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16 Sep 2021 at 01:54
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Bibliography on: Mesothelioma and Asbestos


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RJR: Recommended Bibliography 16 Sep 2021 at 01:54 Created: 

Mesothelioma and Asbestos

Mesothelioma is a rare, but deadly form of cancer that is often (nearly always) associated with prior exposure to asbestos. The latency between exposure and disease onset is long, usually 20-50 years, making this a difficult cause-effect system to study.

Created with PubMed® Query: asbestos AND mesothelioma NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2021-09-14

Torkki P, Paajanen J, Kytö V, et al (2021)

Evidence for marked underutilization of insurance billing in malignant pleural mesothelioma in Finland.

Thoracic cancer [Epub ahead of print].

BACKGROUND: Substantial variation in health care costs for malignant pleural mesothelioma (MPM) has previously been identified.

MATERIALS AND METHODS: We analyzed the changes in health care costs in MPM in Finland during 2002-2012. Finland has low-threshold public health care and a mandatory Workers' Compensation scheme that covers all occupational-related disease expenses. The costs include treatment costs for inpatients, hospice care, medication costs, rehabilitation costs, and travel costs. All costs are expressed in 2012 prices, adjusted using the consumer price index.

RESULTS: A total of 907 MPM patients were included in the study. Mean duration of inpatient episodes increased 7% per year from 2002 to 2012, correlating with total costs (R2 = 0.861, p < 0.05). The annual total costs for treatment increased from 1.7 to 4.3 m€ during the study period and the cost per patient from 27 000 to 43 000 €. The overall costs increased progressively by the number of procedures performed. In patients who had been compensated for occupational cause by Workers' Compensation Center, only 36% of the overall care costs were billed from the insurance company. Billing of inpatient costs was 86% in these patients.

CONCLUSION: During the study period, we found that the costs of MPM increased more than the average health care costs. This may be because of advanced diagnostic workup or more costly treatment (e.g., pemetrexed). Moreover, only one-third of all health care costs are charged to Workers' Compensation Insurance.

RevDate: 2021-09-13

Xie D, Hu J, Wu T, et al (2021)

Four Immune-Related Genes (FN1, UGCG, CHPF2 and THBS2) as Potential Diagnostic and Prognostic Biomarkers for Carbon Nanotube-Induced Mesothelioma.

International journal of general medicine, 14:4987-5003 pii:324365.

Background: Malignant pleural mesothelioma (MPM), a highly aggressive cancer, was mainly attributed to asbestos exposure. Carbon nanotubes (CNTs) share similar negative features to asbestos, provoking concerns about their contribution to MPM. This study was used to identify genes associated with CNT-induced MPM.

Methods: Microarray datasets were available in the Gene Expression Omnibus database. The limma method was used to identify differentially expressed genes (DEGs) in CNT-exposed MeT5A cells (GSE48855) or mice (GSE51636). Weighted correlation network analysis (WGCNA) and protein-protein interaction (PPI) network construction were conducted to screen hub DEGs. The mRNA expression levels of hub DEGs were validated on MPM samples of GSE51024, GSE2549 and GSE42977 datasets, and their diagnostic efficacy was determined by receiver operating characteristic curve analysis. The prognostic values of hub DEGs were assessed using online tools based on The Cancer Genome Atlas data. Their functions were annotated by Database for Annotation, Visualization and Integrated Discovery (DAVID) enrichment and correlation with immune cells and markers.

Results: WGCNA identified that two modules were associated with disease status. Thirty-one common DEGs in the GSE48855 and GSE51636 datasets were overlapped with the genes in these two modules. Twenty of them had a high degree centrality (≥4) in the PPI network. Four DEGs (FN1, fibronectin 1; UGCG, UDP-glucose ceramide glucosyltransferase; CHPF2, chondroitin polymerizing factor 2; and THBS2, thrombospondin 2) could predict the overall survival, and they were confirmed to be upregulated in MPM samples compared with controls. Also, they could effectively predict the MPM risk, with an overall accuracy of >0.9. DAVID analysis revealed FN1, CHPF2 and THBS2 functioned in cell-ECM interactions; UGCG influenced glycosphingolipid metabolism. All genes were positively associated with infiltrating levels of immune cells (macrophages or dendritic cells) and the expression of the dendritic cell marker (NRP1, neuropilin 1).

Conclusion: These four immune-related genes represent potential biomarkers for monitoring CNT-induced MPM and predicting the prognosis.

RevDate: 2021-09-07

Nowak AK, Jackson A, C Sidhu (2021)

Management of Advanced Pleural Mesothelioma-At the Crossroads.

JCO oncology practice [Epub ahead of print].

The management of pleural mesothelioma has changed with the demonstration that first-line checkpoint blockade therapy improves survival. This review covers issues of relevance to the practicing medical oncologist, with an emphasis on the palliative setting and on new information. Until recently, standard systemic therapy for mesothelioma was combination chemotherapy with platinum and pemetrexed. In 2020, combination immunotherapy with ipilimumab and nivolumab was approved as first-line systemic therapy for mesothelioma following release of the results from the CheckMate 743 trial. This trial showed improved overall survival for patients receiving ipilimumab and nivolumab over those treated with platinum and pemetrexed chemotherapy. When the survival results were examined by histologic subtype, the survival benefit was most significant in those with nonepithelioid mesothelioma, a group for which combination immunotherapy is now standard of care. The most important outstanding issue from CheckMate-743 is a better understanding, through translational studies, of which patients with epithelioid mesothelioma may benefit from combination immunotherapy. The next generation of first-line clinical trials in mesothelioma will report the results of first-line combination chemoimmunotherapy. For those patients who receive first-line dual checkpoint blockade, there is no evidence as to the efficacy of subsequent chemotherapy. However, given the known first-line efficacy of cisplatin or carboplatin and pemetrexed, combination chemotherapy is an appropriate subsequent choice for those who progress on or after dual immunotherapy. For those who previously received chemotherapy without immunotherapy, single-agent nivolumab provides benefit over best supportive care. In summary, both chemotherapy and immunotherapy should be considered for all patients during their disease course. Another topical issue is the growing appreciation that some individuals have an inherited predisposition to mesothelioma; referral to a clinical geneticist should be considered under some circumstances. The role of surgery and multimodality therapy is controversial, with results awaited from the fully recruited MARS-2 clinical trial. Patient selection, staging, and multidisciplinary review are critical to identify those who might benefit from a multimodality approach. Finally, a proactive, multidisciplinary approach to symptom management and the principles of management of pleural effusions are critical to manage the symptom burden of mesothelioma and optimize patient well-being.

RevDate: 2021-09-06

Dick IM, Lee YCG, Cheah HM, et al (2021)

Profile of soluble factors in pleural effusions predict prognosis in mesothelioma.

Cancer biomarkers : section A of Disease markers pii:CBM210280 [Epub ahead of print].

BACKGROUND: Pleural mesothelioma is a deadly asbestos induced cancer. Less than 10% of mesothelioma patients survive 5 years post diagnosis. However survival can range from a few months to a number of years. Accurate prediction of survival is important for patients to plan for their remaining life, and for clinicians to determine appropriate therapy. One unusual features of mesothelioma is that patients frequently present with tumor-associated pleural effusions early in the course of the disease.

OBJECTIVE: To study whether cells and molecules present in pleural effusions provide prognostic information for mesothelioma.

METHODS: We profiled the cellular constituents and concentrations of 40 cytokines, chemokines and cellular factors (collectively "soluble factors") involved in inflammatory and immune signalling pathways in pleural effusion samples from 50 mesothelioma patients.Associations with survival were evaluated by Cox proportional hazards regression methods. Results for the two soluble factors most significantly and independently associated with survival were validated in an independent set of samples (n= 51) using a separate assay system.

RESULTS: Survival analysis revealed thatIL8, IL2Ra (CD25) and PF4 were independent determinants of a more negative prognosis in mesothelioma patients, independent of other known prognostic factors. Lipocalin2 and IL4 were associated with better prognosis.

CONCLUSIONS: This study demonstrates that pleural effusions rich in a range of soluble factors are associated with poor prognosis. These findings will enhance our ability to prognosticate outcomes in mesothelioma patients.

RevDate: 2021-08-30
CmpDate: 2021-08-30

Laubenthal TG (2020)

Regulated Asbestos Analysis: EPA Polarized Light Microscopy Method and the Implications for Reported Fiber Sizes.

New solutions : a journal of environmental and occupational health policy : NS, 30(2):83-85.

RevDate: 2021-08-27

Lisini D, Lettieri S, Nava S, et al (2021)

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

International journal of molecular sciences, 22(16): pii:ijms22169014.

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.

RevDate: 2021-08-27

Lemen RA, PJ Landrigan (2021)

Sailors and the Risk of Asbestos-Related Cancer.

International journal of environmental research and public health, 18(16): pii:ijerph18168417.

Sailors have long been known to experience high rates of injury, disease, and premature death. Many studies have shown asbestos-related diseases among shipyard workers, but few have examined the epidemiology of asbestos-related disease and death among asbestos-exposed sailors serving on ships at sea. Chrysotile and amphibole asbestos were used extensively in ship construction for insulation, joiner bulkhead systems, pipe coverings, boilers, machinery parts, bulkhead panels, and many other uses, and asbestos-containing ships are still in service. Sailors are at high risk of exposure to shipboard asbestos, because unlike shipyard workers and other occupationally exposed groups, sailors both work and live at their worksite, making asbestos standards and permissible exposure limits (PELs). based on an 8-h workday inadequate to protect their health elevated risks of mesothelioma and other asbestos-related cancers have been observed among sailors through epidemiologic studies. We review these studies here.

RevDate: 2021-08-27

Brims F (2021)

Epidemiology and Clinical Aspects of Malignant Pleural Mesothelioma.

Cancers, 13(16): pii:cancers13164194.

Mesothelioma is a cancer predominantly of the pleural cavity. There is a clear association of exposure to asbestos with a dose dependent risk of mesothelioma. The incidence of mesothelioma in different countries reflect the historical patterns of commercial asbestos utilisation in the last century and predominant occupational exposures mean that mesothelioma is mostly seen in males. Modern imaging techniques and advances in immunohistochemical staining have contributed to an improved diagnosis of mesothelioma. There have also been recent advances in immune checkpoint inhibition, however, mesothelioma remains very challenging to manage, especially considering its limited response to conventional systemic anticancer therapy and that no cure exists. Palliative interventions and support remain paramount with a median survival of 9-12 months after diagnosis. The epidemiology and diagnosis of mesothelioma has been debated over previous decades, due to a number of factors, such as the long latent period following asbestos exposure and disease occurrence, the different potencies of the various forms of asbestos used commercially, the occurrence of mesothelioma in the peritoneal cavity and its heterogeneous pathological and cytological appearances. This review will describe the contemporary knowledge on the epidemiology of mesothelioma and provide an overview of the best clinical practice including diagnostic approaches and management.

RevDate: 2021-08-27

Carbotti G, Dozin B, Martini S, et al (2021)

IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells.

Cancers, 13(16): pii:cancers13164011.

Malignant mesothelioma (MM) is a rare tumor with an unfavorable prognosis. MM genesis involves asbestos-mediated local inflammation, supported by several cytokines, including IL-6. Recent data showed that targeting PD-1/PD-L1 is an effective therapy in MM. Here, we investigated the effects of IL-6 trans-signaling and the IL-6-related cytokine IL-27 on human MM cells in vitro by Western blot analysis of STAT1/3 phosphorylation. The effects on PD-L1 expression were tested by qRT-PCR and flow-cytometry and the release of soluble (s)PD-L1 by ELISA. We also measured the concentrations of sPD-L1 and, by multiplexed immunoassay, IL-6 and IL-27 in pleural fluids obtained from 77 patients in relation to survival. IL-27 predominantly mediates STAT1 phosphorylation and increases PD-L1 gene and surface protein expression and sPD-L1 release by human MM cells in vitro. IL-6 has limited activity, whereas a sIL-6R/IL-6 chimeric protein mediates trans-signaling predominantly via STAT3 phosphorylation but has no effect on PD-L1 expression and release. IL-6, IL-27, and sPD-L1 are present in pleural fluids and show a negative correlation with overall survival, but only IL-27 shows a moderate albeit significant correlation with sPD-L1 levels. Altogether these data suggest a potential role of IL-27 in PD-L1-driven immune resistance in MM.

RevDate: 2021-08-25

Mathilakathu A, Borchert S, Wessolly M, et al (2021)

Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study.

Translational lung cancer research, 10(7):3030-3042.

Background: Malignant pleural mesothelioma (MPM) is a rare malignant tumor associated with asbestos exposure, with infaust prognosis and overall survival below 20 months in treated patients. Platinum is still the backbone of the chemotherapy protocols, and the reasons for the rather poor efficacy of platinum compounds in MPM remain largely unknown. Therefore, we aimed to analyze differences in key signaling pathways and biological mechanisms in therapy-naïve samples and samples after chemotherapy in order to evaluate the effect of platinum-based chemotherapy.

Methods: The study cohort comprised 24 MPM tumor specimens, 12 from therapy-naïve and 12 from patients after platinum-based therapy. Tumor samples were screened using the NanoString nCounter platform for digital gene expression analysis with an appurtenant custom-designed panel comprising a total of 366 mRNAs covering the most important tumor signaling pathways. Significant pathway associations were identified by gene set enrichment analysis using the WEB-based GEne SeT AnaLysis Toolkit (WebGestalt).

Results: We have found reduced activity of TNF (normalized enrichment score: 2.03), IL-17 (normalized enrichment score: 1.93), MAPK (normalized enrichment score: 1.51), and relaxin signaling pathways (normalized enrichment score: 1.42) in the samples obtained after platinum-based therapy. In contrast, AMPK (normalized enrichment score: -1.58), mTOR (normalized enrichment score: -1.50), Wnt (normalized enrichment score: -1.38), and longevity regulating pathway (normalized enrichment score: -1.31) showed significantly elevated expression in the same samples.

Conclusions: We could identify deregulated signaling pathways due to a directed cellular response to platinum-induced cell stress. Our results are paving the ground for a better understanding of cellular responses and escape mechanisms, carrying a high potential for improved clinical management of patients with MPM.

RevDate: 2021-08-16

Tran T, Egilman D, Rigler M, et al (2021)

A Critique of Helsinki Criteria for Using Lung Fiber Levels to Determine Causation in Mesothelioma Cases.

