Editorial

3 pages, 186 KiB

Open AccessEditorial

Malignant Mesothelioma

by Daniel L. Pouliquen and Joanna Kopecka

Cancers 2021, 13(14), 3447; https://doi.org/10.3390/cancers13143447 - 09 Jul 2021

Cited by 2 | Viewed by 2217

Malignant mesothelioma (MM) is a rare and aggressive cancer, related to chronic inflammation and oxidative stress caused mainly by exposure to asbestos [...] Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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14 pages, 1155 KiB

Open AccessArticle

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment

by Giovanni Cugliari, Alessandra Allione, Alessia Russo, Chiara Catalano, Elisabetta Casalone, Simonetta Guarrera, Federica Grosso, Daniela Ferrante, Marika Sculco, Marta La Vecchia, Chiara Pirazzini, Roberta Libener, Dario Mirabelli, Corrado Magnani, Irma Dianzani and Giuseppe Matullo

Cancers 2021, 13(11), 2636; https://doi.org/10.3390/cancers13112636 - 27 May 2021

Cited by 5 | Viewed by 4295

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 [...] Read more.

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10⁻⁷), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10⁻⁶). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10⁻¹¹) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10⁻⁸) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10⁻⁷; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10⁻⁸. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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13 pages, 576 KiB

Open AccessArticle

Liquid Biopsies from Pleural Effusions and Plasma from Patients with Malignant Pleural Mesothelioma: A Feasibility Study

by Gabriele Moretti, Paolo Aretini, Francesca Lessi, Chiara Maria Mazzanti, Guntulu Ak, Muzaffer Metintaş, Cecilia Lando, Rosa Angela Filiberti, Marco Lucchi, Alessandra Bonotti, Rudy Foddis, Alfonso Cristaudo, Andrea Bottari, Alessandro Apollo, Marzia Del Re, Romano Danesi, Luciano Mutti, Federica Gemignani and Stefano Landi

Cancers 2021, 13(10), 2445; https://doi.org/10.3390/cancers13102445 - 18 May 2021

Cited by 5 | Viewed by 2054

Abstract

Background: Malignant pleural mesothelioma (MPM) is a fatal tumor with a poor prognosis. The recent developments of liquid biopsies could provide novel diagnostic and prognostic tools in oncology. However, there is limited information about the feasibility of this technique for MPMs. Here, we [...] Read more.

Background: Malignant pleural mesothelioma (MPM) is a fatal tumor with a poor prognosis. The recent developments of liquid biopsies could provide novel diagnostic and prognostic tools in oncology. However, there is limited information about the feasibility of this technique for MPMs. Here, we investigate whether cancer-specific DNA sequences can be detected in pleural fluids and plasma of MPM patients as free circulating tumor DNA (ctDNA). Methods: We performed whole-exome sequencing on 14 tumor biopsies from 14 patients, and we analyzed 20 patient-specific somatic mutations with digital droplet PCR (ddPCR) in pleural fluids and plasma, using them as cancer-specific tumor biomarkers. Results: Most of the selected mutations could be detected in pleural fluids (94%) and, noteworthy, in plasma (83%) with the use of ddPCR. Pleural fluids showed similar levels of somatically mutated ctDNA (median = 12.75%, average = 16.3%, standard deviation = 12.3) as those detected in solid biopsies (median = 21.95%; average = 22.21%; standard deviation = 9.57), and their paired difference was weakly statistically significant (p = 0.048). On the other hand, the paired difference between solid biopsies and ctDNA from plasma (median = 0.29%, average = 0.89%, standard deviation = 1.40) was highly statistically significant (p = 2.5 × 10⁻⁷), corresponding to the important drop of circulating somatically mutated DNA in the bloodstream. However, despite the tiny amount of ctDNA in plasma, varying from 5.57% down to 0.14%, the mutations were detectable at rates similar to those possible for other tumors. Conclusions: We found robust evidence that mutated DNA is spilled from MPMs, mostly into pleural fluids, proving the concept that liquid biopsies are feasible for MPM patients. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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14 pages, 3781 KiB

