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Bibliography on: Mesothelioma and Asbestos

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 22 May 2022 at 01:50 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®)

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RevDate: 2022-05-19

Williams M, Cheng YY, Phimmachanh M, et al (2019)

Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways.

Cancer drug resistance (Alhambra, Calif.), 2(4):1193-1206.

Aim: Aberrant microRNA expression is a common event in cancer drug resistance, however its involvement in malignant pleural mesothelioma (MPM) drug resistance is largely unexplored. We aimed to investigate the contribution of microRNAs to the resistance to drugs commonly used in the treatment of MPM. Methods: Drug resistant MPM cell lines were generated by treatment with cisplatin, gemcitabine or vinorelbine. Expression of microRNAs was quantified using RT-qPCR. Apoptosis and drug sensitivity assays were carried out following transfection with microRNA mimics or BCL2 siRNAs combined with drugs. Results: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only. Similarly, in parental cell lines, miR-15a or miR-16 mimics sensitised cells to all drugs, whereas miR-34a increased response to cisplatin and vinorelbine. Increased microRNA expression increased drug-induced apoptosis and caused BCL2 mRNA and protein reduction. RNAi-mediated knockdown of BCL2 partly recapitulated the increase in drug sensitivity in cisplatin and vinorelbine treated cells. Conclusion: Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs. Increasing tumour suppressor of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents, in part through targeting of BCL2. Taken together, these data suggest that miR-15a, miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells.

RevDate: 2022-05-18

Mielgo-Rubio X, Cardeña Gutiérrez A, Sotelo Peña V, et al (2022)

Tsunami of immunotherapy reaches mesothelioma.

World journal of clinical oncology, 13(4):267-275.

Malignant pleural mesothelioma (MPM) is the most common type of malignant mesothelioma. It is a rare tumor linked to asbestos exposure and is associated with a poor prognosis. Until very recently, patients with advanced or unresectable disease had limited treatment options, primarily based on doublet chemotherapy with cisplatin and pemetrexed. In 2020 and 2021, after more than a decade with no major advances or new drugs, two phase III clinical trials published results positioning immunotherapy as a promising option for the first- and second-line treatment of MPM. Immunotherapy has revolutionized the treatment of many cancers and is also showing encouraging results in malignant mesothelioma. Both immune checkpoint inhibition and dual cytotoxic T-lymphocyte-associated antigen 4 and programmed death-ligand 1 pathway blockade resulted in significantly improved overall survival in randomized phase III trials. In the CheckMate 743 trial, first-line therapy with nivolumab plus ipilimumab outperformed standard chemotherapy, while in the CONFIRM trial, nivolumab outperformed placebo in patients previously treated with chemotherapy. These two trials represent a major milestone in the treatment of MPM and are set to position immunotherapy as a viable alternative for treatment-naïve patients and patients with progressive disease after chemotherapy.

RevDate: 2022-05-14

Nagamatsu Y, Sakyo Y, Barroga E, et al (2022)

Bereaved Family Members' Perspectives of Good Death and Quality of End-of-Life Care for Malignant Pleural Mesothelioma Patients: A Cross-Sectional Study.

Journal of clinical medicine, 11(9): pii:jcm11092541.

OBJECTIVE: This study investigated whether malignant pleural mesothelioma (MPM) patients achieved good deaths and good quality of end-of-life care compared with other cancer patients from the perspective of bereaved family members in Japan.

METHODS: This cross-sectional study was part of a larger study on the achievement of good deaths of MPM patients and the bereavement of their family members. Bereaved family members of MPM patients in Japan (n = 72) were surveyed. The Good Death Inventory (GDI) was used to assess the achievement of good death. The short version of the Care Evaluation Scale (CES) version 2 was used to assess the quality of end-of-life care. The GDI and CES scores of MPM patients were compared with those of a Japanese cancer population from a previous study.