Annals of global health, 87(1):73.

Asbestos is a known human carcinogen and the chief known cause of mesothelioma. In 1997, a group of experts developed the Helsinki Criteria, which established criteria for attribution of mesothelioma to asbestos. The criteria include two methods for causation attribution: 1) a history of significant occupational, domestic, or environmental exposure and/or 2) pathologic evidence of exposure to asbestos. In 2014, the Helsinki Criteria were updated, and these attribution criteria were not changed. However, since the Helsinki Criteria were first released in 1997, some pathologists, cell biologists, and others have claimed that a history of exposure cannot establish causation unless the lung asbestos fiber burden exceeds "the background range for the laboratory in question to attribute mesothelioma cases to exposure to asbestos." This practice ignores the impact on fiber burden of clearance/translocation over time, which in part is why the Helsinki Criteria concluded that a history of exposure to asbestos was independently sufficient to attribute causation to asbestos. After reviewing the Helsinki Criteria, we conclude that their methodology is fatally flawed because a quantitative assessment of a background lung tissue fiber level cannot be established. The flaws of the Helsinki Criteria are both technical and substantive. The 1995 paper that served as the scientific basis for establishing background levels used inconsistent methods to determine exposures in controls and cases. In addition, historic controls cannot be used to establish background fiber levels for current cases because ambient exposures to asbestos have decreased over time and control cases pre-date current cases by decades. The use of scanning electron microscope (SEM) compounded the non-compatibility problem; the applied SEM cannot distinguish talc from anthophyllite because it cannot perform selected area electron diffraction, which is a crucial identifier in ATEM for distinguishing the difference between serpentine asbestos, amphibole asbestos, and talc.

RevDate: 2021-08-14

Ciocan C, Pira E, Coggiola M, et al (2021)

Mortality in the cohort of talc miners and millers from Val Chisone, Northern Italy: 74 years of follow-up.

Environmental research pii:S0013-9351(21)01159-2 [Epub ahead of print].

OBJECTIVE: To update the analysis of mortality of a cohort of talc miners and millers in Northern Italy.

METHODS: We analyzed overall mortality and mortality from specific causes of death during 1946-2020 of 1749 male workers in a talc mine where asbestos was not detected (1184 miners and 565 millers) employed during 1946-2002.

RESULTS: The overall standardized mortality ratio (SMR) was 1.21 (95 % confidence interval [CI] 1.14-1.28); no deaths were observed from pleural cancer. Mortality from lung cancer was not increased (SMR = 1.02 95 % CI 0.82-1.27), while mortality from pneumoconiosis was (SMR 9.55; 95 % CI 7.43-12.08), especially among miners (SMR 12.74; 95 % CI 9.79-16.31). The was a trend in risk of pneumoconiosis with increasing duration of employment in the overall cohort, and the SMR for 25+ years of employment was 15.12 (95 % CI 10.89-20.43).

CONCLUSIONS: This uniquely long-term follow up confirms the results of previous analyses, namely the lack of association between exposure to talc with no detectable level of asbestos and lung cancer and mesothelioma. Increased mortality from pneumoconiosis among miners is related to past exposure to silica.

RevDate: 2021-08-14

Grosso S, Marini A, Gyuraszova K, et al (2021)

The pathogenesis of mesothelioma is driven by a dysregulated translatome.

Nature communications, 12(1):4920.

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.

RevDate: 2021-08-13

Zhang C, Wu L, de Perrot M, et al (2021)

Carbon Nanotubes: A Summary of Beneficial and Dangerous Aspects of an Increasingly Popular Group of Nanomaterials.

Frontiers in oncology, 11:693814.

Carbon nanotubes (CNTs) are nanomaterials with broad applications that are produced on a large scale. Animal experiments have shown that exposure to CNTs, especially one type of multi-walled carbon nanotube, MWCNT-7, can lead to malignant transformation. CNTs have characteristics similar to asbestos (size, shape, and biopersistence) and use the same molecular mechanisms and signaling pathways as those involved in asbestos tumorigenesis. Here, a comprehensive review of the characteristics of carbon nanotubes is provided, as well as insights that may assist in the design and production of safer nanomaterials to limit the hazards of currently used CNTs.

RevDate: 2021-08-11

Zhai Z, Ruan J, Zheng Y, et al (2021)

Assessment of Global Trends in the Diagnosis of Mesothelioma From 1990 to 2017.

JAMA network open, 4(8):e2120360 pii:2782981.

Importance: It is difficult for policy makers and clinicians to formulate targeted management strategies for mesothelioma because data on current epidemiological patterns worldwide are lacking.

Objective: To evaluate the mesothelioma burden across the world and describe its epidemiological distribution over time and by sociodemographic index (SDI) level, geographic location, sex, and age.

Annual case data and age-standardized rates of incidence, death, and disability-adjusted life-years associated with mesothelioma among different age groups were obtained from the Global Burden of Disease 2017 database. The estimated annual percentage changes in age-standardized rates were calculated to evaluate temporal trends in incidence and mortality. The study population comprised individuals from 21 regions in 195 countries and territories who were diagnosed with mesothelioma between 1990 and 2017. Data were collected from May 23, 2019, to January 18, 2020.

Main Outcomes and Measures: Primary outcomes were incident cases, deaths, and their age-standardized rates and estimated annual percentage changes. Secondary outcomes were disability-adjusted life-years and relative temporal trends.

Results: Overall, 34 615 new cases (95% uncertainty interval [UI], 33 530-35 697 cases) of mesothelioma and 29 909 deaths (95% UI, 29 134-30 613 deaths) associated with mesothelioma were identified in 2017, and more than 70% of these cases and deaths were among male individuals. In 1990, the number of incident cases was 21 224 (95% UI, 17 503-25 450), and the number of deaths associated with mesothelioma was 17 406 (95% UI, 14 495-20 660). These numbers increased worldwide from 1990 to 2017, with more than 50% of cases recorded in regions with high SDI levels, whereas the age-standardized incidence rate (from 0.52 [95% UI, 0.43-0.62] in 1990 to 0.44 [95% UI, 0.42-0.45] in 2017) and the age-standardized death rate (from 0.44 [95% UI, 0.37-0.52] in 1990 to 0.38 [95% UI, 0.37-0.39] in 2017) decreased, with estimated annual percentage changes of -0.61 (95% CI, -0.67 to -0.54) for age-standardized incidence rate and -0.44 (95% CI, -0.52 to -0.37) for age-standardized death rate. The proportion of incident cases among those 70 years or older continued to increase (from 36.49% in 1990 to 44.67% in 2017), but the proportion of patients younger than 50 years decreased (from 16.74% in 1990 to 13.75% in 2017) over time. In addition, mesothelioma incident cases and age-standardized incidence rates began to decrease after 20 years of a complete ban on asbestos use. For example, in Italy, a complete ban on asbestos went into effect in 1992; incident cases increased from 1409 individuals (95% UI, 1013-1733 individuals) in 1990, peaked in 2015 after 23 years of the asbestos ban, then decreased from 1820 individuals (95% UI, 1699-1981 individuals) in 2015 to 1746 individuals (95% UI, 1555-1955 individuals) in 2017.

Conclusions and Relevance: This cross-sectional study found that incident cases of mesothelioma and deaths associated with mesothelioma continuously increased worldwide, especially in resource-limited regions with low SDI levels. Based on these findings, global governments and medical institutions may consider formulating optimal policies and strategies for the targeted prevention and management of mesothelioma.

RevDate: 2021-08-10

Ferrante P (2021)

Hospitalisation costs of malignant mesothelioma: results from the Italian hospital discharge registry (2001-2018).

BMJ open, 11(8):e046456 pii:bmjopen-2020-046456.

OBJECTIVES: This paper aims to establish hospitalisation costs of mesothelioma in Italy and to evaluate hospital-related trends associated with the 1992 asbestos ban.

DESIGN: This is a retrospective population-based study of Italian hospitalisations treating pleura, peritoneum and pericardium mesothelioma in the period 2001-2018.

SETTINGS: Public and private Italian hospitals reached by the Ministry of Health (coverage close to 100%).

PARTICIPANTS: 157 221 admissions with primary or contributing diagnosis of pleural, peritoneal or hearth cancer discharged from 2001 to 2018.Primary and secondary outcome measures: number, length and cost of hospitalisations with related percentages.

RESULTS: Each year, Italian hospitals treated a mesothelioma in 6025 admissions on average. Mean annual costs by site were €20 293 733, €3183 632 and €40 443 for pleura, peritoneum and pericardium, respectively. Pericardial mesothelioma showed the highest cost per admission (€6117), followed by peritoneal (€4549) and pleural cases (€3809). Percentage of hospitalisation costs attributable to mesothelioma was higher when it is located in pleura (53.4%) and pericardium (51.8%) with respect to peritoneum (41.2%). Overall annual hospitalisation cost, percentages of number and length of admissions showed an inverted U-shape, with maxima (of €25 850 276, 0.064% and 0.096%, respectively) reached in 2011-2013. Mean age at discharge and percentages of surgery and of urgent cases increased over time.

CONCLUSIONS: The highest impact of mesothelioma on the National Health System was recorded 20 years after the asbestos ban (2011-2013). Hospitals should expect soon fewer but more severe patients needing more cares. To study the disease prevalence could help assistance planning of next decade.

RevDate: 2021-08-07

Chmielewska-Kassassir M, LA Wozniak (2021)

Phytochemicals in Malignant Pleural Mesothelioma Treatment-Review on the Current Trends of Therapies.

International journal of molecular sciences, 22(15): pii:ijms22158279.

Malignant pleural mesothelioma (MPM) is a rare but highly aggressive tumor of pleura arising in response to asbestos fibers exposure. MPM is frequently diagnosed in the advanced stage of the disease and causes poor prognostic outcomes. From the clinical perspective, MPM is resistant to conventional treatment, thus challenging the therapeutic options. There is still demand for improvement and sensitization of MPM cells to therapy in light of intensive clinical studies on chemotherapeutic drugs, including immuno-modulatory and targeted therapies. One way is looking for natural sources, whole plants, and extracts whose ingredients, especially polyphenols, have potential anticancer properties. This comprehensive review summarizes the current studies on natural compounds and plant extracts in developing new treatment strategies for MPM.

RevDate: 2021-08-07

Li N, Yang C, Zhou S, et al (2021)

Combination of Plasma-Based Metabolomics and Machine Learning Algorithm Provides a Novel Diagnostic Strategy for Malignant Mesothelioma.

Diagnostics (Basel, Switzerland), 11(7): pii:diagnostics11071281.

BACKGROUND: Malignant mesothelioma (MM) is an aggressive and incurable carcinoma that is primarily caused by asbestos exposure. However, the current diagnostic tool for MM is still under-developed. Therefore, the aim of this study is to explore the diagnostic significance of a strategy that combined plasma-based metabolomics with machine learning algorithms for MM.

METHODS: Plasma samples collected from 25 MM patients and 32 healthy controls (HCs) were randomly divided into train set and test set, after which analyzation was performed by liquid chromatography-mass spectrometry-based metabolomics. Differential metabolites were screened out from the samples of the train set. Subsequently, metabolite-based diagnostic models, including receiver operating characteristic (ROC) curves and Random Forest model (RF), were established, and their prediction accuracies were calculated for the test set samples.

RESULTS: Twenty differential plasma metabolites were annotated in the train set; 10 of these metabolites were validated in the test set. The seven most prevalent diagnostic metabolites were taurocholic acid), 0.7142 (uracil), 0.7142 (biliverdin), 0.8571 (histidine), 0.5000 (tauroursodeoxycholic acid), 0.8571 (pyrroline hydroxycarboxylic acid), and 0.7857 (phenylalanine). Furthermore, RF based on 20 annotated metabolites showed a prediction accuracy of 0.9286, and its optimized version achieved 1.0000 in the test set. Moreover, the comparison between the samples of peritoneal MM (n = 8) and pleural MM (n = 17) illustrated a significant increase in levels of taurocholic acid and tauroursodeoxycholic acid, as well as an evident decrease in biliverdin.

CONCLUSIONS: Our results revealed the potential diagnostic value of plasma-based metabolomics combined with machine learning for MM. Further research with large sample size is worthy conducting. Moreover, our data demonstrated dysregulated metabolism pathways in MM, which aids in better understanding of molecular mechanisms related to the initiation and development of MM.

RevDate: 2021-08-07

Visonà SD, Capella S, Bodini S, et al (2021)

Evaluation of Deposition and Clearance of Asbestos (Detected by SEM-EDS) in Lungs of Deceased Subjects Environmentally and/or Occupationally Exposed in Broni (Pavia, Northern Italy).

Frontiers in public health, 9:678040.

Biodurability is one of the main determinants of asbestos hazardousness for human health. Very little is known about the actual persistence of asbestos in lungs and its clearance, nor about differences in this regard between the different mineralogical types of asbestos. The aim of the present study was to evaluate the amount, the dimensional characteristics and the mineralogic kinds of asbestos in lungs (measured using SEM-EDS) of a series of 72 deceased subjects who were certainly exposed to asbestos (mainly crocidolite and chrysotile) during their life. Moreover, we investigated possible correlations between the lung burden of asbestos (in general and considering each asbestos type), as well as their dimension (length, width, and l/w ratio) and the duration of exposure, the latency- in case of malignant mesothelioma (MM), the survival and the time since the end of exposure. In 62.5% of subjects, asbestos burden in lungs was lower that the threshold considered demonstrative for occupational exposure. In 29.1% of cases no asbestos was found. Chrysotile was practically not detected. The mean length of asbestos fibers and the length to width ratio were significantly related to the duration of exposure to asbestos. No other statistically significant correlations were found between the amount and dimensional characteristics of asbestos (nor with the relative amount of each asbestos type) and the other chronological variables considered. In conclusion, it was pointed out that chrysotile can be completely removed from human lungs in <8 years and, instead, amphiboles persist much more time. The present results suggest, as well, that the finding of no asbestos in lungs cannot rule out the attribution of MM to asbestos (in particular, chrysotile) inhaled in an occupational setting. This point is of crucial importance from a legal point of view.

RevDate: 2021-08-05

Mensi C, Zellino C, Polonioli M, et al (2021)

Pleural mesothelioma in a circus worker.

Journal of occupational health, 63(1):e12250.

OBJECTIVES: To describe an unusual occupational asbestos exposure in a patient with mesothelioma.