Open AccessArticle

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

by Dario P. Anobile, Paolo Bironzo, Francesca Picca, Marcello F. Lingua, Deborah Morena, Luisella Righi, Francesca Napoli, Mauro G. Papotti, Alessandra Pittaro, Federica Di Nicolantonio, Chiara Gigliotti, Federico Bussolino, Valentina Comunanza, Francesco Guerrera, Alberto Sandri, Francesco Leo, Roberta Libener, Pablo Aviles, Silvia Novello, Riccardo Taulli, Giorgio V. Scagliotti and Chiara Riganti Show full author list Hide full author list

Cancers 2021, 13(10), 2332; https://doi.org/10.3390/cancers13102332 - 12 May 2021

Cited by 4 | Viewed by 4239

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making [...] Read more.

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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16 pages, 961 KiB

Open AccessArticle

Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity

by Luka Brcic, Alexander Mathilakathu, Robert F. H. Walter, Michael Wessolly, Elena Mairinger, Hendrik Beckert, Daniel Kreidt, Julia Steinborn, Thomas Hager, Daniel C. Christoph, Jens Kollmeier, Thomas Mairinger, Jeremias Wohlschlaeger, Kurt Werner Schmid, Sabrina Borchert and Fabian D. Mairinger

Cancers 2021, 13(8), 1761; https://doi.org/10.3390/cancers13081761 - 07 Apr 2021

Cited by 5 | Viewed by 2598

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain [...] Read more.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain unsatisfying. Adequate patient stratification to improve response rates is still lacking. This retrospective study analyzed formalin fixed paraffin embedded specimens from a cohort of 22 MPM. Twelve of those samples showed sarcomatoid, ten epithelioid differentiation. Complete follow-up, including radiological assessment of response by modRECIST and time to death, was available with reported deaths of all patients. RNA of all samples was isolated and subjected to digital gene expression pattern analysis. Our study revealed a notable difference between epithelioid and sarcomatoid mesothelioma, showing differential gene expression for 304/698 expressed genes. Whereas antigen processing and presentation to resident cytotoxic T cells as well as phagocytosis is highly affected in sarcomatoid mesothelioma, cell–cell interaction via cytokines seems to be of greater importance in epithelioid cases. Our work reveals the specific role of the immune system within the different histologic subtypes of MPM, providing a more detailed background of their immunogenic potential. This is of great interest regarding therapeutic strategies including immunotherapy in mesothelioma. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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29 pages, 5102 KiB

Open AccessArticle

Malignant Pleural Mesothelioma Interactome with 364 Novel Protein-Protein Interactions

by Kalyani B. Karunakaran, Naveena Yanamala, Gregory Boyce, Michael J. Becich and Madhavi K. Ganapathiraju

Cancers 2021, 13(7), 1660; https://doi.org/10.3390/cancers13071660 - 01 Apr 2021

Cited by 7 | Viewed by 3802

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer affecting the outer lining of the lung, with a median survival of less than one year. We constructed an ‘MPM interactome’ with over 300 computationally predicted protein-protein interactions (PPIs) and over 2400 known PPIs of [...] Read more.

Malignant pleural mesothelioma (MPM) is an aggressive cancer affecting the outer lining of the lung, with a median survival of less than one year. We constructed an ‘MPM interactome’ with over 300 computationally predicted protein-protein interactions (PPIs) and over 2400 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from Biological General Repository for Interaction Datasets (BioGRID) and Human Protein Reference Database (HPRD). Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, and gene expression in microarray experiments, and classifies the pairwise features as interacting or non-interacting based on a random forest model. We validated five novel predicted PPIs experimentally. The interactome is significantly enriched with genes differentially ex-pressed in MPM tumors compared with normal pleura and with other thoracic tumors, genes whose high expression has been correlated with unfavorable prognosis in lung cancer, genes differentially expressed on crocidolite exposure, and exosome-derived proteins identified from malignant mesothelioma cell lines. 28 of the interactors of MPM proteins are targets of 147 U.S. Food and Drug Administration (FDA)-approved drugs. By comparing disease-associated versus drug-induced differential expression profiles, we identified five potentially repurposable drugs, namely cabazitaxel, primaquine, pyrimethamine, trimethoprim and gliclazide. Preclinical studies may be con-ducted in vitro to validate these computational results. Interactome analysis of disease-associated genes is a powerful approach with high translational impact. It shows how MPM-associated genes identified by various high throughput studies are functionally linked, leading to clinically translatable results such as repurposed drugs. The PPIs are made available on a webserver with interactive user interface, visualization and advanced search capabilities. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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15 pages, 1646 KiB