RESULTS: MPM patients failed to achieve good deaths. Only 12.5% of the MPM patients were free from physical pain. The GDI scores of most of the MPM patients were significantly lower than those of the Japanese cancer population. The CES scores indicated a significantly poorer quality of end-of-life care for the MPM patients than the Japanese cancer population. The total GDI and CES scores were correlated (r = 0.55).

CONCLUSIONS: The quality of end-of-life care for MPM patients remains poor. Moreover, MPM patients do not achieve good deaths from the perspective of their bereaved family members.

RevDate: 2022-05-14

Holzknecht A, Illini O, Hochmair MJ, et al (2022)

Multimodal Treatment of Malignant Pleural Mesothelioma: Real-World Experience with 112 Patients.

Cancers, 14(9): pii:cancers14092245.

Malignant pleural mesothelioma (MPM) is a rare pleural cancer associated with asbestos exposure. According to current evidence, the combination of chemotherapy, surgery and radiotherapy improves patients' survival. However, the optimal sequence and weighting of the respective treatment modalities is unclear. In anticipation of the upcoming results of the MARS-2 trial, we sought to determine the relative impact of the respective treatment modalities on complications and overall survival in our own consecutive institutional series of 112 patients. Fifty-seven patients (51%) underwent multimodality therapy with curative intent, while 55 patients (49%) were treated with palliative intent. The median overall survival (OS) of the entire cohort was 16.9 months (95% CI: 13.4-20.4) after diagnosis; 5-year survival was 29% for patients who underwent lung-preserving surgery. In univariate analysis, surgical treatment (p < 0.001), multimodality therapy (p < 0.001), epithelioid subtype (p < 0.001), early tumor stage (p = 0.02) and the absence of arterial hypertension (p = 0.034) were found to be prognostic factors for OS. In multivariate analysis, epithelioid subtype was associated with a survival benefit, whereas the occurrence of complications was associated with worse OS. Multimodality therapy including surgery significantly prolonged the OS of MPM patients compared with multimodal therapy without surgery.

RevDate: 2022-05-13

Murphy F, Dekkers S, Braakhuis H, et al (2021)

An integrated approach to testing and assessment of high aspect ratio nanomaterials and its application for grouping based on a common mesothelioma hazard.

NanoImpact, 22:100314.

Here we describe the development of an Integrated Approach to Testing and Assessment (IATA) to support the grouping of different types (nanoforms; NFs) of High Aspect Ratio Nanomaterials (HARNs), based on their potential to cause mesothelioma. Hazards posed by the inhalation of HARNs are of particular concern as they exhibit physical characteristics similar to pathogenic asbestos fibres. The approach for grouping HARNs presented here is part of a framework to provide guidance and tools to group similar NFs and aims to reduce the need to assess toxicity on a case-by-case basis. The approach to grouping is hypothesis-driven, in which the hypothesis is based on scientific evidence linking critical physicochemical descriptors for NFs to defined fate/toxicokinetic and hazard outcomes. The HARN IATA prompts users to address relevant questions (at decision nodes; DNs) regarding the morphology, biopersistence and inflammatory potential of the HARNs under investigation to provide the necessary evidence to accept or reject the grouping hypothesis. Each DN in the IATA is addressed in a tiered manner, using data from simple in vitro or in silico methods in the lowest tier or from in vivo approaches in the highest tier. For these proposed methods we provide justification for the critical descriptors and thresholds that allow grouping decisions to be made. Application of the IATA allows the user to selectively identify HARNs which may pose a mesothelioma hazard, as demonstrated through a literature-based case study. By promoting the use of alternative, non-rodent approaches such as in silico modelling, in vitro and cell-free tests in the initial tiers, the IATA testing strategy streamlines information gathering at all stages of innovation through to regulatory risk assessment while reducing the ethical, time and economic burden of testing.

RevDate: 2022-05-13

Martens M, Kreidl F, Ehrhart F, et al (2022)

A Community-Driven, Openly Accessible Molecular Pathway Integrating Knowledge on Malignant Pleural Mesothelioma.