METHODS: Since 2000, the Lombardy Mesothelioma Registry (LMR) collects cases of malignant mesothelioma (MM) occurring among people residing in the Lombardy Region, North-West Italy, with a population of 10 million inhabitants. For each case, clinical records and asbestos exposure are collected. Each case is then classified in agreement with the guidelines of the National Mesothelioma Registry.

RESULTS: We identified a male (86 years old), former smoker, who had been working for 53 years as a circus truck driver and tamer of lions and tigers. The first circumstance of exposure was the use of an asbestos tape that wrapped around the hoop in the feline jumping show with a flaming hoop. The second one was the presence of insulating panels protecting the engine placed inside the trucks.

CONCLUSION: A new MM case with an occupational etiology has been found in the public entertainment, an occupational sector not usually considered at risk for the presence of asbestos.

RevDate: 2021-08-06

Iyoda A, Azuma Y, Sakai T, et al (2021)

Intraoperative argon-plasma coagulation treatment for patients with malignant pleural mesothelioma.

Molecular and clinical oncology, 15(3):188.

Malignant pleural mesothelioma (MPM) is often associated with asbestos exposure and carries an extremely poor prognosis. The present study assessed the effectiveness of argon plasma coagulation (APC) treatment in patients with MPM who underwent radical pleural decortication (PD). The clinical data from 11 patients who underwent radical PD treated with APC at Toho University Omori Medical Center from July 2015 to March 2020 were retrospectively analyzed. Clinical features, local recurrence, and clinical prognoses were evaluated. The median overall survival was 18.5 months, and the 1- and 2-year overall survival rates were 71.6 and 43.0%, respectively. One patient survived 5 years but had recurrent tumors. The median disease-free survival was 11.1 months. The 1- and 2-year disease-free survival rates were 49.9 and 12.5%, respectively. Three patients had no recurrences, two of whom were followed continuously (39.6 and 10.2 months). The present study revealed that APC treatment for MPM might be associated with good survival and prognosis. APC as an additional intraoperative treatment for patients with MPM may be further investigated with larger multi-center clinical trials to support its efficacy.

RevDate: 2021-08-06

Gualtieri AF (2021)

Bridging the gap between toxicity and carcinogenicity of mineral fibres by connecting the fibre crystal-chemical and physical parameters to the key characteristics of cancer.

Current research in toxicology, 2:42-52.

Airborne fibres and particularly asbestos represent hazards of great concern for human health because exposure to these peculiar particulates may cause malignancies such as lung cancer and mesothelioma. Currently, many researchers worldwide are focussed on fully understanding the patho-biological mechanisms leading to carcinogenesis prompted by pathogenic fibres. Along this line, the present work introduces a novel approach to correlate how and to what extent the physical/crystal-chemical and morphological parameters (including length, chemistry, biodurability, and surface properties) of mineral fibres cause major adverse effects with an emphasis on asbestos. The model described below conceptually attempts to bridge the gap between toxicity and carcinogenicity of mineral fibres and has several implications: 1) it provides a tool to measure the toxicity and pathogenic potential of asbestos minerals, allowing a quantitative rank of the different types (e.g. chrysotile vs. crocidolite); 2) it can predict the toxicity and pathogenicity of "unregulated" or unclassified fibres; 3) it reveals the parameters of a mineral fibre that are active in stimulating key characteristics of cancer, thus offering a strategy for developing specific cancer prevention strategies and therapies. Chrysotile, crocidolite and fibrous glaucophane are described here as mineral fibres of interest.

RevDate: 2021-08-02

Prusak A, van der Zwan JM, Aarts MJ, et al (2021)

The psychosocial impact of living with mesothelioma: Experiences and needs of patients and their carers regarding supportive care.

European journal of cancer care [Epub ahead of print].

OBJECTIVE: Mesothelioma is a rare cancer with a poor prognosis caused by exposure to asbestos. Psychosocial support and care for mesothelioma patients and their carers is limited and not tailored to their specific needs. The aim of this study was to explore patients' and carers' needs and experiences regarding psychosocial support and their coping mechanisms dealing with psychosocial problems.

METHODS: A qualitative study was performed using semi-structured interviews with both mesothelioma patients and their carers. Participants were recruited through two specialised hospitals and two patient organisations. All interviews were transcribed verbatim and thematically analysed.

RESULTS: Ten patients (70% male, mean age 67.7) and five carers (20% male, mean age 65) participated in the study. The main themes identified for patients were active coping, limited needs and limited knowledge and awareness about psychosocial support. The main themes for carers were passive coping and 'it's all about the patient'.

CONCLUSION: Mesothelioma patients do not seem to have high needs for psychosocial support, whereas carers do. However, knowledge about and awareness of psychosocial support is low among mesothelioma patients. The findings from this study should be used to adjust guidelines for psychosocial support in mesothelioma patients and their carers.

RevDate: 2021-08-06

Onagi H, Hayashi T, Saito T, et al (2021)

Malignant pleural mesothelioma showing rare morphology indistinguishable from myxofibrosarcoma concomitant with EGFR-mutated lung adenocarcinoma: A case report.

International journal of surgery case reports, 85:106237 pii:S2210-2612(21)00739-2 [Epub ahead of print].

INTRODUCTION AND IMPORTANCE: Primary tumors of the pleura are rare, with malignant mesothelioma being the most common of these neoplasms. Pathological diagnosis of sarcomatoid mesothelioma can be more challenging than that of epithelioid malignant mesothelioma because of its similarities with true sarcomas and restricted or inconsistent expression of mesothelial markers in immunohistochemistry analysis.

PRESENTATION OF CASE: Here, we present an unusual case of malignant pleural mesothelioma concomitant with lung adenocarcinoma in a 72-year-old Japanese man, a smoker with no family history of cancer and asbestos exposure. Malignant pleural mesothelioma is composed of epithelial and spindle-shaped cells. Spindle-shaped cells with scant eosinophilic cytoplasm and hyperchromatic nuclei proliferated in abundant myxoid stroma containing thin-walled blood vessels, mimicking myxofibrosarcoma. The loss of BAP1 (BRCA1-associated protein 1) expression, as assessed by immunohistochemistry, and homozygous deletions of CDKN2A, detected using fluorescence in situ hybridization (FISH), were observed in both components. Targeted sequencing revealed that lung adenocarcinoma harbored EGFR mutations, whereas no mutations were detected in either component of biphasic mesothelioma.

DISCUSSION: Although alcian blue-stained mucins were detected in biphasic mesothelioma subsets, the clinicopathological significance of myxoid stroma in biphasic and sarcomatoid mesothelioma remains largely unknown.

CONCLUSION: Our case presented a unique morphology mimicking myxofibrosarcoma in a sarcomatoid component of biphasic mesothelioma; therefore, it raises a question on the clinicopathological significance of myxoid stroma in sarcomatous areas of biphasic and sarcomatoid mesothelioma.

RevDate: 2021-07-30

Scopa P (2021)

Reconstruction of asbestos exposure in workers suffering from pleural neoplasms and employed in sectors not generally associated with high exposure levels: the importance of an accurate standardized assessment of occupational medicine.

Journal of preventive medicine and hygiene, 62(1):E148-E151.

Introduction: Malignant pleural mesothelioma onset in workers exposed to asbestos is well known with reference to multiple working sectors. In some cases, occurring among workers of sectors characterized by a presumed lower relevance of asbestos exposure, the absence of a well-defined correlation can prevent their emergence and compensation. To improve definition of these cases, this article underlines the importance of a standardized approach to occupational anamnesis.

Methods: Thorough standardized occupational health assessment method application in a case of pleural malignant neoplasm occurred in a hauler, a job generally not associated with high levels of exposure to asbestos fibres.

Results: Assessment of malignant pleural mesothelioma diagnosis and dual mode relevant occupational exposure to asbestos during both truck driving and loading and unloading operations of asbestos-containing goods.

Conclusions: Systematic occupational medicine assessment with accurate standardized approach is essential for reconstruction of asbestos exposure, in order to highlight every aspect useful to establish causal link between cases of pleural mesothelioma and possible occupational and non-occupational exposure to the mineral, even in cases where the first-level occupational history does not appear to be suggestive.

RevDate: 2021-07-27

Brustugun OT, Nilssen Y, IJZ Eide (2021)

Epidemiology and outcome of peritoneal and pleural mesothelioma subtypes in Norway. A 20 year nation-wide study.

Acta oncologica (Stockholm, Sweden) [Epub ahead of print].

BACKGROUND: Mesothelioma of the pleural or peritoneal cavities is one of the deadliest cancer types. The incidence of pleural subtypes has decreased over time due to decrease in asbestos exposure, and the current treatment landscape is changing due to introduction of novel therapies. In this study we have analysed contemporary epidemiological data of mesothelioma on a national level before the advent of immunotherapy.

MATERIAL AND METHODS: Complete national data on 1509 pleural and peritoneal malignant mesothelioma from the Cancer Registry of Norway from 2000 to 2019 are presented. Age standardised incidence and median survival were calculated.

RESULTS: The age-standardised incidence of pleural mesothelioma among males has decreased from 1.7 per 100 000 in 2000-2004 to 1.1 in 2015-2019, whereas the incidence for females has been stable, lower than 0.3 per 100 000 throughout the period. Incidence of peritoneal mesotheliomas remained low, below 0.08 per 100 000. The female to male ratio among pleural mesotheliomas was 1:7 with no differences among morphological subtypes, whereas this ratio was 1:1.2 in peritoneal mesotheliomas. Median age at diagnosis for pleural mesothelioma was 73 years and 76 years for females and males respectively in the last 5-year period, and 67 years for peritoneal mesotheliomas of both sexes. Median survival among pleural mesotheliomas has been stable, with significantly worse prognosis among sarcomatoid subtype (5.4 months) compared to epithelioid subtype (15.8 months). Peritoneal mesothelioma of the epithelioid subtype, representing 38% of cases, had a median survival of 43.3 months, contrasting the non-epithelioid subtype of 5.1 months.

DISCUSSION: Mesothelioma is still a significant disease with a dismal prognosis. Improvement in treatment is warranted.

RevDate: 2021-07-29

Fang YJ, Chuang HY, Pan CH, et al (2021)

Increased Risk of Gastric Cancer in Asbestos-Exposed Workers: A Retrospective Cohort Study Based on Taiwan Cancer Registry 1980-2015.

International journal of environmental research and public health, 18(14):.

Asbestos has been recognized as a human carcinogen associated with malignant mesothelioma, cancers of lung, larynx, and ovary. However, a putative association between gastric cancer and asbestos exposure remains controversial. In this study, we aimed to explore gastric cancer risk of workers potentially exposed to asbestos in Taiwan. The asbestos occupational cohort was established from 1950 to 2015 based on the Taiwan Labor Insurance Database, and Taiwan Environmental Protection Agency regulatory datasets, followed by the Taiwan Cancer Registry for the period 1980-2015. Standardized incidence ratios (SIRs) for cancer were computed for the whole cohort using reference rates of the general population, and also reference labor population. Compared with the general population, SIR of the asbestos occupational cohort for the gastric cancer increased both in males (1.05, 95% confidence interval (CI): 1.02-1.09) and females (1.10, 95% CI: 1.01-1.18). A total of 123 worksites were identified to have cases of malignant mesothelioma, where increased risk for gastric cancer was found with a relative risk of 1.76 (95% CI: 1.63-1.90). This 35-year retrospective cohort study of asbestos-exposed workers in Taiwan may provide support for an association between occupational exposure to asbestos and gastric cancer.

RevDate: 2021-07-29
CmpDate: 2021-07-29

Yuan L, Sun B, Xu L, et al (2021)

The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma.

International journal of molecular sciences, 22(14):.

SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase that exerts important effects on epigenetic gene regulation. SETDB1 complexes (SETDB1-KRAB-KAP1, SETDB1-DNMT3A, SETDB1-PML, SETDB1-ATF7IP-MBD1) play crucial roles in the processes of histone methylation, transcriptional suppression and chromatin remodelling. Therefore, aberrant trimethylation at H3K9 due to amplification, mutation or deletion of SETDB1 may lead to transcriptional repression of various tumour-suppressing genes and other related genes in cancer cells. Lung cancer is the most common type of cancer worldwide in which SETDB1 amplification and H3K9 hypermethylation have been indicated as potential tumourigenesis markers. In contrast, frequent inactivation mutations of SETDB1 have been revealed in mesothelioma, an asbestos-associated, locally aggressive, highly lethal, and notoriously chemotherapy-resistant cancer. Above all, the different statuses of SETDB1 indicate that it may have different biological functions and be a potential diagnostic biomarker and therapeutic target in lung cancer and mesothelioma.

RevDate: 2021-07-29

Pouliquen DL, J Kopecka (2021)

Malignant Mesothelioma.

Cancers, 13(14):.

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

RevDate: 2021-07-24

Menis J, Pasello G, J Remon (2021)

Immunotherapy in malignant pleural mesothelioma: a review of literature data.

Translational lung cancer research, 10(6):2988-3000.

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the pleural surface, associated with asbestos exposure, whose incidence is still growing in some areas of the world. MPM is still considered a rare and an orphan disease with an unchanged median overall survival (OS) ranging from 8 to 14 months and no treatment advances in the last 15 years both in local and advanced disease. In the recent years, chronic inflammation of the mesothelium together with local tumor suppression plays a major role in the malignant transformation. Also, significant heterogeneity in both tumor and the microenvironment is at the basis of MPM biology. Preclinical data have demonstrated the immunogenicity and the lack of an effective antitumor response by the immune system in MPM thus paving the way to the development of immune therapeutics in this disease. Still there is no clear evidence of any predictive biomarker so that, given the close interaction between the immune infiltrate and mesothelial cells, a number of trials are ongoing to investigate the role and prognostic value of the immune microenvironment. In this review we summarize the rationale for immune therapeutics development in MPM, as well as, the relevant literature and ongoing trials of immune checkpoint inhibitors (ICIs) and vaccines used as both first-line treatment and beyond.

RevDate: 2021-07-24

Gu R, Jiang L, Duan T, et al (2021)

A Case of Pulmonary Embolism with Sarcomatoid Malignant Pleural Mesothelioma with Long-Term Pleural Effusion.

OncoTargets and therapy, 14:4231-4237.

