bims-mesote Biomed News
on Mesothelioma
Issue of 2023‒03‒12
twelve papers selected by
Laura Mannarino
Humanitas Research

  1. Transl Lung Cancer Res. 2023 Feb 28. 12(2): 193-196
    Keywords:  Extrapleural pneumonectomy (EPP); immune checkpoint inhibitor; malignant pleural mesothelioma (MPM); pleurectomy/decortication (P/D)
  2. Transl Lung Cancer Res. 2023 Feb 28. 12(2): 187-189
    Keywords:  Pleural mesothelioma; diffuse pleural mesothelioma (DPM); intrathoracic chemotherapy; malignant pleural mesothelioma (MPM)
  3. J Clin Med. 2023 Feb 22. pii: 1757. [Epub ahead of print]12(5):
      Malignant pleural mesothelioma (MPM) is a rare cancer usually caused by asbestos exposure and associated with a very poor prognosis. After more than a decade without new therapeutic options, immune checkpoint inhibitors (ICIs) demonstrated superiority over standard chemotherapy, with improved overall survival in the first and later-line settings. However, a significant proportion of patients still do not derive benefit from ICIs, highlighting the need for new treatment strategies and predictive biomarkers of response. Combinations with chemo-immunotherapy or ICIs and anti-VEGF are currently being evaluated in clinical trials and might change the standard of care in the near future. Alternatively, some non-ICI immunotherapeutic approaches, such as mesothelin targeted CAR-T cells or denditric-cells vaccines, have shown promising results in early phases of trials and are still in development. Finally, immunotherapy with ICIs is also being evaluated in the peri-operative setting, in the minority of patients presenting with resectable disease. The goal of this review is to discuss the current role of immunotherapy in the management of malignant pleural mesothelioma, as well as promising future therapeutic directions.
    Keywords:  biomarker mesothelioma; immune checkpoint inhibitors; immunotherapy; malignant pleural mesothelioma
  4. Front Oncol. 2023 ;13 1158416
    Keywords:  diagnosis; malignant pleural mesothelioma; molecular mechanisms; multimodality strategy; precision oncology; treatment
  5. Cancers (Basel). 2023 Feb 28. pii: 1537. [Epub ahead of print]15(5):
      Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer that is mainly associated with prior exposure to asbestos fibers. Despite being a rare cancer, its global rate is increasing and the prognosis remains extremely poor. Over the last two decades, despite the constant research of new therapeutic options, the combination chemotherapy with cisplatin and pemetrexed has remained the only first-line therapy for MPM. The recent approval of immune checkpoint blockade (ICB)-based immunotherapy has opened new promising avenues of research. However, MPM is still a fatal cancer with no effective treatments. Enhancer of zeste homolog 2 (EZH2) is a histone methyl transferase that exerts pro-oncogenic and immunomodulatory activities in a variety of tumors. Accordingly, a growing number of studies indicate that EZH2 is also an oncogenic driver in MPM, but its effects on tumor microenvironments are still largely unexplored. This review describes the state-of-the-art of EZH2 in MPM biology and discusses its potential use both as a diagnostic and therapeutic target. We highlight current gaps of knowledge, the filling of which will likely favor the entry of EZH2 inhibitors within the treatment options for MPM patients.
    Keywords:  EZH2; epigenetic; immune infiltrate; immunotherapy; macrophages; malignant pleural mesothelioma; targeted therapy; tumor microenvironment
  6. Transl Lung Cancer Res. 2023 Feb 28. 12(2): 190-192
    Keywords:  Pleural mesothelioma (PM); extended pleurectomy decortication (EPD); extra pleural pneumonectomy (EPP); macroscopic complete resection (MCR)
  7. Acta Cytol. 2023 Mar 08.
      INTRODUCTION: In most cases the diagnostic workup of pleural mesotheliomas (MPM) starts with cytological examination of pleural effusion, but histology is needed to confirm the diagnosis. The introduction of BAP1 and MTAP immunohistochemistry have become a powerful tool to confirm the malignant nature of mesothelial proliferations also in cytological specimens. The objective of this study is to determine the concordance of BAP1, MTAP and p16 expression between cytological and histological samples of patients with MPM.METHODS: Immunohistochemistry of BAP1, MTAP and p16 was performed on cytological samples and compared with the corresponding histological specimen of 25 patients with MPM. Inflammatory and stromal cells served as positive internal control for all three markers. In addition, samples of 11 patients with reactive mesothelial proliferations served as an external control group.