Frontiers in oncology, 12:849640.

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy mainly triggered by exposure to asbestos and characterized by complex biology. A significant body of knowledge has been generated over the decades by the research community which has improved our understanding of the disease toward prevention, diagnostic opportunities and new treatments. Omics technologies are opening for additional levels of information and hypotheses. Given the growing complexity and technological spread of biological knowledge in MPM, there is an increasing need for an integrating tool that may allow scientists to access the information and analyze data in a simple and interactive way. We envisioned that a platform to capture this widespread and fast-growing body of knowledge in a machine-readable and simple visual format together with tools for automated large-scale data analysis could be an important support for the work of the general scientist in MPM and for the community to share, critically discuss, distribute and eventually advance scientific results. Toward this goal, with the support of experts in the field and informed by existing literature, we have developed the first version of a molecular pathway model of MPM in the biological pathway database WikiPathways. This provides a visual and interactive overview of interactions and connections between the most central genes, proteins and molecular pathways known to be involved or altered in MPM. Currently, 455 unique genes and 247 interactions are included, derived after stringent manual curation of an initial 39 literature references. The pathway model provides a directly employable research tool with links to common databases and repositories for the exploration and the analysis of omics data. The resource is publicly available in the WikiPathways database (Wikipathways : WP5087) and continues to be under development and curation by the community, enabling the scientists in MPM to actively participate in the prioritization of shared biological knowledge.

RevDate: 2022-05-13

Costa A, Forte IM, Ventura E, et al (2022)

Pharmacological reactivation of RBL2/p130 could be an effective antitumoral strategy for malignant pleural mesothelioma.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36 Suppl 1:.

Malignant mesothelioma (MM) is an aggressive tumor developing from the mesothelium covering the body cavities. The most common MM type affects the pleura surrounding the lungs. MM is mainly associated with asbestos exposure. At present, no curative modalities are effective against MM exist. The molecular mechanisms underlying MM development seem to depend mostly on the inactivation of tumor suppressors, among which also the dysfunction of the retinoblastoma (RB) protein pathway that is a hallmark of cancers. We previously demonstrated that RBL2/p130 is a direct AKT target and its reactivation following AKT inhibition mediates apoptosis in MM. So, we hypothesize that concomitant inhibition of CDK and AKT activity, both converging on the reactivation of RBL2/p130 tumor suppressor role, synergize in counteracting MM. We first assessed, through an MTS assay, the effect of three new generation CDK inhibitors (CDKi), palbociclib, ribociclib, abemaciclib, on the cell viability of MM (NCI-H28, IST-MES TWO, NCI-H2452, MMB, MSTO-211H, NCI-H2052) and immortalized human normal mesothelial (MET-5A) cells at 72h. Then, to verify whether CDKi exerted long-term cell growth inhibition, we performed clonogenic assays upon treatment of all the MM All the MM and mesothelial cell lines. Finally, we also examined, by MTS, the possible synergistic effects of abemaciclib in combination with an AKT inhibitor (AKT1/2 VIII). Our preliminary data show that ribociclib and palbociclib only moderately reduce viability of the MPM cells, whereas abemaciclib shows cytotoxic effects at very low doses in all MM cell lines. Abemaciclib treatment induces a dose-dependent cytotoxic effect in all the MM cell lines without meaningfully affecting the normal mesothelial cells. Interestingly, abemaciclib also induced a cytotoxic effect in the most aggressive histotype, the sarcomatoid NCI-H2052 cells. To verify whether abemaciclib exerted long-term cell growth inhibition, we performed clonogenic assays upon treatment with IC50 of abemaciclib and found that the CDKi dramatically reduced colony formation in all the MM cell lines. We also examined, by MTS, the possible synergistic effects of abemaciclib in combination with a kinase AKT inhibitor (iAKT1/2 VIII), so we treated the MM cell lines for 72 h with the two agents, both alone and in combination, at five different concentrations, in a constant ratio. The cell viability data were evaluated through the Chou-Talalay method and showed a strong synergism revealing a combination index (CI) values < 1 for all cell. Although reactivating oncosoppressor genes is difficult to achieve because they are hardly 'druggable', our preliminary findings will provide the rationale for pharmacological strategies able to unleash RBL2/p130 tumor suppressor potential. The pharmacological reactivation of RBL2/p130 could be an effective strategy against MM, which can be rapidly implemented in the clinical practice.