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that originates from pleural mesothelial cells. In recent years, with the development of asbestos-related industries and the increase in air pollution, its incidence has been increased. The incidence of pulmonary embolism combined with sarcomatoid MPM is very low and the prognosis is extremely poor. We here report a case of a patient with long term of pleural effusion and finally diagnosed as pulmonary embolism with sarcomatoid MPM.

Case: A 75-year-old male with a 30-year history of asbestos exposure was admitted to our hospital due to chest pain and difficulty in breathing after exercise. Radiologic examination revealed pleural effusion, computed tomography pulmonary angiography (CTPA) suggests pulmonary embolism, and we consider pleural effusion caused by pulmonary embolism. After anticoagulant therapy for pulmonary embolism and pleural puncture to reduce pleural effusion, the patient's symptoms improved. However, after that, the patient was still admitted to the hospital several times because of recurrent chest pain and dyspnea symptoms, and radiologic examination always showed unexplained pleural effusion. Finally, pathological and immunohistochemical examinations of the pleural biopsy specimens were performed, and the diagnosis was confirmed as sarcomatoid MPM.

Conclusion: In summary, sarcomatoid MPM with pulmonary embolism is relatively rare, and the prognosis is poor. Clinicians need to be alert to its occurrence. When the first diagnosis is confirmed and the effect of targeted treatment is still not good, the possibility of other diseases should be considered. In clinical practice, pleural biopsy guided by PET-CT is a good choice for patients with sarcomatoid MPM who cannot tolerate open pleural biopsies or thoracoscopy. And patients should undergo pleural morphology and immunohistochemistry as soon as possible, which are helpful for timely diagnosis.

RevDate: 2021-07-22

Santana VS, Salvi L, Cavalcante F, et al (2021)

Underreporting of mesothelioma, asbestosis and pleural plaques in Brazil.

Occupational medicine (Oxford, England) pii:6325429 [Epub ahead of print].

BACKGROUND: Brazil has a long history of heavy asbestos consumption. However, the number of asbestos-related diseases (ARDs) falls far below the one expected compared with other asbestos consumer countries.

AIMS: To examine underreporting of ARDs, that is mesothelioma, asbestosis and pleural plaques, in Brazil's Mortality Information System (SIM).

METHODS: Health information systems (HIS) were mapped, datasets retrieved and records of ARD deaths extracted. Records were pair-matched using anonymous linkage to create a single database. ARD-reported cases missing in SIM were considered unreported. The study's period ranged from 2008 to 2014, when every HIS contributed to the ARD records pool.

RESULTS: A total of 1298 registered ARD deaths were found, 996 cases of mesothelioma (77%) and 302 (23%) of asbestosis and pleural plaques. SIM was the major single data source of ARD but 335 mesothelioma deaths were missing, an average underreporting of 33%, with no clear time trend. For asbestosis and pleural plaques, underreporting of ARD oscillated from 55% in 2010 to 25% in 2014, a declining trend. ARD underreporting was not associated with sex or age.

CONCLUSIONS: One-third of underreported ARD deaths in the universal SIM is unacceptably high and, apparently, it has not been improving substantially over time. After recoveries from multiple databases, the number of cases is still below, which could be expected based on asbestos consumption. Interoperability of multiple information systems could enhance case detection and improve the precision of mortality estimates, which are crucial for surveillance and for evaluation of remedial policies.

RevDate: 2021-07-23

Oddone E, Bollon J, Nava CR, et al (2021)

Effect of Asbestos Consumption on Malignant Pleural Mesothelioma in Italy: Forecasts of Mortality up to 2040.

Cancers, 13(13):.

Statistical models used to forecast malignant pleural mesothelioma (MPM) trends often do not take into account historical asbestos consumption, possibly resulting in less accurate predictions of the future MPM death toll. We used the distributed lag non-linear model (DLNM) approach to predict future MPM cases in Italy until 2040, based on past asbestos consumption figures. Analyses were conducted using data on male MPM deaths (1970-2014) and annual asbestos consumption using data on domestic production, importation, and exportation. According to our model, the peak of MPM deaths is expected to occur in 2021 (1122 expected cases), with a subsequent decrease in mortality (344 MPM deaths in 2039). The exposure-response curve shows that relative risk (RR) of MPM increased almost linearly for lower levels of exposure but flattened at higher levels. The lag-specific RR grew until 30 years since exposure and decreased thereafter, suggesting that the most relevant contributions to the risk come from exposures which occurred 20-40 years before death. Our results show that the Italian MPM epidemic is approaching its peak and underline that the association between temporal trends of MPM and time since exposure to asbestos is not monotonic, suggesting a lesser role of remote exposures in the development of MPM than previously assumed.

RevDate: 2021-08-02
CmpDate: 2021-08-02

Visonà SD, Capella S, Bodini S, et al (2021)

Reply to Mirabelli et al. Is Mesothelioma Unrelated to the Lung Asbestos Burden? Comment on "Visonà et al. Inorganic Fiber Lung Burden in Subjects with Occupational and/or Anthropogenic Environmental Asbestos Exposure in Broni (Pavia, Northern Italy): An SEM-EDS Study on Autoptic Samples. Int. J. Environ. Res. Public Health 2021, 18, 2053".

International journal of environmental research and public health, 18(13):.

We appreciate very much the interest of Mirabelli et al. [...].

RevDate: 2021-08-02
CmpDate: 2021-08-02

Mirabelli D, Angelini A, Barbieri PG, et al (2021)

Is Mesothelioma Unrelated to the Lung Asbestos Burden? Comment on Visonà et al. Inorganic Fiber Lung Burden in Subjects with Occupational and/or Anthropogenic Environmental Asbestos Exposure in Broni (Pavia, Northern Italy): An SEM-EDS Study on Autoptic Samples. Int. J. Environ. Res. Public Health 2021, 18, 2053.

International journal of environmental research and public health, 18(13):.

We read with interest the report by Visonà and coworkers on the lung asbestos fiber burden in an autopsy series of decedents from mesothelioma (MM: 59 cases) and individuals who "suffered from asbestosis and died of its complications" (13 cases) [...].

RevDate: 2021-07-20

Freudenberger DC, RD Shah (2021)

A narrative review of the health disparities associated with malignant pleural mesothelioma.

Journal of thoracic disease, 13(6):3809-3815.

Malignant pleural mesothelioma (MPM) is a cancer of the mesothelial lining of the pleura that has traditionally been associated with asbestos exposure in an industrial setting. Asbestos usage has fortunately been banned or phased out in most industrialized countries resulting in its decline in countries such as the United States. Despite this, MPM continues to place significant burden on its affected patients resulting in overall poor prognosis and survival. Questions arise as to what factors, especially what health disparities, contribute to the disease's dismal prognosis. This article will present a narrative review of recent literature that identifies the impact age, sex, race, access to medical centers, and economics have on the diagnosis, treatment, and prognosis of MPM. As will be discussed, research has shown that factors including younger age, female sex, non-white race, private insurance, Medicare, and higher income have been associated with better survival in MPM. Whereas older age, male sex, white race, lack of insurance, and lower income are associated with worse survival. The identification of these and other health disparities related to MPM may allow for future research, clinical guidelines, and policies to be implemented to decrease the burden health disparities create in the diagnosis, treatment, and prognosis of patients with MPM.

RevDate: 2021-07-13

Hiltbrunner S, Mannarino L, Kirschner MB, et al (2021)

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma.

Frontiers in oncology, 11:660039.

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

RevDate: 2021-07-10

Thomsen RW, Riis AH, Flachs EM, et al (2021)

Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study.

Thorax pii:thoraxjnl-2020-215041 [Epub ahead of print].

INTRODUCTION: The risk of asbestosis, malignant mesothelioma and lung cancer among motor vehicle mechanics is of concern because of potential exposure to chrysotile asbestos during brake, clutch and gasket repair and maintenance. Asbestos has also been used in insulation and exhaust systems.

METHODS: We examined the long-term risk of incident mesothelioma, lung cancer, asbestosis and other lung diseases and mortality due to mesothelioma, lung cancer, asbestosis and other lung diseases in a nationwide cohort of all men registered as motor vehicle mechanics since 1970 in Denmark. This was compared with the corresponding risk in a cohort of male workers matched 10:1 by age and calendar year, with similar socioeconomic status (instrument makers, dairymen, upholsterers, glaziers, butchers, bakers, drivers, farmers and workers in the food industry, trade or public services).

RESULTS: Our study included 138 559 motor vehicle mechanics (median age 24 years; median follow-up 20 years (maximum 45 years)) and 1 385 590 comparison workers (median age 25 years; median follow-up 19 years (maximum 45 years)). Compared with other workers, vehicle mechanics had a lower risk of morbidity due to mesothelioma/pleural cancer (n=47 cases) (age-adjusted and calendar-year-adjusted HR=0.74 (95% CI 0.55 to 0.99)), a slightly increased risk of lung cancer (HR=1.09 (95% CI 1.03 to 1.14)), increased risk of asbestosis (HR=1.50 (95% CI 1.10 to 2.03)) and a chronic obstructive pulmonary disease risk close to unity (HR=1.02 (95% CI 0.99 to 1.05)). Corresponding HRs for mortality were 0.86 (95% CI 0.64 to 1.15) for mesothelioma/pleural cancer, 1.06 (95% CI 1.01 to 1.12) for lung cancer, 1.79 (95% CI 1.10 to 2.92) for asbestosis, 1.06 (95% CI 0.86 to 1.30) for other lung diseases caused by external agents and 1.00 (95% CI 0.98 to 1.01) for death due to all causes.

CONCLUSIONS: We found that the risk of asbestosis was increased among vehicle mechanics. The risk of malignant mesothelioma/pleural cancers was not increased among vehicle mechanics.

RevDate: 2021-07-30
CmpDate: 2021-07-30

Golka K, Böthig R, Jungmann O, et al (2021)

[Occupational cancers in urology].

Der Urologe. Ausg. A, 60(8):1061-1072.

Cancers can be triggered by occupational causes. In the field of urology, bladder cancer is by far the most frequent occupationally induced tumor disease. Causes are particularly carcinogenic aromatic amines and carcinogenic polycyclic aromatic hydrocarbons. The frequency of this disease has shifted over the last decades from the classical hazard in the chemical industry to the users. Among a variety of hazardous occupations, hairdressers and painters are the best known. Rarely, renal cell carcinoma can be triggered by high trichloroethylene exposure and mesothelioma of the tunica vaginalis testis by asbestos. If a disease that can be caused by occupational activities has been confirmed (e.g. urinary bladder cancer), the risk factors must be recorded by a complete occupational history from the first employment on in order to be able to report a suspected occupational disease. In addition, spinal cord injury due to occupational and commuting accidents can lead to urinary bladder cancer over the long term.

RevDate: 2021-07-09

Hiroshima K, Wu D, Koh E, et al (2021)

Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Pathology international [Epub ahead of print].

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.

RevDate: 2021-07-09

Behrouzfar K, Burton K, Mutsaers SE, et al (2021)

How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers.

Frontiers in oncology, 11:679609.

Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC-MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.

RevDate: 2021-07-06

Pagliuca F, Zito Marino F, Morgillo F, et al (2021)

Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond.

European review for medical and pharmacological sciences, 25(12):4236-4246.

Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called "BAP1-related tumour predisposition syndrome". Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients.

RevDate: 2021-07-06

Obacz J, Yung H, Shamseddin M, et al (2021)

Biological basis for novel mesothelioma therapies.

British journal of cancer [Epub ahead of print].

Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.

RevDate: 2021-07-03

Faversani A, Favero C, Dioni L, et al (2021)

An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls.

Frontiers in oncology, 11:643280.

Background: Despite significant improvement in screening programs for cancers of the respiratory district, especially in at-risk subjects, early disease detection is still a major issue. In this scenario, new molecular and non-invasive biomarkers are needed to improve early disease diagnosis.

Methods: We profiled the miRNome in exhaled breath condensate (EBC) and plasma samples from fourteen patients affected by lung AdCa, nine healthy subjects. miRNA signatures were then analyzed in another neoplasia of the respiratory district, i.e. pleural mesothelioma (n = 23) and subjects previously exposed to asbestos were used as controls for this cohort (n = 19). Selected miRNAs were analyzed in purified pulmonary neoplastic or normal epithelial and stromal cell subpopulation from AdCa patients. Finally, the plasmatic miRNA signature was analyzed in a publicly available cohort of NSCLC patients for data validation and in silico analysis was performed with predicted miRNA targets using the multiMiR tool and STRING database.

Results: miR-597-5p and miR-1260a are significantly over-expressed in EBC from lung AdCa and are associated with AdCa. Similarly, miR-1260a is also up-regulated in the plasma of AdCa patients together with miR-518f-3p and correlates with presence of lung cancer, whereas let-7f-5p is under-expressed. Analysis of these circulating miRNAs in pleural mesothelioma cases confirmed that up-regulation of miR-518f-3p, -597-5p and -1260a, is specific for lung AdCa. Lastly, quantification of the miRNAs in laser-assisted microdissected lung tissues revealed that miR-518f-3p, 597-5p and miR-1260a are predominantly expressed in tumor epithelial cells. Validation analysis confirmed miR-518f-3p as a possible circulating biomarker of NSCLC. In silico analysis of the potentially modulated biological processes by these three miRNAs, shows that tumor bioenergetics are the most affected pathways.

Conclusions: Overall, our data suggest a 3-miRNAs signature as a non-invasive and accurate biomarker of lung AdCa. This approach could supplement the current screening approaches for early lung cancer diagnosis.

RevDate: 2021-07-07

Saracino L, Bortolotto C, Tomaselli S, et al (2021)

Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study.

BMC cancer, 21(1):762.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20-40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis.

METHODS: Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance.

RESULTS: The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine.

CONCLUSION: A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.

RevDate: 2021-07-24
CmpDate: 2021-07-21

Broggi G, Angelico G, Filetti V, et al (2021)

Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Study.

International journal of environmental research and public health, 18(12):.

The Serine and Arginine-Rich Splicing Factor 1 (SRSF1) has a proto-oncogenic function, being associated with angiogenesis and frequently overexpressed in many human malignant neoplasms. Its immunohistochemical expression has never been investigated in malignant pleural mesothelioma (MPM). We evaluated SRSF1 immunoexpression and its possible relation to angiogenesis in a selected cohort of 10 fluoro-edenite(FE)-induced MPM cases.

METHODS: Immunohistochemical analyses with an anti-SRSF1 antibody were performed. We interpreted the cases as positive if tumor cell nuclei were stained; a semi-quantitative analysis of the cases was performed by evaluating the intensity of staining and the percentage of tumor positive cells. A microvessel density (MVD) count was also performed.

