bims-mesote 2022-01-02 papers

Issue of 2022–01–02
five papers selected by
Laura Mannarino, Humanitas Research

Front Surg. 2021 ;8 766033

Quality of Life Is Not Deteriorated After Extrapleural Pneumonectomy vs. (Extended) Pleurectomy/Decortication in Patients With Malignant Pleural Mesothelioma.

Olivia Lauk, Miriam Patella, Thomas Neuer, Ilhan Inci, Walter Weder, Isabelle Opitz.

Background: Extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is highly abandoned due to high morbidity and mortality rates and impaired quality of life (QoL). However, there are still rare indications for this intervention. The aim of this longitudinal prospective study was to monitor QoL and lung function in patients undergoing EPP and compare the outcomes with extended pleurectomy/decortication [(E)PD]. Methods: Between June 2013 and June 2017, 42 patients underwent induction chemotherapy followed by either EPP (n = 7) or (E)PD (n = 35). All patients filled out the EORTC QLC-C15-PAL, -LC13, and SF-36 self-rating questionnaires pre-operatively, 6 weeks and 4 months after the operation. Additionally, lung function was measured pre-operatively and 4 months post-operatively. Results: We observed no significant differences in all QoL categories (general global health, pain, and dyspnea) between both surgical procedures, over the whole observation period. Moreover, a general tendency toward restoration of the pre-operative QoL status was documented at 4 months after the both operations. Forced expiratory volume in 1 s (FEV1) showed a significant decrease after surgery in both the groups [EPP group p = 0.06 and (E)PD group p < 0.001]; also, the forced volume vital capacity (FVC) significantly decreased (EPP group p = 0.046 P/D group <0.001). Diffusion capacity did not show significant changes. Conclusion: According to these results, QoL is no longer severely impaired after EPP compared with EPD, and therefore should not be used as an argument against EPP in principle. However, indication has to be carefully evaluated for each patient.

Keywords: extended pleurectomy/decortication; extrapleural pneumonectomy (EPP); induction chemotherapy; lung function; macroscopic complete resection; malignant pleural mesothelioma; quality of life

DOI: https://doi.org/10.3389/fsurg.2021.766033

Epigenomes. 2021 Dec 14. pii: 27. [Epub ahead of print]5(4):

Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy.

Maria Fortunata Lofiego, Sara Cannito, Carolina Fazio, Francesca Piazzini, Ornella Cutaia, Laura Solmonese, Francesco Marzani, Carla Chiarucci, Anna Maria Di Giacomo, Luana Calabrò, Sandra Coral, Michele Maio, Alessia Covre, On Behalf Of The EPigenetic Immune-Oncology Consortium Airc Epica Investigators.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a severe prognosis, and with a long-standing need for more effective therapeutic approaches. However, treatment with immune checkpoint inhibitors is becoming an increasingly effective strategy for MPM patients. In this scenario, epigenetic modifications may negatively regulate the interplay between immune and malignant cells within the tumor microenvironment, thus contributing to the highly immunosuppressive contexture of MPM that may limit the efficacy of immunotherapy. Aiming to further improve prospectively the clinical efficacy of immunotherapeutic approaches in MPM, we investigated the immunomodulatory potential of different classes of epigenetic drugs (i.e., DNA hypomethylating agent (DHA) guadecitabine, histone deacetylase inhibitors VPA and SAHA, or EZH2 inhibitors EPZ-6438) in epithelioid, biphasic, and sarcomatoid MPM cell lines, by cytofluorimetric and real-time PCR analyses. We also characterized the effects of the DHA, guadecitabine, on the gene expression profiles (GEP) of the investigated MPM cell lines by the nCounter platform. Among investigated drugs, exposure of MPM cells to guadecitabine, either alone or in combination with VPA, SAHA and EPZ-6438 demonstrated to be the main driver of the induction/upregulation of immune molecules functionally crucial in host-tumor interaction (i.e., HLA class I, ICAM-1 and cancer testis antigens) in all three MPM subtypes investigated. Additionally, GEP demonstrated that treatment with guadecitabine led to the activation of genes involved in several immune-related functional classes mainly in the sarcomatoid subtype. Furthermore, among investigated MPM subtypes, DHA-induced CDH1 expression that contributes to restoring the epithelial phenotype was highest in sarcomatoid cells. Altogether, our results contribute to providing the rationale to develop new epigenetically-based immunotherapeutic approaches for MPM patients, potentially tailored to the specific histologic subtypes.

Keywords: DNA methylation; epigenetic drugs; immunotherapy; malignant pleural mesothelioma

DOI: https://doi.org/10.3390/epigenomes5040027

Pathol Int. 2021 Dec 29.

Asbestos-induced mesothelial injury and carcinogenesis: Involvement of iron and reactive oxygen species.

Yasumasa Okazaki.

Asbestos fibers have been used as an industrial and construction material worldwide due to their high durability and low production cost. Commercial usage of asbestos is currently prohibited in Japan; however, the risk of asbestos-induced malignant mesothelioma (MM) remains. According to epidemiological data, the onset of MM is estimated to occur after a latent period of 30-40 years from initial exposure to asbestos fibers; thus, the continuous increase in MM is a concern. To explore the molecular mechanisms of MM using animal models, iron saccharate with iron chelator-induced sarcomatoid mesothelioma (SM) revealed hallmarks of homozygous deletion of Cdkn2a/2b by aCGH and microRNA-199/214 by expression microarray. Oral treatment of iron chelation by deferasirox decreased the rate of high-grade SM. Moreover, phlebotomy delayed MM development in crocidolite-induced MM in rats. In Divalent metal transporter 1 (Dmt1) transgenic mice, MM development was delayed because of low reactive oxygen species (ROS) production. These results indicate the importance of iron and ROS in mesothelial carcinogenesis. The aims of this review focus on the pathogenesis of elongated mineral particles (EMPs), including asbestos fibers and multiwalled carbon nanotubes (MWCNTs) that share similar rod-like shapes in addition to the molecular mechanisms of MM development.

