Radiotherapy, Intensity-Modulated; Thoracic Surgical Procedures; Treatment Outcome
PubMed: 34985934
DOI: 10.1200/JCO.21.01567 -
Thoracic Surgery Clinics Nov 2020Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural lining associated with asbestos exposure in greater than 80% of cases. It is... (Review)
Review
Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural lining associated with asbestos exposure in greater than 80% of cases. It is characterized by molecular heterogeneity both between patients and within individual tumors. Next-generation sequencing technology and novel computational techniques have resulted in a greater understanding of the epigenetic, genetic, and transcriptomic hallmarks of MPM. This article reviews these features and discusses the implications of advances in MPM molecular biology in clinical practice.
Topics: Asbestos; Computational Biology; Epigenesis, Genetic; Gene Expression; High-Throughput Nucleotide Sequencing; Humans; Mesothelioma, Malignant; Pleural Neoplasms; Transcriptome
PubMed: 33012428
DOI: 10.1016/j.thorsurg.2020.08.005 -
Proceedings of the National Academy of... Feb 2023Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage...
Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial-mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, , and , could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.
Topics: Animals; Mice; Mesothelioma, Malignant; Tumor-Associated Macrophages; Macrophages; Mesothelioma; Monocytes; Tumor Microenvironment; Membrane Glycoproteins; Receptors, Immunologic; Cell Adhesion Molecules, Neuronal
PubMed: 36821580
DOI: 10.1073/pnas.2210836120 -
Cancer Research Oct 2020Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In...
Identification of tumor-specific cell surface antigens has proven challenging, as the vast majority of tumor-associated antigens are also expressed in normal tissues. In mesothelioma, we identified a highly specific tumor cell surface antigen that can be targeted for therapy development. Mesothelioma is caused by malignant transformation of the mesothelium, is incurable, and can be categorized into three histologic subtypes: epithelioid, biphasic, and sarcomatoid. To identity novel mesothelioma cell surface antigens with broad subtype coverage and high tissue specificity, we have previously selected phage antibody display libraries on live mesothelioma cells and tissues following counterselection on normal cells and identified a panel of human antibodies that bind all subtypes of mesothelioma, but not normal mesothelium. One of the antibodies, M25, showed high specificity against an antigen we identify here as ALPPL2. IHC on normal human tissues found that ALPPL2 is expressed only on placental trophoblasts, but not on any other normal tissues. This significant tissue specificity and broad tumor type coverage suggest that ALPPL2 could be an excellent cell surface target for therapeutic development against mesothelioma. To evaluate therapeutic potential of ALPPL2 targeting, an ALPPL2-targeted antibody-drug conjugate was developed and demonstrated potent and specific tumor killing and against both epithelioid and sarcomatoid mesothelioma. Thus, ALPPL2 belongs to a rare class of cell surface antigens classified as truly tumor specific and is well suited for therapy development against ALPPL2-expressing tumors. SIGNIFICANCE: These findings identify ALPP2 as a true tumor-specific cell surface antigen whose tissue specificity enables the development of novel therapies.
Topics: Alkaline Phosphatase; Animals; Antigens, Surface; Antineoplastic Agents, Immunological; CHO Cells; Cell Line, Tumor; Cricetulus; Epitopes; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Immunoglobulin G; Male; Mesothelioma, Malignant; Mice, Inbred NOD; Molecular Targeted Therapy; Xenograft Model Antitumor Assays
PubMed: 32868383
DOI: 10.1158/0008-5472.CAN-20-1418 -
The Lancet. Oncology Nov 2021No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.
METHODS
This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.
FINDINGS
Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.
INTERPRETATION
Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.
FUNDING
Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.
Topics: Aged; Antineoplastic Agents, Immunological; B7-H1 Antigen; Double-Blind Method; Female; Humans; Immune Checkpoint Inhibitors; Male; Mesothelioma, Malignant; Nivolumab; Peritoneal Neoplasms; Pleural Neoplasms; Progression-Free Survival; Recurrence; Survival Rate
PubMed: 34656227
DOI: 10.1016/S1470-2045(21)00471-X -
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 -
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 -
Thoracic Cancer Apr 2021Malignant pleural mesothelioma is an infrequent neoplasia with a poor prognosis and the majority of patients already have advanced disease at the time of presentation....
BACKGROUND
Malignant pleural mesothelioma is an infrequent neoplasia with a poor prognosis and the majority of patients already have advanced disease at the time of presentation. Exposure to asbestos is the most important risk factor for malignant pleural mesothelioma. Mesothelioma is a neoplasia with a long preclinical stage that can span from 15 to 40 years.
METHODS
This was a descriptive, observational, retrospective study of 136 patients with a confirmed diagnosis of mesothelioma, which compared histological subtypes, immunohistochemical biomarkers, concomitant chronic degenerative diseases, tobacco use, age at the time of diagnosis, clinical stage and chemotherapy agents used or other treatments such as radiotherapy and surgery to identify all the factors that impact in the prognosis of overall survival (OS) and progression-free survival (PFS).
RESULTS
A total of 136 patients were included in the study. In the total study population, 84 patients were male (61.8%) and 52 were female (38.2%). Median PFS was nine months (95% confidence interval [CI]: 8.4-9.5 months) and median OS was 12 months (95% CI: 11.3-12.6). The results indicated that the most determining prognostic factors for OS and PFS were cell differentiation measured by immunohistochemical biomarkers, the treatment chosen, and that RECIST was the most significant in the evaluation of patient response to treatment.
CONCLUSIONS
Malignant pleural mesothelioma is a cancer with a poor prognosis usually diagnosed at an advanced stage of disease. Our study revealed that the prognostic factors for OS and PS were cell differentiation, the treatment chosen and RECIST.
Topics: Adolescent; Adult; Female; Humans; Male; Mesothelioma, Malignant; Prognosis; Progression-Free Survival; Retrospective Studies; Young Adult
PubMed: 33660947
DOI: 10.1111/1759-7714.13814 -
Journal of Thoracic Oncology : Official... Jul 2017Although the association between exposure to asbestos and malignant mesothelioma (particularly malignant pleural mesothelioma) has been well established, the health... (Review)
Review
Although the association between exposure to asbestos and malignant mesothelioma (particularly malignant pleural mesothelioma) has been well established, the health impact of environmental exposure (EE) to asbestos has been less studied. This review summarizes the most recent studies on the association between malignant mesothelioma and EE with asbestos to identify features associated with EE and quantify the association with malignant mesothelioma. There were 44 studies from 18 countries that met our selection criteria, with a considerable amount of heterogeneity in their study design, measures of exposure, and health outcomes. The male-to-female ratio was close to or less than 1 and generally lower than the ratio reported when both occupational and environmental exposures were considered. Although recent studies have continued to improve our understanding of environmental exposure to asbestos, challenges remain. We have highlighted a few new research directions, such as a need for reliable matrices to identify common and less recognized types of EE, asbestos biomarker studies specifically focusing on EE, and research on populations and geographic areas that have not been previously studied.
Topics: Asbestos; Environmental Exposure; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant
PubMed: 28412495
DOI: 10.1016/j.jtho.2017.04.002