RevDate: 2022-05-13

Mazurek JM, Blackley DJ, DN Weissman (2022)

Malignant Mesothelioma Mortality in Women - United States, 1999-2020.

MMWR. Morbidity and mortality weekly report, 71(19):645-649.

Inhalation of asbestos fibers can cause malignant mesothelioma, a rapidly progressing and lethal cancer of the mesothelium, the thin layer of tissues surrounding internal organs in the chest and abdomen. Patients with malignant mesothelioma have a poor prognosis, with a median survival of 1 year from diagnosis. The estimated median interval from initial occupational asbestos exposure to death is 32 years (range = 13-70 years) (1). Occupational asbestos exposure is most often reported in men working in industries such as construction and manufacturing; however, women are also at risk for exposure to asbestos fibers, and limited data exist on longer-term trends in mesothelioma deaths among women. To characterize deaths associated with mesothelioma and temporal trends in mesothelioma mortality among women in the United States, CDC analyzed annual Multiple Cause of Death records from the National Vital Statistics System for 1999-2020, the most recent years for which complete data are available. The annual number of mesothelioma deaths among women increased significantly, from 489 in 1999 to 614 in 2020; however, the age-adjusted death rate per 1 million women declined significantly, from 4.83 in 1999 to 4.15 in 2020. The largest number of deaths was associated with the health care and social assistance industry (89; 15.7%) and homemaker occupation (129; 22.8%). Efforts to limit exposure to asbestos fibers, including among women, need to be maintained.

RevDate: 2022-05-13

Li X, Wang D, Liu A, et al (2022)

Epidemiological Characteristics of Occupational Cancers Reported - China, 2006-2020.

China CDC weekly, 4(17):370-373.

Introduction: Occupational cancers are a major threat to workers' health in China. The latest version of the Classification and Catalogue of the Occupational Diseases includes 11 occupational cancers. This study analyzed the epidemiological characteristics of occupational cancers in China reported to the National Occupational Disease Reporting System during 2006-2020.

Methods: Occupational cancers reported during 2016-2020 were obtained from the National Occupational Disease Reporting System. Epidemiological characteristics were analyzed by year, region, industry, gender, age at diagnosis, and exposure duration to occupational hazards.

Results: Overall, a total of 1,116 cases of occupational cancers were reported between 2006 and 2020. The main types reported were leukemia caused by benzene exposure (511, 45.79%), lung cancer caused by coke oven exhaust exposure (266, 23.84%), and lung cancer and mesothelioma caused by asbestos exposure (226, 20.25%). There were 6 provincial-level administrative divisions (PLADs) that had reported over 50 new cases in the last 15 years. Most cases (913, 81.18%) were distributed in the manufacturing industry. There were 870 (77.96%) male cases and 246 (22.04%) female cases. The average age at diagnosis of all reported cases was 51.91±15.85 years, and the median exposure duration to occupational hazards was 12 (5.29-23.25) years.

Conclusions: There is a large discrepancy between the high morbidity of occupational cancers and a low number of cases diagnosed and reported cases. Occupational cancers in China may be underestimated, and comprehensive measures should be taken to improve the diagnosis and reporting of occupational cancers.

RevDate: 2022-05-09

Anobile DP, Montenovo G, Pecoraro C, et al (2022)

Splicing deregulation, microRNA and Notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma.