    RESULTS: Loss of BAP1, MTAP and p16 expression was found in 68%, 72% and 92% of MPM, respectively. Loss of MTAP was associated with loss of p16 expression in all cases. Concordance of BAP1 between cytological and corresponding histological samples was 100% (kappa coefficient 1; p = 0.008). For MTAP and p16 kappa coefficient was 0.9 (p = 0.01) and 0.8 (p = 0.7788), respectively.
    CONCLUSIONS: Concordant BAP1, MTAP and p16 expression is found between cytological and corresponding histological samples, indicating that a reliable diagnosis of MPM can be made on cytology only. Of the three markers BAP1 and MTAP are most reliable in distinguishing malignant from reactive mesothelial proliferations.
  8. Lung Cancer. 2023 Mar 01. pii: S0169-5002(23)00085-5. [Epub ahead of print]178 213-219
      OBJECTIVES: Pleural mesothelioma (PM) is an aggressive malignancy with limited treatment options. The first-line therapy has remained unchanged for two decades and consists of pemetrexed in combination with cisplatin. Immune-checkpoint inhibitors (nivolumab plus ipilimumab) have high response rates, resulting in recent updates in treatment recommendations by the U.S. Food and Drug Administration. However, the overall benefits of combination treatment are modest, suggesting that other targeted therapy options should be investigated.MATERIALS AND METHODS: We employed high-throughput drug sensitivity and resistance testing on five established PM cell lines using 527 cancer drugs in a 2D setting. Drugs of the greatest potential (n = 19) were selected for further testing in primary cell models derived from pleural effusions of seven PM patients.
    RESULTS: All established and primary patient-derived PM cell models were sensitive to the mTOR inhibitor AZD8055. Furthermore, another mTOR inhibitor (temsirolimus) showed efficacy in most of the primary patient-derived cells, although a less robust effect was observed when compared with the established cell lines. Most of the established cell lines and all patient-derived primary cells exhibited sensitivity to the PI3K/mTOR/DNA-PK inhibitor LY3023414. The Chk1 inhibitor prexasertib showed activity in 4/5 (80%) of the established cell lines and in 2/7 (29%) of the patient-derived primary cell lines. The BET family inhibitor JQ1 showed activity in four patient-derived cell models and in one established cell line.
    CONCLUSION: mTOR and Chk1 pathways had promising results with established mesothelioma cell lines in an ex vivo setting. In patient-derived primary cells, drugs targeting mTOR pathway in particular showed efficacy. These findings may inform novel treatment strategies for PM.
    Keywords:  Drug sensitivity testing; Pleural mesothelioma; Prexasertib; mTOR inhibitors
  9. JAMA Netw Open. 2023 Mar 01. 6(3): e232526
      Importance: Diffuse malignant peritoneal mesothelioma (DMPM) represents a rare and clinically distinct entity among malignant mesotheliomas. Pembrolizumab has activity in diffuse pleural mesothelioma but limited data are available for DMPM; thus, DMPM-specific outcome data are needed.Objective: To evaluate outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with DMPM.
    Design, Setting, and Participants: This retrospective cohort study was conducted in 2 tertiary care academic cancer centers (University of Pennsylvania Hospital Abramson Cancer Center and Memorial Sloan Kettering Cancer Center). All patients with DMPM treated between January 1, 2015, and September 1, 2019, were retrospectively identified and followed until January 1, 2021. Statistical analysis was performed between September 2021 and February 2022.