Open AccessArticle

Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma

by Martina Schiavello, Elena Gazzano, Loredana Bergandi, Francesca Silvagno, Roberta Libener, Chiara Riganti and Elisabetta Aldieri

Cancers 2021, 13(5), 1138; https://doi.org/10.3390/cancers13051138 - 07 Mar 2021

Cited by 5 | Viewed by 2075

Abstract

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces [...] Read more.

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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15 pages, 2985 KiB

Open AccessArticle

Response to Immune Checkpoint Inhibitor Therapy in Patients with Unresectable Recurrent Malignant Pleural Mesothelioma Shown by FDG-PET and CT

by Kazuhiro Kitajima, Mitsunari Maruyama, Hiroyuki Yokoyama, Toshiyuki Minami, Takashi Yokoi, Akifumi Nakamura, Masaki Hashimoto, Nobuyuki Kondo, Kozo Kuribayashi, Takashi Kijima, Seiki Hasegawa and Koichiro Yamakado

Cancers 2021, 13(5), 1098; https://doi.org/10.3390/cancers13051098 - 04 Mar 2021

Cited by 7 | Viewed by 2053

Abstract

Background: To compare three FDG-PET criteria (EORTC, PERCIST, imPERCIST) with CT criteria (combined modified RECIST and RECIST 1.1) for response evaluation and prognosis prediction in patients with recurrent MPM treated with ICI monotherapy. Methods: Thirty MPM patients underwent FDG-PET/CT and contrast-enhanced CT at [...] Read more.

Background: To compare three FDG-PET criteria (EORTC, PERCIST, imPERCIST) with CT criteria (combined modified RECIST and RECIST 1.1) for response evaluation and prognosis prediction in patients with recurrent MPM treated with ICI monotherapy. Methods: Thirty MPM patients underwent FDG-PET/CT and contrast-enhanced CT at the baseline and during nivolumab therapy (median 10 cycles). Therapeutic response was evaluated according to EORTC, PERCIST, imPERCIST, and CT criteria. PFS and OS were examined using log-rank and Cox methods. Results: CMR/PMR/SMD/PMD numbered 5/3/4/18 for EORTC, 5/1/7/17 for PERCIST, and 5/3/9/13 for imPERCIST. With CT, CR/PR/SD/PD numbered 0/6/10/14. There was high concordance between EORTC and PERCIST (κ = 0.911), and PERCIST and imPERCIST (κ = 0.826), while that between EORTC and imPERCIST (κ = 0.746) was substantial, and between CT and the three PET criteria moderate (κ = 0.516–0.544). After median 14.9 months, 26 patients showed progression and nine died. According to both PET and CT findings, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and somewhat longer OS than PMD and PD patients (EORTC p = 0.0004 and p = 0.055, respectively; PERCIST p = 0.0003 and p = 0.052; imPERCIST p < 0.0001 and p = 0.089; CT criteria p = 0.0015 and p = 0.056). Conclusions: Both FDG-PET and CT criteria are accurate for response evaluation of ICI therapy and prediction of MPM prognosis. In comparison with CT, all three FDG-PET/CT criteria judged a greater percentage of patients (16.7%) as CMR, while two (EORTC, PERCIST) judged a greater percentage (10–13.3%) as PMD. For predicting PFS, the three FDG-PET criteria were superior to the CT criteria, and imPERCIST demonstrated the highest rate of accurate prediction. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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9 pages, 501 KiB