Keywords: asbestos; carbon nanotubes; iron; malignant mesothelioma; oxidative stress

DOI: https://doi.org/10.1111/pin.13196

Viruses. 2021 Dec 08. pii: 2458. [Epub ahead of print]13(12):

The Oncolytic Caprine Herpesvirus 1 (CpHV-1) Induces Apoptosis and Synergizes with Cisplatin in Mesothelioma Cell Lines: A New Potential Virotherapy Approach.

Iris Maria Forte, Paola Indovina, Serena Montagnaro, Aurora Costa, Carmelina Antonella Iannuzzi, Francesca Capone, Rosa Camerlingo, Anna Maria Malfitano, Francesca Pentimalli, Gianmarco Ferrara, Massimiliamo Quintiliani, Giuseppe Portella, Antonio Giordano, Roberto Ciarcia.

Malignant mesothelioma (MM) is an aggressive asbestos-related cancer, against which no curative modalities exist. Oncolytic virotherapy is a promising therapeutic approach, for which MM is an ideal candidate; indeed, the pleural location provides direct access for the intra-tumoral injection of oncolytic viruses (OVs). Some non-human OVs offer advantages over human OVs, including the non-pathogenicity in humans and the absence of pre-existing immunity. We previously showed that caprine herpesvirus 1 (CpHV-1), a non-pathogenic virus for humans, can kill different human cancer cell lines. Here, we assessed CpHV-1 effects on MM (NCI-H28, MSTO, NCI-H2052) and non-tumor mesothelial (MET-5A) cells. We found that CpHV-1 reduced cell viability and clonogenic potential in all MM cell lines without affecting non-tumor cells, in which, indeed, we did not detect intracellular viral DNA after treatment. In particular, CpHV-1 induced MM cell apoptosis and accumulation in G0/G1 or S cell cycle phases. Moreover, CpHV-1 strongly synergized with cisplatin, the drug currently used in MM chemotherapy, and this agent combination did not affect normal mesothelial cells. Although further studies are required to elucidate the mechanisms underlying the selective CpHV-1 action on MM cells, our data suggest that the CpHV-1-cisplatin combination could be a feasible strategy against MM.

Keywords: apoptosis; caprine herpesvirus 1 (CpHV-1); cisplatin; malignant mesothelioma (MM); oncolytic virus (OV); synergism

DOI: https://doi.org/10.3390/v13122458

Front Oncol. 2021 ;11 789244

Aurora Kinase A as a Diagnostic and Prognostic Marker of Malignant Mesothelioma.

Zhenying Guo, Li Shen, Ningning Li, Xiaoxiao Wu, Canming Wang, Zheng Gu, Zhongjian Chen, Junping Liu, Weimin Mao, Yuchen Han.

Background: Malignant mesothelioma (MM) is a highly aggressive cancer with a poor prognosis. Despite the use of several well-known markers, the diagnosis of MM is still challenging in some cases. we applied bioinformatics to identify key genes and screen for diagnostic and prognostic markers of MM.
Methods: The expression profiles of GSE2549 and GSE112154 microarray datasets from the Gene Expression Omnibus database contained 87 cases of MM tissue and 8 cases of normal mesothelial tissue in total. The GEO2R tool was used to detect differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed using DAVID Bioinformatics Resources. The DEGs protein-protein interaction networks were constructed from the STRING database. Cytoscape was used to identify significant modules and hub genes. The GEPIA database was used to explore relationships between hub genes and prognosis of MM. Immunohistochemistry was used to analyze protein expression in tissue microarrays with 47 Chinese MM tissues. Statistical analyses diagnostic and prognostic values.
Results: 346 DEGs were identified: 111 genes upregulated, and 235 downregulated. GO analysis showed that the primary biological processes of these DEGs were cell adhesion, leukocyte migration, and angiogenesis. The main cellular components included the extracellular space, extracellular exosome, and extracellular region. The molecular functions were integrin binding, heparin binding, and calcium ion binding. KEGG pathway analysis showed that DEGs are primarily involved in PPAR signaling pathway, extracellular matrix-receptor interactions, and regulation of lipolysis in adipocytes. Survival analysis showed that seven genes-AURKA, GAPDH, TOP2A, PPARG, SCD, FABP4, and CEBPA-may be potential prognostic markers for MM. Immunohistochemical studies showed that Aurora kinase A (AURKA gene encode, Aurora-A) and GAPDH were highly expressed in MM tissue in comparison with normal mesothelial tissue. Kaplan-Meier analysis confirmed a correlation between Aurora-A protein expression and overall survival but did not confirm a correlation with GAPDH. The receiver operating characteristic curves of Aurora-A protein expression suggested acceptable accuracy (AUC = 0.827; 95% CI [0.6686 to 0.9535]; p = 0.04). The sensitivity and specificity of Aurora-A were 83.33% and 77.78%, respectively.
Conclusion: Aurora-A could be an optimal diagnostic biomarker and a potential prognostic marker for MM.

Keywords: Aurora kinase A; bioinformatics; biomarkers; malignant mesothelioma; tissue microarray

DOI: https://doi.org/10.3389/fonc.2021.789244