Expert review of clinical pharmacology [Epub ahead of print].

INTRODUCTION: Malignant mesothelioma (MMe) is an aggressive rare cancer of the mesothelium, associated with asbestos exposure. MMe is currently an incurable disease at all stages mainly due to resistance to treatments. It is therefore necessary to elucidate key mechanisms underlying chemoresistance, in an effort to exploit them as novel therapeutic targets.

AREAS COVERED: Chemoresistance is frequently elicited by microRNA (miRNA) alterations and splicing deregulations. Indeed, several miRNAs, such as miR-29c, have been shown to exert oncogenic or oncosuppressive activity. Alterations in the splicing machinery might also be involved in chemoresistance. Moreover, the Notch signaling pathway, often deregulated in MMe, plays a key role in cancer stem cells formation and self-renewal, leading to drug resistance and relapses.

EXPERT OPINION: The prognosis of MMe in patients varies among different tumors and patient characteristics, and novel biomarkers and therapies are warranted. This work aims at giving an overview of MMe, with a special focus on state-of-the-art treatments and new therapeutic strategies against vulnerabilities emerging from studies on epigenetics factors. Besides, this review is also the first to discuss the interplay between miRNAs and alternative splicing as well as the role of Notch as new promising frontiers to overcome drug resistance in MMe.

RevDate: 2022-05-07

Almeida GC, Santos UP, Parente YDM, et al (2022)

Mesothelioma in situ with regressive malignant pleural effusion and an unexpected evolution: A case report.

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that originates from hyperplasia and metaplasia of the mesothelial cells that cover the pleural cavity. Previous exposure to asbestos is the main risk factor. Since MPM is often diagnosed at an advanced stage with rapid evolution and resistance to treatment, it is associated with an unfavorable outcome. Mesothelioma in situ (MIS) has been postulated as a preinvasive phase of MPM; however, its diagnostic criteria have been defined only recently. Diagnosis of MIS may represent an opportunity for early therapies with better results, but the optimal approach has not been defined thus far. Here, we report on a case of a 74-year-old man with right-sided pleural effusion and a previous history of occupational exposure to asbestos for 9 years who was diagnosed with MIS after a latency of 36 years. During follow-up, spontaneous disease regression was observed 5 months after the initial diagnosis; however, it recurred in the form of invasive epithelioid MPM. There is a paucity of literature on MIS and its evolution; however, our case provides relevant knowledge of this unusual behavior, which is important to define follow-up and therapeutic strategies for future cases.

RevDate: 2022-05-06
CmpDate: 2022-05-06

Korchevskiy AA, AG Wylie (2022)

Dimensional characteristics of the major types of amphibole mineral particles and the implications for carcinogenic risk assessment.

Inhalation toxicology, 34(1-2):24-38.

Context: Though some significant advances have been made in recent decades to evaluate the importance of size and morphology (habit) of elongate mineral particles (EMPs), further research is needed to better understand the role of each dimensional metric in determining the levels of cancer potency.Objective: To determine dimensional parameters most relevant for predicting cancer potency of durable elongate particles, specifically amphibole and durable silicate minerals generally.Methods: A database on dimensional and other relevant characteristics of elongate amphibole mineral particles was created, containing particle-by-particle information for 128 099 particles. Integral statistical characteristics on dimensionality of various amphibole types and morphological habits of EMPs were calculated, compared, and correlated with published mesothelioma and lung cancer potency factors.Results: The highest absolute Pearson correlation (r = 0.97, r2 = 0.94, p < 0.05) was achieved between mesothelioma potency (RM) and specific surface area. The highest correlation with adjusted lung cancer potency was found with particle aspect ratio (AR) (r = 0.80, r2 = 0.64, p < 0.05). Cluster analysis demonstrates that fractions of thin fibers (width less than 0.15 and 0.25 µm) also closely relate both to lung cancer and RM. Asbestiform and non-asbestiform populations of amphiboles significantly differ by dimensionality and carcinogenic potency.Conclusions: Dimensional parameters and morphological habits of EMPs are the main drivers for the observable difference in cancer potency among amphibole populations.