Open AccessArticle

VATS Pleurectomy Decortication Is a Reasonable Alternative for Higher Risk Patients in the Management of Malignant Pleural Mesothelioma: An Analysis of Short-Term Outcomes

by Dong-Seok Lee, Andrea Carollo, Naomi Alpert, Emanuela Taioli and Raja Flores

Cancers 2021, 13(5), 1068; https://doi.org/10.3390/cancers13051068 - 03 Mar 2021

Cited by 4 | Viewed by 3355

Abstract

Surgery is a mainstay of treatment allowing for debulking of tumor and expansion of the lung for improvement in median survival and quality of life for patients with malignant pleural mesothelioma (MPM). Although optimal surgical technique remains open for debate—extrapleural pneumonectomy (EPP) vs. [...] Read more.

Surgery is a mainstay of treatment allowing for debulking of tumor and expansion of the lung for improvement in median survival and quality of life for patients with malignant pleural mesothelioma (MPM). Although optimal surgical technique remains open for debate—extrapleural pneumonectomy (EPP) vs. pleurectomy/decortication (P/D)—minimally invasive surgery (VATS-P/D) remains underutilized in the management of MPM. We examined whether VATS-P/D is a feasible alternative to EPP and P/D. We evaluated the New York Statewide Planning and Research Cooperative System (SPARCS) from 2007–2017 to assess the short-term complications of EPP vs. P/D, including a subanalysis of open P/D vs. VATS-P/D. There were 331 patients with open surgery; 269 with P/D and 62 with EPP. There were 384 patients with P/D; 269 were open and 115 VATS. Rates of any complication were similar between EPP and P/D patients, but EPP had significantly higher rates of cardiovascular complications. After adjusting for confounders, those with a VATS approach were less likely to have any complication, compared to an open approach and significantly less likely to have a pulmonary complication. VATS-P/D remains a viable alternative to radical surgery in MPM patients allowing for improved short-term outcomes. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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16 pages, 2146 KiB

Open AccessArticle

Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients

by Emanuela Di Gregorio, Gianmaria Miolo, Asia Saorin, Elena Muraro, Michela Cangemi, Alberto Revelant, Emilio Minatel, Marco Trovò, Agostino Steffan and Giuseppe Corona

Cancers 2021, 13(3), 508; https://doi.org/10.3390/cancers13030508 - 29 Jan 2021

Cited by 4 | Viewed by 2592

Abstract

Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual [...] Read more.

Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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14 pages, 938 KiB

Open AccessArticle

DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma

by Giovanni Cugliari, Chiara Catalano, Simonetta Guarrera, Alessandra Allione, Elisabetta Casalone, Alessia Russo, Federica Grosso, Daniela Ferrante, Clara Viberti, Anna Aspesi, Marika Sculco, Chiara Pirazzini, Roberta Libener, Dario Mirabelli, Corrado Magnani, Irma Dianzani and Giuseppe Matullo

Cancers 2020, 12(11), 3470; https://doi.org/10.3390/cancers12113470 - 21 Nov 2020

Cited by 8 | Viewed by 2316

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. [...] Read more.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10⁻⁹) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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19 pages, 3864 KiB

Open AccessArticle

Cross-Species Proteomics Identifies CAPG and SBP1 as Crucial Invasiveness Biomarkers in Rat and Human Malignant Mesothelioma

by Joëlle S. Nader, Alice Boissard, Cécile Henry, Isabelle Valo, Véronique Verrièle, Marc Grégoire, Olivier Coqueret, Catherine Guette and Daniel L. Pouliquen

Cancers 2020, 12(9), 2430; https://doi.org/10.3390/cancers12092430 - 27 Aug 2020

Cited by 10 | Viewed by 2367

Abstract

Malignant mesothelioma (MM) still represents a devastating disease that is often detected too late, while the current effect of therapies on patient outcomes remains unsatisfactory. Invasiveness biomarkers may contribute to improving early diagnosis, prognosis, and treatment for patients, a task that could benefit [...] Read more.

