bims-mesote 2024-04-14 papers

Cancers (Basel). 2024 Mar 22. pii: 1252. [Epub ahead of print]16(7):

Emerging New Targets in Systemic Therapy for Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM.

Keywords: BAP1; NF2; malignant pleural mesothelioma; mesothelin; targeted therapy

DOI: https://doi.org/10.3390/cancers16071252

Pathol Res Pract. 2024 Mar 30. pii: S0344-0338(24)00187-0. [Epub ahead of print]257 155276

Diagnostic performance of immunohistochemistry markers for malignant pleural mesothelioma diagnosis and subtypes. A systematic review and meta-analysis.

Rafael Parra-Medina, Juan Pablo Castañeda-González, Viviana Chaves-Cabezas, Juan Pablo Alzate, Juan José Chaves.

BACKGROUND: Malignant pleural mesothelioma (MPM) poses diagnostic challenges due to its resemblance to benign pleural pathologies and different histological subtypes. Several immunohistochemistry markers have been employed to aid in accurate diagnosis.
METHODS: The present systematic review and meta-analysis aimed to assess the diagnostic performance of various immunohistochemistry markers in malignant pleural mesothelioma diagnosis and its histological subtypes. Following the PRISMA guidelines, we systematically searched the literature for articles on using different immunohistochemical markers in MPM and its histological subtypes. EMBASE, LILACS, MEDLINE, and Virtual Health Library were searched for studies published up to August 2023. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) criteria to assess the quality of the included articles. Meta-analyses were performed to determine prevalence using a random-effects model.
RESULTS: 103 studies met the inclusion criteria, comprising a diverse range of immunohistochemistry markers. EMA and desmin-loss exhibited high sensitivity (96% and 92%, respectively) in distinguishing malignant pleural mesothelioma from benign pleural pathologies. Specificity was notably high for both BAP1-loss and survivin expression at 100%. Subtype-specific analyses demonstrated that EMA and HEG1 were sensitive markers for epithelioid mesothelioma, while GLUT1 showed high sensitivity for sarcomatoid mesothelioma. In cases comparing epithelioid mesothelioma and lung adenocarcinoma, CAM5.2 and calretinin displayed high sensitivity, while WT1 and BAP1-loss demonstrated exceptional specificity for malignant epithelioid mesothelioma. In the case of sarcomatoid mesothelioma and sarcomatoid lung carcinoma, GATA3 exhibited the most heightened sensitivity, while GATA3 and D2-40 displayed the best specificity for sarcomatoid malignant mesothelioma diagnosis.
CONCLUSION: Immunohistochemistry markers are essential in accurately diagnosing malignant pleural mesothelioma and its histological subtypes. This systematic review and meta-analysis provide a comprehensive insight into the diagnostic performance of these markers, facilitating their potential clinical utility in the discrimination of malignant pleural mesothelioma from other pleural pathologies and the differentiation of malignant pleural mesothelioma subtypes.

Keywords: Immunohistochemistry; Lung neoplasms; Mesothelioma; Pleural neoplasms

DOI: https://doi.org/10.1016/j.prp.2024.155276

J Thorac Oncol. 2024 Apr;pii: S1556-0864(24)00037-6. [Epub ahead of print]19(4): 547-550

Immunotherapy Is a Good Standard Option for Patients With Malignant Pleural Mesothelioma, Despite the Real-World Results From Australia.

Illaa Smesseim, Paul Baas.

DOI: https://doi.org/10.1016/j.jtho.2024.01.017

J Cell Mol Med. 2024 Apr;28(8): e18330

YAP/TAZ-TEAD signalling axis: A new therapeutic target in malignant pleural mesothelioma.

Kostas A Papavassiliou, Amalia A Sofianidi, Athanasios G Papavassiliou.

The Hippo signalling pathway, a highly conserved signalling cassette, regulates organ size by controlling cell growth, apoptosis and stem cell self-renewal. The tumourigenic potential of this pathway is largely attributed to the activity of YAP/TAZ, which activate the TEAD1-4 transcription factors, leading to the expression of genes involved in cell proliferation and suppression of cell death. Aberrant regulation of the YAP/TAZ-TEAD signalling axis is commonly observed in malignant pleural mesothelioma (MPM), an insidious neoplasm of the pleural tissue that lines the chest cavity and covers the lungs with poor prognosis. Given the limited effectiveness of current treatments, targeting the YAP/TAZ-TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ-TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.