RESULTS: High and low immunoexpressions of SRSF1 were seen in six and four MPMs, respectively. A trend of shorter overall survival was found in FE-induced MPM patients with SRSF1 overexpression. In addition, a significant association between high-MVD and high SRSF1 immunoexpression (p = 0.0476) was found.

CONCLUSIONS: SRSF1 appears to be involved in MPM pathogenesis and its immunoexpression may represent a prognostic biomarker capable of identifying subgroups of patients with different prognosis. However, given the preliminary nature of the present study, further investigations on larger series, and additional in vitro studies, are required to validate our findings.

RevDate: 2021-07-11

Désage AL, Karpathiou G, Peoc'h M, et al (2021)

The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review.

Cancers, 13(13):.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.

RevDate: 2021-07-24
CmpDate: 2021-07-23

Kwak K, Cho SI, D Paek (2021)

Future Incidence of Malignant Mesothelioma in South Korea: Updated Projection to 2038.

International journal of environmental research and public health, 18(12):.

Malignant mesothelioma (MM) is a cancer that is largely caused by exposure to asbestos. Although asbestos is no longer used in South Korea, the incidence of MM continues to increase due to its long latent period. We aimed to update the previous prediction of MM incidence until 2038. We predicted the incidence of MM over the next 20 years (2019-2038) in South Korea using Møller's age-period-cohort (APC) model and a Poisson regression model based on asbestos consumption. The APC model predicted that the crude incidence rate would increase sharply in men and slowly in women. Despite the sex discrepancy in the rate of increase, the incidence rate for both sexes is expected to continue increasing until 2038. In the Poisson model, the crude incidence rate was predicted to increase continuously until 2038, and far more cases of MM were predicted to occur compared with the results of the APC model. When compared with actual incidence data, the APC model was deemed more suitable than the Poisson model. The APC model predicted a continuous increase over the next 20 years with no peak, suggesting that the incidence of MM will continue to rise far into the future.

RevDate: 2021-07-05

Coccè V, La Monica S, Bonelli M, et al (2021)

Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells.

Cells, 10(6):.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM.

METHODS: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice.

RESULTS: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment.

CONCLUSIONS: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.

RevDate: 2021-07-05

Terenziani R, Zoppi S, Fumarola C, et al (2021)

Immunotherapeutic Approaches in Malignant Pleural Mesothelioma.

Cancers, 13(11):.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design.

RevDate: 2021-07-05

Lorenzini E, Ciarrocchi A, F Torricelli (2021)

Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations.

Journal of clinical medicine, 10(11):.

Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.

RevDate: 2021-06-26

Marant Micallef C, Charvat H, Houot MT, et al (2021)

Estimated number of cancers attributable to occupational exposures in France in 2017: an update using a new method for improved estimates.

Journal of exposure science & environmental epidemiology [Epub ahead of print].

BACKGROUND: Over the last 50 years, occupational exposure to carcinogenic agents has been widely regulated in France.

OBJECTIVE: Report population-attributable fraction (PAF) and number of attributable cancer cases linked to occupational exposure in France based on an updated method to estimate lifetime occupational exposure prevalence.

METHODS: Population-level prevalence of lifetime exposure to ten carcinogenic agents (asbestos, benzene, chromium VI, diesel engine exhaust, formaldehyde, nickel compounds, polycyclic aromatic hydrocarbons, silica dust, trichloroethylene, wood dust) and two occupational circumstances (painters and rubber industry workers) were estimated using the French Census linked with MATGÉNÉ job-exposure matrices and French occupational surveys. PAF and number of attributable cancer cases were calculated using the estimated prevalence, relative risks from systematic review and national estimates of cancer incidence in 2017.

RESULTS: The lifetime occupational exposure prevalences were much higher in men than in women ranging from 0.2% (workers in the rubber industry) to 10.2% in men (silica), and from 0.10% (benzene, PAH and workers in the rubber industry) to 5.7% in women (formaldehyde). In total, 4,818 cancer cases (men: 4,223; women: 595) were attributable to the ten studied carcinogens and two occupational circumstances, representing 5.2% of cases among the studied cancer sites (M: 7.0%; W: 1.9%). In both sexes, mesothelioma (M: 689 cases; W: 160) and lung cancer (M: 3,032; W: 308) were the largest cancer sites impacted by the studied occupational agents and circumstances.

SIGNIFICANCE: A moderate proportion of the cancer cases in France is linked to carcinogens in occupational settings. Our method provides more precise estimates of attributable cancer taking into account evolution of exposure to occupational agents by sex, age and time. This methodology can be easily replicated using cross-sectional occupational data to aid priority making and implementation of prevention strategies in the workplace.

RevDate: 2021-06-23

Ke H, Kao S, Lee K, et al (2021)

The minimum standard of care for managing malignant pleural mesothelioma in developing nations within the Asia-Pacific Region.

Asia-Pacific journal of clinical oncology [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is an incurable malignancy associated with high symptom burden and poor prognosis. The relationship between asbestos exposure and MPM incidence is well-established. The incidence rate of MPM in Australia and New Zealand is among the highest globally. Matching the experience of other nations with legal restrictions on asbestos, incidence is expected to fall. In contrast, the incidence of MPM is rising in the developing nations of the Asia-Pacific as consumption and mining (albeit to a lesser extent) of asbestos continues. The incidence of MPM in these nations is currently low or unknown, reflecting insufficient latency periods since industrial use of asbestos, deficient resources for accurate diagnosis, and lack of occupational disease or cancer registries. The landscape of treatment for MPM is rapidly changing with combination immunotherapy now demonstrating improved survival in the first-line setting. Considering vast global inequity in access to anticancer treatments, establishing minimum standard of care for MPM in developing nations is of greater significance. Here, we review the evidence that form the basis of our minimum-standard recommendations for diagnosis, systemic treatment, management of recurrent pleural effusions, and symptom management. We also briefly review evidence-based treatment that may be considered for those with access.

RevDate: 2021-06-25

Kishimoto T, Kojima Y, N Fujimoto (2021)

Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion.

Scientific reports, 11(1):12965.

Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p < 0.0001). The area under the curve (AUC) for SLPI's ability to distinguish BAPE from MPM was 0.902, with a sensitivity of 82.4% and a specificity of 86.5%. This AUC was not only favourable but was better than the AUC for the ability of CYFRA21-1 to distinguish BAPE (0.853). The combination of SLPI and CYFRA21-1 achieved an AUC of 0.965 for the differentiation between BAPE and MPM. Pleural fluid SLPI as well as CYFRA21-1 and HA is useful as a biomarker to diagnose BAPE, which needs to be distinguished from early-stage MPM.

RevDate: 2021-06-14

Ramada Rodilla JM, Calvo Cerrada B, Serra Pujadas C, et al (2021)

Fiber burden and asbestos-related diseases: an umbrella review.

Gaceta sanitaria pii:S0213-9111(21)00082-0 [Epub ahead of print].

OBJECTIVE: What are the levels of asbestos exposure that cause each type of health effect? The objective of this study was to review the available scientific evidence on exposure levels for asbestos and their relationship to health effects.

METHOD: An umbrella review of English-language reviews and meta-analyses, from 1980 to March 2021 was conducted. We included reviews involving quantified asbestos exposures and health outcomes. The review has been adapted to the indications of the PRISMA declaration. Methodological quality of the selected studies was assessed using the AMSTAR instrument.

RESULTS: We retrieved 196 references. After applying the search strategy and quality analysis, 10 reviews were selected for in-depth analysis. For lung cancer, the highest risk was observed with exposure to amphiboles. Longer, thinner fibers had the greatest capacity to cause lung cancer, especially those > 10 μm in length. For mesothelioma, longer and thinner fibers were also more pathogenic; amphiboles ≥ 5 μm are especially associated with increased mesothelioma risk. No studies observed an increased risk for lung cancer or mesothelioma at asbestos exposure levels <0.1 f/ml. No reviews provided information on exposure concentrations for pulmonary fibrosis. Currently, there is limited evidence in humans to establish the causal relationship between gastrointestinal cancer and asbestos exposure.

CONCLUSIONS: Banning all asbestos exposure remains the best measure to preventing its negative health effects. The highest quality reviews and meta-analyses support that there is little risk of lung cancer or mesothelioma at daily exposure levels below 0.1 f/ml.

RevDate: 2021-06-24

Tsim S, Alexander L, Kelly C, et al (2021)

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(21)02189-4 [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.

METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.

RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.

CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

RevDate: 2021-06-20

Vandenhoeck J, van Meerbeeck JP, Fransen E, et al (2021)

DNA Methylation as a Diagnostic Biomarker for Malignant Mesothelioma: A Systematic Review and Meta-Analysis.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(21)02186-9 [Epub ahead of print].

Malignant mesothelioma is an aggressive cancer type linked to asbestos exposure. Because of several intrinsic challenges, mesothelioma is often diagnosed in an advanced disease stage. Therefore, there is a need for diagnostic biomarkers that may contribute to early detection. Recently, the epigenome of tumors is being extensively investigated to identify biomarkers. This manuscript is a systematic review summarizing the state-of-the-art research investigating DNA methylation in mesothelioma. Four literature databases (PubMed, Scopus, Web of Science, MEDLINE) were systematically searched for studies investigating DNA methylation in mesothelioma up to October 16, 2020. A meta-analysis was performed per gene investigated in at least two independent studies. A total of 53 studies investigated DNA methylation of 97 genes in mesothelioma and are described in a qualitative overview. Furthermore, ten studies investigating 13 genes (APC, CDH1, CDKN2A, DAPK, ESR1, MGMT, miR-34b/c, PGR, RARβ, RASSF1, SFRP1, SFRP4, WIF1) were included in the quantitative meta-analysis. In this meta-analysis, the APC gene is significantly hypomethylated in mesothelioma, whereas CDH1, ESR1, miR-34b/c, PGR, RARβ, SFRP1, and WIF1 are significantly hypermethylated in mesothelioma. The three genes that are the most appropriate candidate biomarkers from this meta-analysis are APC, miR-34b/c, and WIF1. Nevertheless, both study number and study objects comprised in this meta-analysis are too low to draw final conclusions on their clinical applications. The elucidation of the genome-wide DNA methylation profile of mesothelioma is desirable in the future, using a standardized genome-wide methylation analysis approach. The most informative CpG sites from this signature could then form the basis of a panel of highly sensitive and specific biomarkers that can be used for the diagnosis of mesothelioma and even for the screening of an at high-risk population of asbestos-exposed individuals.

RevDate: 2021-06-15

Napoli F, Listì A, Zambelli V, et al (2021)

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

Cancers, 13(11):.

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.

RevDate: 2021-06-15

Cugliari G, Allione A, Russo A, et al (2021)

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment.

Cancers, 13(11):.

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.

RevDate: 2021-06-15

Rossi G, Davoli F, Poletti V, et al (2021)

When the Diagnosis of Mesothelioma Challenges Textbooks and Guidelines.

Journal of clinical medicine, 10(11):.

The diagnosis of malignant mesothelioma (MPM) does not pose difficulties when presenting with usual clinico-radiologic features and morphology. Pathology textbooks and national/international guidelines generally describe the findings of classic MPM, underlining common clinical presentation, the gold standard of sampling techniques, usual morphologic variants, immunohistochemical results of several positive and negative primary antibodies in the differential diagnosis, and the role of novel molecular markers. Nevertheless, MPM often does not follow the golden rules in routine practice, while the literature generally does not sufficiently emphasize unusual features of its manifestation. This gap may potentially create problems for patients in sustaining a difficult diagnosis of MPM in clinical practice and during legal disputes. Indeed, the guidelines accidentally tend to favor the job of lawyers and pathologists defending asbestos-producing industries against patients suffering from MPM characterized by uncommon features. The current review is aimed at underlining the wide spectrum of clinical and radiological presentation of MPM, the possibility to consistently use cytology for diagnostic intent, the aberrant immunohistochemical expression using so-called specific negative and positive primary antibodies, and finally proposing some alternative and more unbiased approaches to the diagnosis of MPM.

RevDate: 2021-06-24
CmpDate: 2021-06-24

Lee KM, Godderis L, Furuya S, et al (2021)

Comparison of Asbestos Victim Relief Available Outside of Conventional Occupational Compensation Schemes.

International journal of environmental research and public health, 18(10):.

The asbestos victim relief schemes were introduced to resolve the issue of victims of asbestos-related diseases not receiving compensation through conventional legal orders. This article seeks to derive the differences and commonalities of various asbestos victim relief schemes available outside of the conventional occupational compensation system along with a systematic understanding and to propose plans for improvement through a comparative study. After the degree of asbestos exposure, the population, and the period of implementation were corrected, the recognized claims of the total of conventional occupational compensation schemes and the asbestos victim relief schemes could be ranked in the order of South Korea (KOR) (1867, total), France (FRA) (1571), Japan (JPN) (966), KOR (847, asbestosis grade 2,3 excluded), the United Kingdom (GBR) (670), and the Netherlands (NLD) (95). The average amount of compensation per person, in the case of mesothelioma, was higher in the order of FRA (4.60 times), KOR (1.46 times), GBR (1.03 times), and NLD (0.73 times) of the median income per year. The differences between countries were largely caused by the purpose of institutional design and influenced by the level of qualification, the existence of an expiration date, type of disease, type of benefit, level of judgment criteria, the existence of a procedure for appeals, and recognition rate (GBR: 102%, FRA: 84%, NLD: 81%, JPN: 76%, KOR: 73%, and BEL: 54%). Based on this analysis, suggestions could be made regarding the expansion of disease types, benefit types, and the overall review of judgment criteria.

RevDate: 2021-06-05

Vimercati L, Cavone D, Delfino MC, et al (2021)

Primary Ovarian Mesothelioma: A Case Series with Electron Microscopy Examination and Review of the Literature.

Cancers, 13(9):.