Malignant mesothelioma (MM) still represents a devastating disease that is often detected too late, while the current effect of therapies on patient outcomes remains unsatisfactory. Invasiveness biomarkers may contribute to improving early diagnosis, prognosis, and treatment for patients, a task that could benefit from the development of high-throughput proteomics. To limit potential sources of bias when identifying such biomarkers, we conducted cross-species proteomic analyzes on three different MM sources. Data were collected firstly from two human MM cell lines, secondly from rat MM tumors of increasing invasiveness grown in immunocompetent rats and human MM tumors grown in immunodeficient mice, and thirdly from paraffin-embedded sections of patient MM tumors of the epithelioid and sarcomatoid subtypes. Our investigations identified three major invasiveness biomarkers common to the three tumor sources, CAPG, FABP4, and LAMB2, and an additional set of 25 candidate biomarkers shared by rat and patient tumors. Comparing the data to proteomic analyzes of preneoplastic and neoplastic rat mesothelial cell lines revealed the additional role of SBP1 in the carcinogenic process. These observations could provide new opportunities to identify highly vulnerable MM patients with poor survival outcomes, thereby improving the success of current and future therapeutic strategies. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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20 pages, 5501 KiB

Open AccessArticle

Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma

by Haitang Yang, Duo Xu, Zhang Yang, Feng Yao, Heng Zhao, Ralph A. Schmid and Ren-Wang Peng

Cancers 2020, 12(8), 2310; https://doi.org/10.3390/cancers12082310 - 17 Aug 2020

Cited by 17 | Viewed by 3508

Abstract

Background: Malignant pleural mesothelioma (MPM) is driven by the inactivation of tumor suppressor genes (TSGs). An unmet need in the field is the translation of the genomic landscape into effective TSG-specific therapies. Methods: We correlated genomes against transcriptomes of patients’ MPM [...] Read more.

Background: Malignant pleural mesothelioma (MPM) is driven by the inactivation of tumor suppressor genes (TSGs). An unmet need in the field is the translation of the genomic landscape into effective TSG-specific therapies. Methods: We correlated genomes against transcriptomes of patients’ MPM tumors, by weighted gene co-expression network analysis (WGCNA). The identified aberrant biochemical networks and potential drug targets induced by tumor suppressor loss were validated by integrative data analysis and functional interrogation. Results: CDKN2A/2B loss activates G2/M checkpoint and PI3K/AKT, prioritizing a co-targeting strategy for CDKN2A/2B-null MPM. CDKN2A deficiency significantly co-occurs with deletions of anti-viral type I interferon (IFN-I) genes and BAP1 mutations, that enriches the IFN-I signature, stratifying a unique subset, with deficient IFN-I, but proficient BAP1 for oncolytic viral immunotherapies. Aberrant p53 attenuates differentiation and SETD2 loss acquires the dependency on EGFRs, highlighting the potential of differentiation therapy and pan-EGFR inhibitors for these subpopulations, respectively. LATS2 deficiency is linked with dysregulated immunoregulation, suggesting a rationale for immune checkpoint blockade. Finally, multiple lines of evidence support Dasatinib as a promising therapeutic for LATS2-mutant MPM. Conclusions: Systematic identification of abnormal cellular processes and potential drug vulnerabilities specified by TSG alterations provide a framework for precision oncology in MPM. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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12 pages, 2222 KiB

Open AccessArticle

Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma

by Raunak Shrestha, Noushin Nabavi, Stanislav Volik, Shawn Anderson, Anne Haegert, Brian McConeghy, Funda Sar, Sonal Brahmbhatt, Robert Bell, Stephane Le Bihan, Yuzhuo Wang, Colin Collins and Andrew Churg

Cancers 2020, 12(6), 1568; https://doi.org/10.3390/cancers12061568 - 13 Jun 2020

Cited by 18 | Viewed by 5728

Abstract

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it [...] Read more.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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Review

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13 pages, 596 KiB

Open AccessReview

Ancillary Diagnostic Investigations in Malignant Pleural Mesothelioma

by Alex Dipper, Nick Maskell and Anna Bibby

Cancers 2021, 13(13), 3291; https://doi.org/10.3390/cancers13133291 - 30 Jun 2021

Cited by 5 | Viewed by 2433

Abstract

For a number of patients presenting with an undiagnosed pleural effusion, frailty, medical co-morbidity or personal choice may preclude the use of pleural biopsy, the gold standard investigation for diagnosis of malignant pleural mesothelioma (MPM). In this review article, we outline the most [...] Read more.