Keywords: Hippo signalling; TEAD; TEAD inhibitor; YAP/TAZ; malignant pleural mesothelioma

DOI: https://doi.org/10.1111/jcmm.18330

J Thorac Oncol. 2024 Apr;pii: S1556-0864(24)00036-4. [Epub ahead of print]19(4): 541-546

Based on the Real-World Results From Australia, Immunotherapy Is Not a Good Option for Patients With Mesothelioma.

Steven G Gray, Tomer Meirson, Luciano Mutti.

DOI: https://doi.org/10.1016/j.jtho.2024.01.016

Cancer Res Commun. 2024 Apr 08. 4(4): 1004-1015

Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment.

Yuwaraj Kadariya, Eleonora Sementino, Maggie Ruan, Mitchell Cheung, Parham Hadikhani, Hatice U Osmanbeyoglu, Andres J Klein-Szanto, Kathy Cai, Joseph R Testa.

Asbestos and BAP1 germline mutations are risk factors for malignant mesothelioma (MM). While it is well accepted that amphibole asbestos is carcinogenic, the role of serpentine (chrysotile) asbestos in MM has been debated. To address this controversy, we assessed whether minimal exposure to chrysotile could significantly increase the incidence and rate of MM onset in germline Bap1-mutant mice. With either crocidolite or chrysotile, and at each dose tested, MMs occurred at a significantly higher rate and earlier onset time in Bap1-mutant mice than in wild-type littermates. To explore the role of gene-environment interactions in MMs from Bap1-mutant mice, we investigated proinflammatory and protumorigenic factors and the tumor immune microenvironment (TIME). IHC and immunofluorescence staining showed an increased number of macrophages in granulomatous lesions and MMs. The relative number of CD163-positive (CD163+) M2 macrophages in chrysotile-induced MMs was consistently greater than in crocidolite-induced MMs, suggesting that chrysotile induces a more profound immunosuppressive response that creates favorable conditions for evading immune surveillance. MMs from Bap1-mutant mice showed upregulation of CD39/CD73-adenosine and C-C motif chemokine ligand 2 (Ccl2)/C-C motif chemokine receptor 2 (Ccr2) pathways, which together with upregulation of IL6 and IL10, promoted an immunosuppressive TIME, partly by attracting M2 macrophages. Interrogation of published human MM RNA sequencing (RNA-seq) data implicated these same immunosuppressive pathways and connections with CD163+ M2 macrophages. These findings indicate that increased M2 macrophages, along with upregulated CD39/CD73-adenosine and Ccl2/Ccr2 pathways, contribute to an immunosuppressive TIME in chrysotile-induced MMs of Bap1-mutant mice, suggesting that immunotherapeutic strategies targeting protumorigenic immune pathways could be beneficial in human BAP1 mutation carriers who develop MM.
SIGNIFICANCE: We show that germline Bap1-mutant mice have enhanced susceptibility to MM upon minimal exposure to chrysotile asbestos, not only amphibole fibers. Chrysotile induced a more profound immune tumor response than crocidolite in Bap1-mutant mice by upregulating CD39/CD73-adenosine and Ccl2/Ccr2 pathways and recruiting more M2 macrophages, which together contributed to an immunosuppressive tumor microenvironment. Interrogation of human MM RNA-seq data revealed interconnected immunosuppressive pathways consistent with our mouse findings.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0423

Arch Pathol Lab Med. 2024 Apr 08.

Guidelines for Pathologic Diagnosis of Mesothelioma.

CONTEXT.—: Mesothelioma is an uncommon tumor that can be difficult to diagnose.
OBJECTIVE.—: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma.
DATA SOURCES.—: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks.
CONCLUSIONS.—: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.

DOI: https://doi.org/10.5858/arpa.2023-0304-RA