Primary ovarian mesothelioma is a rare, aggressive neoplastic disease with a poor prognosis. At onset, the tumor is only rarely limited to the ovaries and usually already widespread in the peritoneum. The rarity of this entity and the difficulties differentiating it from either ovarian carcinoma or peritoneal mesothelioma may lead to frequent misdiagnoses and may raise some concerns about its histogenesis. Thus, reporting such rare cases is fundamental to gain greater awareness of this neoplasm and try to answer unsolved questions. Herein, we described four cases of histological diagnoses of ovarian mesothelioma extrapolated by the regional mesothelioma register of Apulia (southern Italy). In all cases, a detailed medical history was collected according to national mesothelioma register guidelines. A broad panel of antibodies was used for immunohistochemistry to confirm the diagnoses. Moreover, ovarian tissue samples were also examined by transmission and scanning electron microscopy, detecting asbestos fibers and talc crystals in two cases. Because of the few cases described, we reviewed the English literature in the Medline database, focusing on articles about ovarian mesothelioma "misclassification", "misdiagnosis", "diagnostic challenge" or "diagnostic pitfall" and on unsolved questions about its histogenesis and possible risk factors.

RevDate: 2021-06-05

Anobile DP, Bironzo P, Picca F, et al (2021)

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.

Cancers, 13(10):.

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.

RevDate: 2021-06-08

Ierardi AM, Mathis C, Urban A, et al (2021)

Potential airborne asbestos exposures in dentistry: a comprehensive review and risk assessment.

Critical reviews in toxicology, 51(4):301-327.

Chrysotile was formerly used in the manufacture of casting ring liner (CRL) and periodontal dressing powder (PDP). The purpose of this study was to describe the potential for airborne asbestos exposure among dental professionals who may have used these products and to assess their risk of asbestos-related disease (ARD). Task-specific exposure data associated with CRL and PDP were identified and compared to regulatory standards for asbestos and health-based benchmarks. Personal airborne fiber concentrations ranged from 0.008-3.5 f/cc by PCM (duration: 3-420 minutes) for CRL (tearing, placement), and from <0.0044-<0.297 f/cc by PCM (duration: 5-28 minutes) for PDP (mixing). Eight-hour time-weighted average (TWA) exposures were calculated using the reported task-based airborne fiber concentrations and associated sampling durations. For CRL tasks, the upper-bound calculated 8-hour TWA of 0.022 f/cc (tearing, placement) did not exceed regulatory standards for asbestos (≥0.1 f/cc). All samples collected during the mixing of PDP resulted in non-measurable fiber concentrations. The greatest estimated cumulative asbestos exposure for dental professionals using CRL (tearing, placement) of 0.33 f/cc-years is well below "best estimate", published chrysotile no-observed-adverse-effect-levels (NOAEL) for ARD (lung cancer = 89-168 f/cc-years; pleural mesothelioma = 208-415 f/cc-years). As such, the use of asbestos-containing CRL and/or PDP is not expected to pose an increased risk of ARD among dental professionals. This conclusion is consistent with the lack of an increased risk of ARD reported in epidemiological studies of these occupations.

RevDate: 2021-06-30
CmpDate: 2021-06-30

Haakensen VD, Nowak AK, Ellingsen EB, et al (2021)

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma.

Journal of translational medicine, 19(1):232.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients.

METHODS: NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy.

DISCUSSION: Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1 .

RevDate: 2021-07-06

Scarselli A, Marinaccio A, S Iavicoli (2021)

Ophiolitic outcrops, naturally occurring asbestos exposure and mortality risk from malignant mesothelioma in Calabria (Southern Italy).

Public health, 195:57-60.

OBJECTIVES: Naturally occurring asbestos from ophiolitic outcrops can pose a health risk to the resident population. Some studies have documented this risk of exposure in many areas around the world. The aim of the study is to estimate the possible impact on health caused by asbestos outcrops present in some areas of Calabria, a region of southern Italy.

STUDY DESIGN: The design of the study is observational and uses routinely collected data on employment, compensations and mortality.

METHODS: Data from archives of mortality in the period 2005-2015 were selected. Standardized mortality ratio (SMR) for malignant mesothelioma (MM) by municipalities of residence with reference to the regional population was estimated assuming a Poisson distribution of the data. Administrative archives of companies' employment records and occupational disease compensation data were used to exclude occupational origin cases.

RESULTS: A total of 163 cases of MM were identified. Statistically significant excess risks (P-value <0.05) were observed for several municipalities, some of which were located in areas where asbestos outcrops had previously been identified. Significant SMRs vary between 44.0 and 5.2. The mean age at death in the areas at risk of ophiolitic outcrops ranges from 65.4 to 77.1 years, and the gender ratio (male/female) ranges from 0.66 to 1.3.

CONCLUSIONS: Monitoring of areas most involved in the risk of environmental contamination from ophiolitic outcrops is highly suggested. Full implementation of the local MM surveillance system is strongly encouraged. Further investigations are recommended to specifically identify the cause of exposure and confirm the hypothesis of a causal association with asbestos naturally occurring in these risk areas.

RevDate: 2021-05-28

Thomas A, Karakattu S, Cagle J, et al (2021)

Malignant Pleural Mesothelioma Epidemiology in the United States From 2000 to 2016.

Cureus, 13(4):e14605.

Introduction Pleural mesothelioma constitutes about 80% of all mesotheliomas. The peak incidence of malignant mesothelioma estimated using the cancer registries was in early 1990 to 2000 in the United States. The disease is primarily associated with asbestos exposure. The latency period between asbestos exposure and the development of malignant pleural mesothelioma (MPM) can range anywhere from 15 to 60 years. Asbestos exposure was peaked during the industrial revolution and World War II due to military and shipyard exposures. It is often difficult for the pathologist to distinguish different histological subtypes; due to the disease's rarity and the inadequate tissue sample obtained. There is no available data on the difference in epidemiology of different subtypes of MPM. Surveillance Epidemiology and End Results (SEER), cancer incidence data include population-based registries covering approximately 34.6% of the U.S. population. Here in our study, we analyze malignant pleural mesothelioma epidemiology in the United States, emphasizing different histological subtypes. Methods SEER data from 2000 to 2016 was used in our study. The primary site of cancer is selected as pleura, and malignant behavior only is selected as the filter. Data were analyzed using the SEER stat program. Overall epidemiology of MPM and epidemiology of epithelioid, fibrous, and biphasic histological subtypes were analyzed separately. We used annual percentage change (APC) to evaluate the trend in the epidemiology of MPM. Results summary A total of 11,857 cases of MPM were included in the primary cohort from the SEER 18 registry from 2000 to 2016. The total prevalence of MPM was highest in 2009 and was lowest in 2016. The APC in MPM incidence during this period is -2.0. After removing 5,989 cases with non-specified histology during the same period, the APC for each histological type is -0.7 for fibrous type, 1.8 for epithelioid type, and 2.9 for biphasic type. Out of 17 regional registries included in the study, the greatest statistically significant change in APC was seen in the Hawaiian registry -4.1. In contrast, the lowest statistically significant difference was seen in Seattle (Puget Sound) registry -1.7. The APC in the incidence of MPM among males during the study period was -2.4 while that of females was -0.9. The Iowa registry showed a statistically significant increase in APC of the epithelioid malignant mesothelioma with a statistically insignificant reduction in the overall MPM APC. Conclusion The overall incidence of MPM in the United States is declining, while the data showed an increase in the incidence of epithelioid and biphasic histological subtypes. The authors believe that these conflicting results can be attributed to improved histological diagnosis and improved biopsy techniques.

RevDate: 2021-06-16

Baur X, Frank AL, Soskolne CL, et al (2021)

Malignant mesothelioma: Ongoing controversies about its etiology in females.

American journal of industrial medicine, 64(7):543-550.

Malignant mesothelioma (MM) is one of the most aggressive cancers with the poorest of outcomes. There is no doubt that mesothelioma in males is related to asbestos exposure, but some authors suggest that most of the cases diagnosed in females are "idiopathic." In our assessment of the science, the "low risk" of mesothelioma in females is because of the nonsystematic recording of exposure histories among females. Indeed, asbestos exposure is mentioned in only some of the studies that include females. We estimate the risk of MM among females to be close to that in males. The absence of detailed exposure histories should be rectified in future studies involving ​women. As a matter of social justice, the ongoing failure to recognize asbestos as the cause of a majority of cases of MM in females does them, and their kin, a profound disservice.

RevDate: 2021-06-15

Louw A, Lee YCG, Acott N, et al (2021)

Diagnostic utility of BAP1 for malignant pleural mesothelioma in pleural fluid specimens with atypical morphology.

Cytopathology : official journal of the British Society for Clinical Cytology [Epub ahead of print].

OBJECTIVE: To assess the utility of BRCA1-associated protein 1 (BAP1) immunohistochemistry (IHC) for the diagnosis of malignant pleural mesothelioma (MPM) in fluid samples with atypical cytology.

METHODS: Pleural fluid samples with an atypical mesothelial proliferation (diagnostic categories: 'atypical' and 'suspicious') received between January 2015 and March 2018 at a tertiary referral centre were identified. Results of routine IHC testing were recorded for each case. BAP1 by IHC was performed and a final diagnosis sought from subsequent pathology specimens, medical records, or consensus clinical diagnosis.

RESULTS: Of 50 cases identified, 41 were reported as atypical and 9 as suspicious. Seven (14%) demonstrated loss of BAP1 staining, 40 retained BAP1 staining, 1 had heterogeneous staining, and 2 had insufficient cells for analysis. All seven cases with BAP1 loss were diagnosed with MPM on follow-up. Of those with retained BAP1, 52.5% (21) were subsequently diagnosed with MPM, while 40% (16) had non-MPM diagnoses after a median follow-up of 24 months. Three cases were not further investigated based on patient and clinician decision. The case with heterogeneous staining was diagnosed as mesothelioma by clinical consensus.

CONCLUSIONS: BAP1 IHC loss is highly specific for malignancy and has value as a rule-in test. Even in a tertiary centre with clinical interest in the cytological diagnosis of MPM this investigation was able to increase diagnostic accuracy beyond routine IHC studies. Cytological criteria remain valuable, as retained BAP1 in an atypical or suspicious mesothelial proliferation cannot exclude malignancy.

RevDate: 2021-05-22

Schumann SO, Kocher G, F Minervini (2021)

Epidemiology, diagnosis and treatment of the malignant pleural mesothelioma, a narrative review of literature.

Journal of thoracic disease, 13(4):2510-2523.

The malignant pleural mesothelioma is a very aggressive tumor which is arising from mesothelial cells and is associated with asbestos exposure. It is a heterogeneous cancer that shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic abnormalities. The malignant pleural mesothelioma is characterized by a silent and slow clinical progression with an average period of 20-40 years from the asbestos exposure phase to the start of the symptoms. Unfortunately, to date, the therapeutic options are very limited, especially if the tumor is detected late. This narrative review provides an extended overview of the present evidence in the literature regarding the epidemiology, diagnostic pathways and treatment approaches of the malignant pleural mesothelioma. The treatment of mesothelioma has evolved slowly over the last 20 years not only from a surgical point of view but also radiotherapy, chemotherapy and immunotherapy play nowadays a key role. Several surgical strategies are available ranging from extrapleural pneumonectomy to cytoreductive surgery but a multidisciplinary approach seems to be mandatory because a single approach has not proved to date to be resolutive. New non-surgical treatment options appear to be promising but the results have to be taken in account with caution because clear evidence with high-quality studies is still lacking.

RevDate: 2021-05-19

Cheung M, Kadariya Y, Sementino E, et al (2021)

Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors.

Human molecular genetics pii:6277787 [Epub ahead of print].

There is irrefutable evidence that germline BAP1 mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on 2 MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 20 cancer-related genes in 10 of the 13 probands. Germline indel, splice site, and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ, XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2, SETD1B) or other cellular pathways: LRRK2 (2 cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.

RevDate: 2021-05-31
CmpDate: 2021-05-31

Wilk E, M Krówczyńska (2021)

Malignant mesothelioma and asbestos exposure in Europe: Evidence of spatial clustering.

Geospatial health, 16(1):.

Exposure to asbestos causes a wide range of diseases, such as asbestosis, malignant mesothelioma (MM) and other types of cancer. Many European countries have reduced production and use of asbestos and some have banned it altogether. Based on data derived from the World Health Organisation (WHO) Cancer Mortality Database, we investigated whether some regions in Europe could have a higher relative risk of MM incidence than others. The data were compared, including the number of MM deaths per million inhabitants and aged-standardized mortality rates. Applying Moran's I and Getis-Ord Gi statistic on the agedstandardized mortality rates of MM cases assisted the spatial analysis of the occurrence of health events leading to an assessment of the heterogeneity of distribution and cluster detection of MM. We found a statistically significant positive autocorrelation for the male population and also the general population, while there was no statistically significant positive one for the female population. Hotspots of relative risk of developing MM were found in northwestern Europe. For the general population, Great Britain and the Netherlands stood out with high levels at the 99% and 95% confidence levels, respectively. For the male population, the results were similar, but with addition of risk also in Belgium and Switzerland. However, in many European countries with high asbestos use per capita, the MM incidence was found to still be low. The reasons for this are not yet clear, but part of the problem is certainly due to incomplete data in registers and databases. The latency time can be longer than 40 years and is related to the intensity and time of exposure (occupational, para-occupational and environmental). In Europe, even though peak production occurred in the 1960s and 1970s, a significant decrease in production did not occur until 25 years later, which means that the impact will continue for as late as The mid 2030s.

RevDate: 2021-05-17

Tanrıverdi Z, Meteroglu F, Yüce H, et al (2021)

The usefulness of biomarkers in diagnosis of asbestos-induced malignant pleural mesothelioma.

Human & experimental toxicology [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a malignant tumor that is associated mostly with asbestos exposure. The present study was to evaluates the diagnostic value of neopterin, periostin, YKL-40, Tenascin-C (TNC), and Indolamine 2,3-dioxygenase (IDO) as noninvasive markers of malign pleural mesothelioma.

METHODS: Included in the study were 30 patients diagnosed with malign pleural mesothelioma, and 25 people as a control group. Biomarker levels were determined using an enzyme immunoassay . A Mann-Whitney U test and Spearman correlation methods were used for the statistical analysis.

RESULTS: All evaluated biomarkers were found to be significantly higher in the MPM group than in the control group (p < 0.05). There was no effect of such variables as gender, age or MPMsubtype on the parameters (p > 0.05) in the patient group. All biomarkers were positively correlated with each other (p < 0.001).

CONCLUSIONS: The current non-invasive biomarkers that can be used in the diagnosis of MPM yielded significant results and can make important contributions to the early diagnosis of MPM.

RevDate: 2021-05-10

Zhou N, Rice DC, Tsao AS, et al (2021)

Extrapleural Pneumonectomy versus Pleurectomy/Decortication for Malignant Pleural Mesothelioma.