For a number of patients presenting with an undiagnosed pleural effusion, frailty, medical co-morbidity or personal choice may preclude the use of pleural biopsy, the gold standard investigation for diagnosis of malignant pleural mesothelioma (MPM). In this review article, we outline the most recent evidence on ancillary diagnostic tests which may be used to support a diagnosis of MPM where histological samples cannot be obtained or where results are non-diagnostic. Immunocytochemical markers, molecular techniques, diagnostic biomarkers and imaging techniques are discussed. No adjunctive test has a sensitivity and specificity profile to support use in isolation; however, correlation of pleural fluid cytology with relevant radiology and supplementary biomarkers can enable an MDT-consensus clinico-radiological-cytological diagnosis to be made where further invasive tests are not possible or not appropriate. Diagnostic challenges surrounding non-epithelioid MPM are recognised, and there is a critical need for reliable and non-invasive investigative tools in this population. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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17 pages, 1528 KiB

Open AccessReview

Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma

by Francesca Napoli, Angela Listì, Vanessa Zambelli, Gianluca Witel, Paolo Bironzo, Mauro Papotti, Marco Volante, Giorgio Scagliotti and Luisella Righi

Cancers 2021, 13(11), 2564; https://doi.org/10.3390/cancers13112564 - 24 May 2021

Cited by 16 | Viewed by 2936

Abstract

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease that arises from pleural mesothelial cells, characterized by a median survival of approximately 13–15 months after diagnosis. The primary cause of this disease is asbestos exposure and the main issues associated with [...] Read more.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease that arises from pleural mesothelial cells, characterized by a median survival of approximately 13–15 months after diagnosis. The primary cause of this disease is asbestos exposure and the main issues associated with it are late diagnosis and lack of effective therapies. Asbestos-induced cellular damage is associated with the generation of an inflammatory microenvironment that influences and supports tumor growth, possibly in association with patients’ genetic predisposition and tumor genomic profile. The chronic inflammatory response to asbestos fibers leads to a unique tumor immune microenvironment (TIME) composed of a heterogeneous mixture of stromal, endothelial, and immune cells, and relative composition and interaction among them is suggested to bear prognostic and therapeutic implications. TIME in MPM is known to be constituted by immunosuppressive cells, such as type 2 tumor-associated macrophages and T regulatory lymphocytes, plus the expression of several immunosuppressive factors, such as tumor-associated PD-L1. Several studies in recent years have contributed to achieve a greater understanding of the pathogenetic mechanisms in tumor development and pathobiology of TIME, that opens the way to new therapeutic strategies. The study of TIME is fundamental in identifying appropriate prognostic and predictive tissue biomarkers. In the present review, we summarize the current knowledge about the pathological characterization of TIME in MPM. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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17 pages, 7286 KiB

Open AccessReview

Assessment of the Carcinogenicity of Carbon Nanotubes in the Respiratory System

by Marcella Barbarino and Antonio Giordano

Cancers 2021, 13(6), 1318; https://doi.org/10.3390/cancers13061318 - 15 Mar 2021

Cited by 28 | Viewed by 4025

Abstract

In 2014, the International Agency for Research on Cancer (IARC) classified the first type of carbon nanotubes (CNTs) as possibly carcinogenic to humans, while in the case of other CNTs, it was not possible to ascertain their toxicity due to lack of evidence. [...] Read more.

