scholarly journals Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1186 ◽  
Author(s):  
David Michael Abbott ◽  
Chandra Bortolotto ◽  
Silvia Benvenuti ◽  
Andrea Lancia ◽  
Andrea Riccardo Filippi ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Current Knowledge ◽  
Asbestos Exposure ◽  
Progressive Increase ◽  
Pleural Mesothelioma ◽  
Therapeutic Approaches ◽  
Reading Frame ◽  
Inflammatory Microenvironment ◽  
One Year ◽  
Global Population

Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches.

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

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2564
Author(s):  
Francesca Napoli ◽  
Angela Listì ◽  
Vanessa Zambelli ◽  
Gianluca Witel ◽  
Paolo Bironzo ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Current Knowledge ◽  
Asbestos Exposure ◽  
Cellular Damage ◽  
Pleural Mesothelioma ◽  
Immune Microenvironment ◽  
Chronic Inflammatory Response ◽  
Inflammatory Microenvironment ◽  
Tumor Immune Microenvironment

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.

scholarly journals Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach

2021 ◽  
Vol 22 (16) ◽  
pp. 9014
Author(s):  
Daniela Lisini ◽  
Sara Lettieri ◽  
Sara Nava ◽  
Giulia Accordino ◽  
Simona Frigerio ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
Local Drug Delivery ◽  
Pleural Mesothelioma ◽  
Therapeutic Approaches ◽  
Cell Therapies ◽  
Complex Interactions ◽  
Biologic Effects ◽  
Drug Doses ◽  
Lower Drug

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.

scholarly journals Redefining mesothelioma types as a continuum uncovers the immune and vascular systems as key players in the diagnosis and prognosis of this disease

2018 ◽  
Author(s):  
Nicolas Alcala ◽  
Christophe Caux ◽  
Nicolas Girard ◽  
J.D. McKay ◽  
Francoise Galateau-Salle ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Checkpoint Inhibitors ◽  
Asbestos Exposure ◽  
Continuous Model ◽  
Therapeutic Options ◽  
Molecular Profile ◽  
Pleural Mesothelioma ◽  
Therapeutic Approaches ◽  
Aggressive Disease ◽  
Key Players

SummaryMalignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, which incidence is expected to increase in the future, and with no effective therapeutic options. We have performed unsupervised analyses of publicly available RNAseq data for 297 MPM. We found that the molecular profile and the prognosis of this disease is better explained by a continuous model rather than by the current WHO classification into the epitheloid, biphasic and sarcomatoid histological types. The main source of variation of this continuum was explained by the immune and vascular pathways, with strong differences in the expression of pro-angiogenic genes and immune checkpoint inhibitors across samples. These data may inform future classifications of MPM and may also guide personalised therapeutic approaches for this disease.SignificanceMalignant Pleural Mesothelioma (MPM) is an aggressive disease with no effective therapeutic options. Unsupervised transcriptomic analyses of 297 MPM unveiled the vascular and the immune systems as key players in the prognosis of this disease, and identified potential therapeutic approaches for this disease targeting these pathways.

scholarly journals A review of malignant pleural mesothelioma in a large North East UK pleural centre

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Declan C. Murphy ◽  
Alexander Mount ◽  
Fiona Starkie ◽  
Leah Taylor ◽  
Avinash Aujayeb
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Survival Rates ◽  
Case Series ◽  
Pleural Mesothelioma ◽  
Retrospective Case ◽  
Pleural Thickening ◽  
North East ◽  
Total Cohort ◽  
Anti Cancer ◽  
One Year

AbstractObjectivesThe National Mesothelioma Audit 2020 showed Northumbria to have low rates of histopathological confirmation, treatment and one-year survival rates for malignant pleural mesothelioma (MPM). We hypothesized that an internal analysis over a 10-year period provides valuable insights into presentation, diagnosis, treatment and outcomes.MethodsA single-centre retrospective case series of all confirmed MPM patients between 1 January 2009 and 31 December 2019 was performed. Demographics, clinical, radiological and histopathological characteristics and outcomes were collected. Statistical analysis was performed using SPSS V26.0.ResultsA total of 247 patients had MPM. About 86% were male, mean age 75.7 years. Dyspnoea (77.4%) and chest pain (38.5%) were commonest symptoms. 64.9 and 71.4% had pleural thickening and effusion, respectively. About 86.8% had at least one attempt to obtain a tissue biopsy, but histopathological confirmation in only 108 (43.7%). About 66.3% with PS 0 and 1 (62.7% of total cohort) had at least one anti-cancer therapy. Death within 12 months was associated with disease progression within 6 months (p≤0.001). Chemotherapy (p≤0.001) and epithelioid histological subtype (p=0.01) were protective.ConclusionsThis study confirms known epidemiology of MPM, demonstrates variability in practices and highlights how some NMA recommendations are not met. This provides the incentive for a regional mesothelioma multi-disciplinary meeting.

scholarly journals SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020)

2021 ◽  
Vol 23 (5) ◽  
pp. 980-987 ◽  
Author(s):  
E. Nadal ◽  
J. Bosch-Barrera ◽  
S. Cedrés ◽  
J. Coves ◽  
R. García-Campelo ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Early Stage ◽  
Asbestos Exposure ◽  
Standard Of Care ◽  
Tumor Board ◽  
Pleural Mesothelioma ◽  
Therapeutic Approaches ◽  
Dismal Prognosis ◽  
Line Chemotherapy ◽  
Multidisciplinary Tumor Board

AbstractMesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future.