The Annals of thoracic surgery pii:S0003-4975(21)00846-8 [Epub ahead of print].

BACKGROUND: Whether extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D) is the optimal resection for malignant pleural mesothelioma (MPM) remains controversial. We therefore compared perioperative outcomes and long-term survival of patients who underwent EPP vs P/D.

METHODS: Patients with the diagnosis of MPM who underwent either EPP or P/D from 2000 to 2019 were identified from our departmental database. Propensity score matching was performed to minimize potential confounders for EPP or P/D. Survival analysis was performed by the Kaplan-Meier method and Cox multivariable analysis.

RESULTS: Of 282 patients, 187 (66%) underwent EPP and 95 (34%) P/D. Even with propensity score matching, perioperative mortality was significantly higher for EPP than for P/D (11% vs. 0%; P=0.031), when adjusted for perioperative mortality, median overall survival between EPP and P/D was 15 vs. 22 months, respectively (P=0.276). Cox multivariable analysis for the matched cohort identified epithelioid histology (hazard ratio [HR], 0.56; P=0.029), macroscopic complete resection (HR, 0.41; P=0.004), adjuvant radiation therapy (HR, 0.57; P=0.019), and more recent operative years (HR, 0.93; P=0.011)-but not P/D-to be associated with better survival. Asbestos exposure (HR, 2.35; P=0.003) and pathological nodal disease (HR, 1.61; P=0.048) were associated with worse survival.

CONCLUSIONS: In a multimodality treatment setting, P/D and EPP had comparable long-term oncological outcomes, although P/D had much lower perioperative mortality. The goal of surgical cytoreduction should be macroscopic complete resection achieved by the safest operation a patient can tolerate.

RevDate: 2021-05-08

Arrieta O, Muñoz-Montaño W, Muñiz-Hernández S, et al (2021)

Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma.

Frontiers in oncology, 11:641975.

Background: Malignant pleural mesothelioma (MPM) is rare and aggressive neoplasia, with a poor prognosis; furthermore, the monetary cost of its treatment represents a major challenge for many patients. The economic burden this malignancy imposes is underscored by the fact that asbestos exposure, which is the most frequent risk factor, is much more prevalent in the lower socioeconomic population of developing countries. The aims of the present study were to evaluate the efficacy, safety, and cost of continuous infusion of low-dose Gemcitabine plus Cisplatin (CIGC) as a treatment strategy for patients with unresectable MPM.

Methods: We performed a prospective cohort study to determine efficacy and safety of continuous infusion gemcitabine at a dose of 250 mg/m2 in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle in patients with unresectable MPM. We also performed a cost-minimization analysis to determine if this chemotherapy regimen is less expensive than other currently used regimens.

Results: The median number of chemotherapy cycles was six (range 1-11 cycles); objective response rate was documented in 46.2%, and disease control rate was seen in 81.2%. Median PFS was 8.05 months (CI 95% 6.97-9.13); median OS was 16.16 months (CI 95% 12.5-19.9). The cost minimization analysis revealed savings of 66.4, 61.9, and 97.7% comparing CIGC with short-infusion gemcitabine plus cisplatin (SIGC), cisplatin plus pemetrexed (CP), and cisplatin plus pemetrexed and bevacizumab (CPB), respectively. Furthermore, this chemotherapy regimen proved to be safe at the administered dosage.

Conclusion: CIGC is an effective and safe treatment option for patients with unresectable MPM; besides, this combination is a cost-saving option when compared with other frequently used chemotherapy schemes. Therefore, this treatment scheme should be strongly considered for patients with unresectable MPM and limited economic resources.

RevDate: 2021-05-09

Gray SG (2021)

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma.

BMC pulmonary medicine, 21(1):148.

BACKGROUND: The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer.

MAIN TEXT: While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer.

CONCLUSIONS: The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.

RevDate: 2021-05-04

Aigner C, Brüning T, Eberhardt WEE, et al (2021)

[The Current Therapy of Asbestos-Associated Malignant Pleural Mesothelioma - An Expert Consensus Paper].

Pneumologie (Stuttgart, Germany) [Epub ahead of print].

Asbestos-related mesotheliomas belong to the group of the most frequent occupational diseases in Germany, reaching about 1,000 new cases per year. The disease has a dismal prognosis because most tumors remain asymptomatic for a long time and therefore are diagnosed as incidental findings at later stages.During the last decade the German Social Accident Insurance (DGUV) has made considerable efforts to prepone the diagnosis in order to detect the disease at earliest possible stages. These efforts resulted in new findings showing that, in a high-risk group, a combination of the biomarkers calretinin and mesothelin was able to advance the diagnosis up to 12 months.Ideally, the diagnosis of a mesothelioma at an early stage has to be accompanied by the best possible individualized therapy. Standard therapeutic strategies are surgery and chemotherapy, added by radiotherapy and psycho-oncology. In recent years, several new therapeutic avenues are being explored. This review comprehensively presents both old and new therapeutic options in mesothelioma, based on international Leitlinien and new studies.

RevDate: 2021-06-21

Ejegi-Memeh S, Robertson S, Taylor B, et al (2021)

Gender and the experiences of living with mesothelioma: A thematic analysis.

European journal of oncology nursing : the official journal of European Oncology Nursing Society, 52:101966.

PURPOSE: Mesothelioma is a terminal cancer caused by exposure to asbestos. As a cancer with a higher rate in men than women, women's experiences of living with mesothelioma are often underexplored. Furthermore, men's experiences are often taken for granted and therefore have remained underexplored. This paper considers men's and women's experiences across the mesothelioma pathway.

METHODS: This qualitative study incorporated semi-structured interviews with 13 men and 11 women living with mesothelioma. Telephone interviews took place between July and December 2019, and were audio recorded, transcribed and anonymised. Thematic analysis was used to analyse the data.

RESULTS: Three themes were developed in relation to the gendered experience of mesothelioma: familial responsibility and social perceptions; support preferences; and treatment and trials. Analysis suggests that men and women's sense of familial responsibility varied. Differences in priorities and motivations influenced approaches to seeking support, compensation and, making decisions around treatments and clinical trials.

CONCLUSIONS: The current study reports on how gender can influence the experience of living with mesothelioma. The findings indicate how the patients' role in their families and society can more broadly influence their experiences, choices and preferences. Nurses caring for mesothelioma patients need high quality research on which to base their practice. Recognition and an understanding of the underlyingfactors influencing patients' decision-making will enable nurses and other professionals to support their patients better.

RevDate: 2021-06-09

Davis AP, Kao SC, Clarke SJ, et al (2021)

Emerging biological therapies for the treatment of malignant pleural mesothelioma.

Expert opinion on emerging drugs, 26(2):179-192.

Introduction: Malignant pleural mesothelioma (MPM) has limited treatment options with minimal new therapy approvals for unresectable disease in the past 15 years. However, considerable work has occurred to develop immunotherapies and biomarker driven therapy to improve patient outcomes over this period.Areas covered: This review examines current standard of care systemic therapy in the first- and second line setting. The last 12 months has seen 2 significant trials (Checkmate 743 and CONFIRM) which provide evidence supporting the role of immunotherapy in the management of MPM. Further trials are underway to assess the role of combination chemoimmunotherapy and personalized therapy. Additionally, a large number of clinical trials are ongoing to assess the efficacy of oncoviral, dendritic cell, anti-mesothelin and chimeric antigen receptor T cell therapy in the treatment of MPM.Expert opinion: Recent Phase III trial results have established a role for immunotherapy in the management of MPM. The optimal sequencing and combination of chemotherapy and immunotherapy remains to be determined. Novel therapies for MPM are promising however efficacy remains to be determined and issues remain regarding access to and delivery of these therapies.

RevDate: 2021-05-02

Muralidhar V (2021)

An unusual presentation of acute abdomen: infarcted peritoneal cyst-a probable asbestos-related benign cystic mesothelioma.

Journal of surgical case reports, 2021(4):rjab129.

This is a report of a rare case of an infarcted pelvic intra-abdominal cyst, having no mesenteric connection presenting as an acute abdomen. The patient had significant asbestos exposure. The cyst was treated successfully by surgical excision. Histopathology showed an infarcted cyst; the lining was destroyed, precluding marker studies. A diagnosis of benign cystic peritoneal mesothelioma (BCPM) was made by excluding other causes of solitary pelvic intra-abdominal cysts. BCPM has been classified as an asbestos-related neoplasm and is usually seen in the pelvis adjunct to the urinary bladder. One-year post-surgery, there was no recurrence. The case report shows that infarcted pelvic mesothelial cysts can present as an acute abdomen and can be treated successfully by total excision with no recurrence.

RevDate: 2021-05-02

Brcic L, Mathilakathu A, Walter RFH, et al (2021)

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

Cancers, 13(8):.

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.

RevDate: 2021-04-30
CmpDate: 2021-04-30

Li N, Wang D, Chen ZJ, et al (2021)

[Asbestos-induced malignant peritoneal mesothelioma complicated with lung cancer:a case report].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 39(4):305-307.

Asbestos is harmful to human, and populations with occupational and environmental exposure to respirable asbestos fibers have higher risk of cancers like malignant mesothelioma and lung cancer. At present, patient with asbestos-induced malignant peritoneal mesothelioma and lung cancer is rare. In this study, we analyzed the clinical data of a case of asbestos-induced malignant peritoneal mesothelioma complicated with lung cancer to investigate the diagnosis and treatment of this disease.

RevDate: 2021-05-05
CmpDate: 2021-05-05

Ouafki I, Nouiakh L, Boujarnija R, et al (2021)

[Malignant mesothelioma of the ovary: a case report].

The Pan African medical journal, 38:92.

Primary malignant mesothelioma of the ovary (PMMO) is an extremely rare tumor which can develop from mesothelial cells. This neoplasia is caused predominantly by exposure to asbestos or other cancer-causing agents. Preoperative assessment, based on computed tomography (CT) scan, magnetic resonance imaging and positron emission tomography, is essential for cancer staging. Anatomopathological diagnosis is based on immunohistochemical findings. PMMO is an exceptional disease involving a multidisciplinary therapeutic strategy including the use of chemotherapy which improves the management and prognosis of patients. This study reports the case of a female patient undergoing suboptimal surgery complemented by adjuvant chemotherapy with complete radiological response and 1-year disease-free survival.

RevDate: 2021-04-23
CmpDate: 2021-04-23

Kumagai-Takei N, Nishimura Y, Matsuzaki H, et al (2021)

Effect of IL-15 addition on asbestos-induced suppression of human cytotoxic T lymphocyte induction.

Environmental health and preventive medicine, 26(1):50.

BACKGROUND: Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8+ T cells. Recently, we reported that asbestos-induced suppression of CTL induction is not due to insufficient levels of interleukin-2 (IL-2). In this study, we continue to investigate the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs and focus on interleukin-15 (IL-15) which is known to be a regulator of T lymphocyte proliferation.

METHODS: For MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 μg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8+ T cells with fluorescence-labeled anti-CD3, anti-CD8, anti-CD45RA, anti-CD45RO, anti-CD25, and anti-granzyme B antibodies using flow cytometry. To examine the effect of IL-15 on the expression level of intracellular granzyme B in proliferating and non-proliferating CD8+ lymphocytes, PBMCs were stained using carboxyfluorescein diacetate succinimidyl ester (CFSE) and then washed and used for the MLR.

RESULTS: IL-15 addition partially reversed the decrease in CD3+CD8+ cell numbers and facilitated complete recovery of granzyme B+ cell percentages. IL-15 completely reversed the asbestos-induced decrease in percentage of granzyme B+ cells in both non-proliferating CFSE-positive and proliferating CFSE-negative CD8+ cells. The asbestos-induced decrease in the percentage of CD25+ and CD45RO+ cells in CD8+ lymphocytes was not reversed by IL-15.

CONCLUSION: These findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.

RevDate: 2021-06-10

Ezeka G, Adhikary G, Kandasamy S, et al (2021)

Sulforaphane inhibits PRMT5 and MEP50 function to suppress the mesothelioma cancer cell phenotype.

Molecular carcinogenesis, 60(7):429-439.

Mesothelioma is a highly aggressive cancer of the mesothelial lining that is caused by exposure to asbestos. Surgical resection followed by chemotherapy is the current treatment strategy, but this is marginally successful and leads to drug-resistant disease. We are interested in factors that maintain the aggressive mesothelioma cancer phenotype as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions in concert with the methylosome protein 50 (MEP50) cofactor to catalyze symmetric dimethylation of key arginine resides in histones 3 and 4 which modifies the chromatin environment to alter tumor suppressor and oncogene expression and enhance cancer cell survival. Our studies show that PRMT5 or MEP50 loss reduces H4R3me2s formation and that this is associated with reduced cancer cell spheroid formation, invasion, and migration. Treatment with sulforaphane (SFN), a diet-derived anticancer agent, reduces PRMT5/MEP50 level and H4R3me2s formation and suppresses the cancer phenotype. We further show that SFN treatment reduces PRMT5 and MEP50 levels and that this reduction is required for SFN suppression of the cancer phenotype. SFN treatment also reduces tumor formation which is associated with reduced PRMT5/MEP50 expression and activity. These findings suggest that SFN may be a useful mesothelioma treatment agent that operates, at least in part, via suppression of PRMT5/MEP50 function.

RevDate: 2021-06-14

DeBono NL, Warden H, Logar-Henderson C, et al (2021)

Incidence of mesothelioma and asbestosis by occupation in a diverse workforce.

American journal of industrial medicine, 64(6):476-487.

OBJECTIVE: We sought to characterize detailed patterns of mesothelioma and asbestosis incidence in the workforce as part of an occupational disease surveillance program in Ontario, Canada.

METHODS: The Occupational Disease Surveillance System (ODSS) cohort was established using workers' compensation claims data and includes 2.18 million workers employed from 1983 to 2014. Workers were followed for mesothelioma and asbestosis diagnoses in Ontario Cancer Registry, physician, hospital, and ambulatory care records through 2016. Trends in incidence rates were estimated over the study period. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: A total of 854 mesothelioma and 737 asbestosis cases were diagnosed during follow-up. Compared with all other workers in the ODSS, those employed in construction trades occupations had the greatest adjusted incidence rate of both mesothelioma (223 cases; HR, 2.38; 95% CI: 2.03-2.78) and asbestosis (261 cases; HR, 3.64; 95% CI: 3.11-4.25). Rates were particularly elevated for insulators, pipefitters and plumbers, and carpenters. Workers in welding and flame cutting, boiler making, and mechanic and machinery repair occupations, as well as those in industrial chemical and primary metal manufacturing industries, had strongly elevated rates of both diseases. Rates were greater than anticipated for workers in electrical utility occupations and education and related services.