In 2014, the International Agency for Research on Cancer (IARC) classified the first type of carbon nanotubes (CNTs) as possibly carcinogenic to humans, while in the case of other CNTs, it was not possible to ascertain their toxicity due to lack of evidence. Moreover, the physicochemical heterogeneity of this group of substances hamper any generalization on their toxicity. Here, we review the recent relevant toxicity studies produced after the IARC meeting in 2014 on an homogeneous group of CNTs, highlighting the molecular alterations that are relevant for the onset of mesothelioma. Methods: The literature was searched on PubMed and Web of Science for the period 2015–2020, using different combinations keywords. Only data on normal cells of the respiratory system after exposure to fully characterized CNTs for their physico-chemical characteristics were included. Recent studies indicate that CNTs induce a sustained inflammatory response, oxidative stress, fibrosis and histological alterations. The development of mesothelial hyperplasia, mesothelioma, and lungs tumors have been also described in vivo. The data support a strong inflammatory potential of CNTs, similar to that of asbestos, and provide evidence that CNTs exposure led to molecular alterations known to have a key role in mesothelioma onset. These evidences call for an urgent improvement of studies on exposed human populations and adequate systems for monitoring the health of workers exposed to this putative carcinogen. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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24 pages, 937 KiB

Open AccessReview

Biomarkers for Malignant Pleural Mesothelioma—A Novel View on Inflammation

by Melanie Vogl, Anna Rosenmayr, Tomas Bohanes, Axel Scheed, Milos Brndiar, Elisabeth Stubenberger and Bahil Ghanim

Cancers 2021, 13(4), 658; https://doi.org/10.3390/cancers13040658 - 06 Feb 2021

Cited by 19 | Viewed by 3532

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive disease with limited treatment response and devastating prognosis. Exposure to asbestos and chronic inflammation are acknowledged as main risk factors. Since immune therapy evolved as a promising novel treatment modality, we want to reevaluate and summarize [...] Read more.

Malignant pleural mesothelioma (MPM) is an aggressive disease with limited treatment response and devastating prognosis. Exposure to asbestos and chronic inflammation are acknowledged as main risk factors. Since immune therapy evolved as a promising novel treatment modality, we want to reevaluate and summarize the role of the inflammatory system in MPM. This review focuses on local tumor associated inflammation on the one hand and systemic inflammatory markers, and their impact on MPM outcome, on the other hand. Identification of new biomarkers helps to select optimal patient tailored therapy, avoid ineffective treatment with its related side effects and consequently improves patient’s outcome in this rare disease. Additionally, a better understanding of the tumor promoting and tumor suppressing inflammatory processes, influencing MPM pathogenesis and progression, might also reveal possible new targets for MPM treatment. After reviewing the currently available literature and according to our own research, it is concluded that the suppression of the specific immune system and the activation of its innate counterpart are crucial drivers of MPM aggressiveness translating to poor patient outcome. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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Other

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9 pages, 360 KiB

Open AccessCommentary

Precision Therapy for Mesothelioma: Feasibility and New Opportunities

by Sean Dulloo, Aleksandra Bzura and Dean Anthony Fennell

Cancers 2021, 13(10), 2347; https://doi.org/10.3390/cancers13102347 - 13 May 2021

Cited by 3 | Viewed by 2509

Abstract

Malignant pleural mesotheliomas (MPMs) are characterised by their wide variation in natural history, ranging from minimally to highly aggressive, associated with both interpatient and intra-tumour genomic heterogeneity. Recent insights into the nature of this genetic variation, the identification of drivers, and the emergence [...] Read more.

Malignant pleural mesotheliomas (MPMs) are characterised by their wide variation in natural history, ranging from minimally to highly aggressive, associated with both interpatient and intra-tumour genomic heterogeneity. Recent insights into the nature of this genetic variation, the identification of drivers, and the emergence of novel strategies capable of targeting vulnerabilities that result from the inactivation of key tumour suppressors suggest that new approaches to molecularly strategy therapy for mesothelioma may be feasible. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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16 pages, 1671 KiB

Open AccessSystematic Review

Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy

by Rupesh Kotecha, Raees Tonse, Muni Rubens, Haley Appel, Federico Albrecht, Paul Kaywin, Evan W. Alley, Martin C. Tom and Minesh P. Mehta

Cancers 2021, 13(9), 2186; https://doi.org/10.3390/cancers13092186 - 02 May 2021

Cited by 8 | Viewed by 2826

Abstract

(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as [...] Read more.

(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables. Full article

(This article belongs to the Special Issue Malignant Mesothelioma)

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