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

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1138
Author(s):  
Martina Schiavello ◽  
Elena Gazzano ◽  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Roberta Libener ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Malignant Pleural Mesothelioma ◽  
Antioxidant Defense ◽  
Asbestos Exposure ◽  
Predictive Biomarkers ◽  
Antioxidant Systems ◽  
Pleural Mesothelioma ◽  
Related Factor ◽  
Aggressive Cancer

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.

scholarly journals Increased Standardised Incidence Ratio of Malignant Pleural Mesothelioma in Taiwanese Asbestos Workers: A 29-Year Retrospective Cohort Study

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Cheng-Kuan Lin ◽  
Yu-Ying Chang ◽  
Jung-Der Wang ◽  
Lukas Jyuhn-Hsiarn Lee
Keyword(s):  
Cohort Study ◽  
General Population ◽  
Incidence Rate ◽  
Malignant Pleural Mesothelioma ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Asbestos Exposure ◽  
Pleural Mesothelioma ◽  
Calendar Period ◽  
Incident Cases

Objective. This paper aimed to determine the standardised incidence ratio (SIR) of malignant pleural mesothelioma (MPM) in workers exposed to asbestos in Taiwan.Methods. All workers employed in asbestos-related factories and registered by the Bureau of Labour Insurance between 1 March, 1950, and 31 December, 1989, were included in the study and were followed from 1 January, 1980, through 31 December, 2009. Incident cases of all cancers, including MPM (ICD-9 code: 163), were obtained from the Taiwan Cancer Registry. SIRs were calculated based on comparison with the incidence rate of the general population of Taiwan and adjusted for age, calendar period, sex, and duration of employment.Results. The highest SIR of MPM was found for male workers first employed before 1979, with a time since first employment more than 30 years (SIR 4.52, 95% CI: 2.25–8.09). After consideration of duration of employment, the SIR for male MPM was 5.78 (95% CI: 1.19–16.89) for the workers employed for more than 20 years in asbestos-related factories.Conclusions. This study corroborates the association between occupational asbestos exposure and MPM. The highest risk of MPM was found among male asbestos workers employed before 1979 and working for more than 20 years in asbestos-related factories.

Case 13.8

2014 ◽  
pp. 628-629
Author(s):  
Christine U. Lee ◽  
James F. Glockner
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
The United States ◽  
Extrapleural Pneumonectomy ◽  
Parietal Pleura ◽  
Pleural Mesothelioma ◽  
Pleural Plaques ◽  
Abnormal Chest ◽  
Left Pleura ◽  
Histologic Subtypes

62-year-old man with shortness of breath and an abnormal chest CT Axial 3D SPGR postgadolinium images (Figure 13.8.1) demonstrate diffuse thickening and enhancement of the left pleura, with a few minimally enhancing, focal right-sided pleural plaques. Malignant pleural mesothelioma Malignant pleural mesothelioma is a rare neoplasm that originates from the mesothelial cells lining the visceral and parietal pleura. The incidence of malignant pleural mesothelioma in the United States is 15 cases per million; there is a strong correlation with asbestos exposure. Malignant pleural mesothelioma is divided into 3 histologic subtypes: epithelial (55%-65%), sarcomatoid (10%-15%), and mixed (20%-35%). Patients with epithelial malignant pleural mesothelioma have the best prognosis, and among those with limited disease who undergo extrapleural pneumonectomy (removal of the pleura, lung, hemidiaphragm, and part of the pericardium), survival is longer (5-year survival, 39%) than among all patients (median survival, 8-18 months after diagnosis)....

scholarly journals Multimodality treatment of malignant pleural mesothelioma

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1681 ◽  
Author(s):  
Lawek Berzenji ◽  
Paul Van Schil
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
Multimodality Treatment ◽  
Treatment Modalities ◽  
Surgical Approaches ◽  
Extrapleural Pneumonectomy ◽  
Pleural Mesothelioma ◽  
Treatment Approaches ◽  
Definitive Answer ◽  
Platinum Based Chemotherapy

Malignant pleural mesothelioma (MPM) is a rare disease of the pleura and is largely related to asbestos exposure. Despite recent advancements in technologies and a greater understanding of the disease, the prognosis of MPM remains poor; the median overall survival rate is about 6 to 9 months in untreated patients. The main therapeutic strategies for MPM are surgery, chemotherapy, and radiation therapy (RT). The two main surgical approaches for MPM are extrapleural pneumonectomy (EPP), in which the lung is removed en bloc, and pleurectomy/decortication, in which the lung stays in situ. Chemotherapy usually consists of a platinum-based chemotherapy, such as cisplatin, often combined with a folate antimetabolite, such as pemetrexed. More recently, immunotherapy has emerged as a possible therapeutic strategy for MPM. Evidence suggests that single-modality treatments are not an effective therapeutic approach for MPM. Therefore, researchers have started to explore different multimodality treatment approaches, in which often combinations of surgery, chemotherapy, immunotherapy, and RT are investigated. There is still no definitive answer to the question of which multimodality treatment combinations are most effective in improving the poor prognosis of MPM. Research into the effects of trimodality treatment approaches have found that radical approaches such as EPP and hemithoracic RT post-EPP are less effective than was previously assumed. In general, there are still a great number of unanswered questions and unknown factors regarding the ideal treatment approach for MPM. Hopefully, more research into multimodality therapy will provide insight into which combination of treatment modalities is most effective.

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