CONCLUSIONS: Results substantiate the risk of mesothelioma and asbestosis in occupation and industry groups in the Ontario workforce with known or suspected asbestos exposure. Sustained efforts to prevent the occurrence of additional cases of disease in high-risk groups are warranted.

RevDate: 2021-04-06

Mizuhashi K, Okamoto K, T Kishimoto (2021)

A patient with epithelioid pleural mesothelioma (Myxoid variant) who survived for a long period without treatment.

Respiratory medicine case reports, 33:101381.

Pleural mesothelioma is a disease with a very poor prognosis. Here, we report a mesothelioma patient who survived for 5 years and a half. As a result of the autopsy, the tumor was diagnosed as a myxoid variant, which is internationally proposed as a histological subtype of epithelioid mesothelioma with a relatively favorable prognosis. Since patients with this disease are expected to survive for a long period even without treatment, careful determination of the therapeutic approach is considered necessary. This report is considered to be the first of a myxoid variant epithelioid pleural mesothelioma in Japan.

RevDate: 2021-04-08

Barbarino M, A Giordano (2021)

Assessment of the Carcinogenicity of Carbon Nanotubes in the Respiratory System.

Cancers, 13(6):.

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.

RevDate: 2021-07-13

Lettieri S, Bortolotto C, Agustoni F, et al (2021)

The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma.

Journal of clinical medicine, 10(5):.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural lining of the lungs. It has a strong association with exposure to biopersistent fibers, mainly asbestos (80% of cases) and-in specific geographic regions-erionite, zeolites, ophiolites, and fluoro-edenite. Individuals with a chronic exposure to asbestos generally have a long latency with no or few symptoms. Then, when patients do become symptomatic, they present with advanced disease and a worse overall survival (about 13/15 months). The fibers from industrial production not only pose a substantial risk to workers, but also to their relatives and to the surrounding community. Modern targeted therapies that have shown benefit in other human tumors have thus far failed in MPM. Overall, MPM has been listed as orphan disease by the European Union. However, molecular high-throughput profiling is currently unveiling novel biomarkers and actionable targets. We here discuss the natural evolution, mainly focusing on the novel concept of molecular epidemiology. The application of innovative endpoints, quantification of genetic damages, and definition of genetic susceptibility are reviewed, with the ultimate goal to point out new tools for screening of exposed subject and for designing more efficient diagnostic and therapeutic strategies.

RevDate: 2021-04-08

Schiavello M, Gazzano E, Bergandi L, et al (2021)

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

Cancers, 13(5):.

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.

RevDate: 2021-04-01

Fujihira H, Takakura D, Matsuda A, et al (2021)

Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells.

Journal of biochemistry pii:6207972 [Epub ahead of print].

Mesothelioma is a highly aggressive tumor associated with asbestos exposure and is histologically classified into three types: epithelioid-type, sarcomatoid-type, and biphasic-type. The prognosis of mesothelioma patients is poor and there is no effective molecular-targeting therapy as yet. ERC/mesothelin is a glycoprotein that is highly expressed on several types of cancers including epithelioid mesothelioma, but also expressed on normal mesothelial cells. This is a predicted reason why there is no clinically approved therapeutic antibody targeting ERC/mesothelin. In the present study, we focused on the differential glycosylation between ERC/mesothelin present on epithelioid mesothelioma and that on normal mesothelial cells and aimed to reveal a distinct feature of epithelioid mesothelioma cells. Lectin microarray analysis of ERC/mesothelin using cells and patient specimens showed significantly stronger binding of PHA-E4 lectin, which recognizes complex-type N-glycans having a so-called bisecting-GlcNAc structure, to ERC/mesothelin from epithelioid mesothelioma cells than that from normal mesothelial cells. Further, LC/MS analysis on ERC/mesothelin from epithelioid mesothelioma cells confirmed the presence of a bisecting-GlcNAc attached to Asn388 of ERC/mesothelin. These results suggest that this glycoproteome could serve as a potential target for the generation of a highly selective and safe therapeutic antibody for epithelioid mesothelioma.

RevDate: 2021-04-02
CmpDate: 2021-03-31

Huang XY, Q Ye (2021)

[Asbestos exposure and asbestos-related malignant diseases:an epidemiological review].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 39(3):233-236.

Asbestos has high fire resistance, electrical insulation and thermal insulation. It is an important fire prevention, insulation and insulation material. It is widely used in industrial production and daily life. In 1987, the international agency for research on cancer (IARC) has listed asbestos as a class I carcinogen; in 2012, IARC confirmed that all types of asbestos have carcinogenic effect. By 2019, asbestos has been banned in 66 countries and regions around the world. Asbestos exposure increases the risk of human malignant tumor. Lung cancer and mesothelioma are known asbestos induced tumors. Epidemiological studies also support that asbestos exposure is related to the incidence of malignant tumors in reproductive system, digestive system, urinary system, nasopharynx head and neck. We summarized the epidemiological studies of asbestos induced tumors in order to provide reference for further research.

RevDate: 2021-03-30

Gill RR, Murphy DJ, Seethamraju RT, et al (2020)

Interobserver Variability of Quantitative and Qualitative Assessment Using MRI in Malignant Pleural Mesothelioma.

Radiology. Cardiothoracic imaging, 2(2):e190066.

Purpose: To evaluate the interobserver variability associated with quantitative and qualitative MRI assessments of malignant pleural mesothelioma (MPM).

Materials and Methods: Patients with MPM who underwent uniform-protocol preoperative MRI between 2009 and 2014 were included. The MRI-derived tumor volume was estimated. Unidimensional measurements of maximal pleural thickness (P max) and average pleural thickness (P avg) on axial MR images; maximal fissural thickness (F max); maximal diaphragmatic thickness (D max); and average diaphragmatic thickness (D avg) on sagittal reconstructed images were acquired. Interobserver agreement regarding the American Joint Committee on Cancer (AJCC) tumor stage at each criterion level was assessed by using Cohen κ statistics. Agreement between quantitative measurements was assessed by using Bland-Altman plots and intraclass correlation coefficients (ICCs).

Results: The study cohort included 349 patients (median age, 68 years [age range, 30-90 years), 273 (78%) of whom were men and 203 (58%) of whom had epithelioid-subtype tumors. Qualitative assessment performed by using the AJCC staging criteria (eighth edition) was concordant in 31% of cases and yielded considerable disagreement (κ = 0.177). Inspection of the Bland-Altman plots led to decisive agreement between the two reviewers regarding MRI-derived tumor volume (ICC, 0.979). There was also a good degree of agreement between the two reviewers regarding unidimensional measurements of D max (ICC, 0.807), D avg (ICC, 0.823), P max (ICC, 0.787), P avg (ICC, 0.787), and F max (ICC, 0.659).

Conclusion: Quantitative assessment can enhance the clinical staging of MPM. Compared with qualitative assessment, quantitative assessment has low interobserver variability and could yield a tumor size criterion that is currently lacking in the AJCC clinical staging of MPM.Supplemental material is available for this article.© RSNA, 2020.

RevDate: 2021-05-17

Klebe S, Nakatani Y, Dobra K, et al (2021)

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Pathology, 53(4):446-453.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.

RevDate: 2021-05-21

Reid G, Klebe S, van Zandwijk N, et al (2021)

Asbestos and Zeolites: from A to Z via a Common Ion.

Chemical research in toxicology, 34(4):936-951.

Asbestos and zeolites are silicate-based minerals, linked inextricably via paradoxical similarities and differences which have emanated from different geological epochs. Both have been employed in the service of humanity through millennia: asbestos, for its "inextinguishable" quality of being an insulator against heat and fire; zeolite, a "boiling stone" with its volcanic and marine sedimentary rock origins, for its propensity to adsorb water and remove metals and toxins. Serious adverse health effects observed in asbestos miners as long ago as the 1st Century AD did not halt the rising popularity of asbestos. As the miracle material of the 1900s, asbestos production and consumption exploded, culminating in its ubiquity in ships, vehicles, homes, commercial buildings, and over 3000 different industrial and household products. Through the 1940s and 1950s, epidemiological studies concluded that asbestos was a likely cause of asbestosis, lung cancer, and malignant mesothelioma, and it is now banned in many but far from all countries. The long latency between exposure to asbestos and the occurrence of cancer has obscured the deadly consequences of asbestos exposure for centuries. Even today, a considerable part of the world population is insufficiently aware of the dangers of asbestos, and millions of tons of this carcinogen continue to be mined and used worldwide. Zeolites, both natural and synthetic, are microporous aluminosilicate minerals commonly used in a myriad of processes, in the petrochemical industry, in domestic appliances and cleaning agents, as commercial adsorbents and exchangers for toxins and pollutants, and as catalysts. Zeolites are found in agriculture, veterinary science, and human health. More recently, new materials such as carbon nanotubes are being employed in materials requiring durability and thermal and electrical conductivity, yet nanotubes are now joining the ranks of more established particulates such as asbestos and silica, in causing human disease. In this review, we compare and contrast the similarities and differences of these two groups of silicate minerals and their waxing and waning use in the employ of humanity.

RevDate: 2021-08-03
CmpDate: 2021-04-05

Zhang M, Luo JL, Sun Q, et al (2021)

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Nature communications, 12(1):1751.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.

RevDate: 2021-07-23

Schiopu SRI, Käsmann L, Schönermarck U, et al (2021)

Pembrolizumab-induced myocarditis in a patient with malignant mesothelioma: plasma exchange as a successful emerging therapy-case report.

Translational lung cancer research, 10(2):1039-1046.

Malignant mesothelioma is an aggressive cancer associated with prior exposure to asbestos and dismal prognosis. Immune checkpoint inhibitor therapy is currently approved by the Food and Drug Administration for pre-treated malignant pleural mesothelioma. We describe a 75-year-old patient with disseminated, progressive malignant mesothelioma receiving 2 cycles of pembrolizumab who presented with generalized muscle weakness, shortness of breath, double vision and ptosis. There was no previous history of cardiovascular disease. The clinical picture, supported by the detection of anti-titin autoantibodies suggested myasthenia gravis (MG). Also, cardiac biomarkers were elevated. Echocardiography showed new severely reduced ejection fraction. A 12-lead resting electrocardiogram (ECG) revealed ST segment elevation in the posterior leads with polymorphic ventricular extrasystoles. Because cardiac catheterization revealed no relevant coronary lesions, immune checkpoint inhibitor-associated myocarditis and MG were suspected. Management and Outcome: The patient was started on steroids. Within a few days of presentation respiratory failure set in and the patient was intubated. Recurrent arrhythmias followed, which were treated by repeated emergency electrical cardioversion. In order to relieve myasthenic symptoms, plasma exchange was initiated and 10 cycles were carried out. This consequently also led to an improvement of myocarditis. Upon discharge, the ejection fraction recovered. The patient recovered and was alive at 1-year follow-up, without relevant limitations to his quality of life. Discussion and Conclusion: The article further discusses the use of plasma exchange for immune checkpoint inhibitor-associated myocarditis based on a review of literature. We conclude that patients showing no improvement after steroid therapy for immune checkpoint inhibitor-related myocarditis should be evaluated for plasma exchange, which appears to be an effective treatment option.

RevDate: 2021-04-05

Sun S, Frontini F, Qi W, et al (2021)

Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development.

Cancer letters, 507:26-38.

Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV ("MesoERV1-12") were identified and verified by qPCR in mouse tissues. "MesoERV1-12" expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. "MesoERV1-12" levels were significantly increased by demethylating agent 5-Aza-2'-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. "MesoERV7" promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy.

RevDate: 2021-03-11

Shamseddin M, Obacz J, Garnett MJ, et al (2021)

Use of preclinical models for malignant pleural mesothelioma.

Thorax pii:thoraxjnl-2020-216602 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12-18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.

RevDate: 2021-03-15
CmpDate: 2021-03-12

Yu M, Yu M, Zhu LJ, et al (2021)

[Expression and clinical significance of SETD2 in maligant pleural mesothelioma].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 39(2):91-98.

Objective: To analyze the gene mutation profile in malignant pleural mesothelioma (MPM) and investigate the expression of high-frequency mutant genes and its relationship with clinicopathological parameters. To screen out key genes and clinicopathologic factors related to the prognosis of MPM patients. Methods: The second generation sequencing data, somatic mutation data and clinical pathological data of 86 MPM cases and gene chip expression data of 89 MPM cases were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) in March 2020. Summarize the gene mutation profile of tissue samples in the TCGA database and analyze the relationship between the expression level of high-frequency mutation genes and the clinicopathological characteristics, asbestos exposure history and prognosis of MPM patients. The genes significantly related to MPM prognosis were screened out for gene set enrichment analysis (GSEA) . Survival analysis and GSEA were performed for the selected key genes and clinicopathological features verification using the microarray expression data from the GEO database. Results: The top 10 genes with highest single nucleotide variations frequencies were BAP1, NF2, TP53, TTN, SETD2, LATS2, CCDC168, FAT4, PTCH1 and ZNF469. The high expression rates of NF2, TP53, SETD2 and CCDC168 genes in wild type were higher than those of mutated type, and the differences were statistically significant (P<0.05) . Cox multivariate analysis of TCGA data showed that MPM patients with epithelial type (HR=0.425, 95%CI: 0.235-0.767, P<0.01) and SETD2 low expression (HR=0.516, 95%CI: 0.307-0.868, P=0.011) had lower risk of death. The survival analysis of GEO data verified that patients with epithelial type MPM had longer survival time, while patients with sarcoma type MPM had shortest survival time (P<0.01) . GSEA showed that SETD2 was involved in G2M checkpoint, E2F targets, MYC signaling pathways, protein secretion, mitotic spindle, MTORC1 pathway, TGF-β pathway, androgen response and uv response. Conclusion: MPM is accompanied with higher frequency of gene mutations represented by BAP1, NF2, TP53, TTN, SETD2, LATS2 and so on. SETD2 expression level and epithelia type of MPM may be influential factors for MPM prognosis.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

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Curriculum Vitae for R J Robbins

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