    Exposures: Pembrolizumab (200 mg or 2 mg/kg every 21 days).
    Main Outcomes and Measures: Median progression-free survival (PFS) and median overall survival (OS) were assessed using Kaplan-Meier estimates. The best overall response was determined using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, version 1.1. The association of disease characteristics with partial response was evaluated using the Fisher exact test.
    Results: This study included 24 patients with DMPM who received pembrolizumab monotherapy. Patients had a median age of 62 years (IQR, 52.4-70.6 years); 14 (58.3%) were women, 18 (75.0%) had epithelioid histology, and most (19 [79.2%]) were White. A total of 23 patients (95.8%) received systemic chemotherapy prior to pembrolizumab, and the median number of lines of prior therapy was 2 (range, 0-6 lines). Of the 17 patients who underwent programmed death ligand 1 (PD-L1) testing, 6 (35.3%) had positive tumor PD-L1 expression (range, 1.0%-80.0%). Of the 19 evaluable patients, 4 (21.0%) had a partial response (overall response rate, 21.1% [95% CI, 6.1%-46.6%]), 10 (52.6%) had stable disease, and 5 (26.3%) had progressive disease (5 of 24 patients [20.8%] were lost to follow-up). There was no association between a partial response and the presence of a BAP1 alteration, PD-L1 positivity, or nonepithelioid histology. With a median follow-up of 29.2 (95% CI, 19.3 to not available [NA]) months, the median PFS was 4.9 (95% CI, 2.8-13.3) months and the median OS was 20.9 (95% CI, 10.0 to NA) months from pembrolizumab initiation. Three patients (12.5%) experienced PFS of more than 2 years. Among patients with nonepithelioid vs epithelioid histology, there was a numeric advantage in median PFS (11.5 [95% CI, 2.8 to NA] vs 4.0 [95% CI, 2.8-8.8] months) and median OS (31.8 [95% CI, 8.3 to NA] vs 17.5 [95% CI, 10.0 to NA] months); however, this did not reach statistical significance.
    Conclusions and Relevance: The results of this retrospective dual-center cohort study of patients with DMPM suggest that pembrolizumab had clinical activity regardless of PD-L1 status or histology, although patients with nonepithelioid histology may have experienced additional clinical benefit. The partial response rate of 21.0% and median OS of 20.9 months in this cohort with 75.0% epithelioid histology warrants further investigation to identify those most likely to respond to immunotherapy.
  10. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2023 Feb 20.
      The association of mesothelioma, a lethal lung disease, with asbestos has led to an absolute ban on asbestos in at least 55 countries worldwide. The purpose of this paper is to review residual exposure to asbestos as well as other emerging causes of mesothelioma outside asbestos. The review provides detailed description of asbestos minerals, their geographical locations, mesothelioma in these areas, as well as contemporary possible sources of asbestos exposure. Second, we examine other emerging causes of mesothelioma including: ionizing radiation as the second most important risk factor after asbestos, particularly relevant to patients undergoing radiotherapy, third, carbon nanotubes which are under investigation and fourth, Simian virus 40. In the case of asbestos per se, the greatest risk is from occupational exposure during mining and subsequent processing. Of the non-occupational exposures, environmental exposure is most serious, followed by exposure from indoor asbestos minerals and secondary familial exposure. Overall, asbestos is still a major risk factor, but alternative causes should not be neglected, especially in young people, in women and those with a history of radiotherapy or living in high-risk locations.
    Keywords:  asbestos; mesothelioma; non-asbestos etiology; non-occupational exposure; occupational exposure
  11. Int J Mol Sci. 2023 Feb 21. pii: 4264. [Epub ahead of print]24(5):
      Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial-mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-β signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-β1/TGFBR1 pathway.
    Keywords:  epithelial–mesenchymal transition (EMT); gene signature; malignant mesothelioma (MESO); multiomic analysis; prognosis