RevDate: 2022-05-03

Malakoti F, Targhazeh N, Abadifard E, et al (2022)

DNA repair and damage pathways in mesothelioma development and therapy.

Cancer cell international, 22(1):176.

Malignant mesothelioma (MMe) is an aggressive neoplasm that occurs through the transformation of mesothelial cells. Asbestos exposure is the main risk factor for MMe carcinogenesis. Other important etiologies for MMe development include DNA damage, over-activation of survival signaling pathways, and failure of DNA damage response (DDR). In this review article, first, we will describe the most important signaling pathways that contribute to MMe development and their interaction with DDR. Then, the contribution of DDR failure in MMe progression will be discussed. Finally, we will review the latest MMe therapeutic strategies that target the DDR pathway.

RevDate: 2022-05-02

Kambara T, Amatya VJ, Kushitani K, et al (2022)

Downregulation of FTL decreases proliferation of malignant mesothelioma cells by inducing G1 cell cycle arrest.

Oncology letters, 23(6):174.

Pleural malignant mesothelioma is a malignant tumor with a poor prognosis that is strongly associated with asbestos exposure during its development. Because there is no adequate treatment for malignant mesothelioma, investigation of its molecular mechanism is important. The ferritin light chain (FTL) is a subunit of ferritin, and its high expression in malignant tumors, including malignant mesothelioma, has recently been reported; however, its role in malignant mesothelioma is unclear. The purpose of the present study was to clarify the function of FTL in malignant mesothelioma. The expression levels of FTL in malignant mesothelioma were examined using the Cancer Cell Line Encyclopedia database and our previous data. The short interfering (si)RNA against FTL was transfected into two mesothelioma cell lines, ACC-MESO-1 and CRL-5915, and functional analysis was performed. Expression of p21, p27, cyclin-dependent kinase 2 (CDK2) and phosphorylated retinoblastoma protein (pRb) associated with the cell cycle were examined as candidate genes associated with FTL. The expression levels of the FTL mRNA were higher in malignant mesothelioma compared with other tumors in the Cancer Cell Line Encyclopedia database, and among other genes in our previous study. Reverse transcription-quantitative PCR and western blotting demonstrated suppression of FTL expression in two cell lines transfected with FTL siRNA compared with cells transfected with negative control (NC) siRNA. In the two cell lines transfected with FTL siRNA, proliferation was significantly suppressed, and cell cycle arrest was observed in the G1 phase. The levels of p21 and p27 were increased, while those of CDK2 and pRb were decreased compared with NC. However, no significant differences in invasion and migration ability were revealed between FTL siRNA-transfected cells and NC. In conclusion, FTL may increase the proliferative capacity of malignant mesothelioma cells by affecting p21, p27, CDK2 and pRb, and promoting the cell cycle at the G1 phase.

RevDate: 2022-04-30

Louw A, Panou V, Szejniuk WM, et al (2022)

BAP1 loss by immunohistochemistry predicts improved survival to first line platinum/pemetrexed chemotherapy for pleural mesothelioma patients: A validation study.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(22)00210-6 [Epub ahead of print].

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumour BRCA associated protein 1 (BAP1) status is a predictive biomarker for survival in patients receiving first-line combination platinum/pemetrexed therapy.introduction METHODS: PM cases (n=114) from Aalborg, Denmark were stained for BAP1 on tissue microarrays. Demographic, clinical and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n=234).

RESULTS: BAP1 loss was demonstrated in 62% and 60.3% of all Danish and Australian samples respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histology, performance status, age, sex and treatment (HR = 2.49, p < 0.001 and 1.48, p = 0.01, respectively). First-line platinum/pemetrexed treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 vs 7.3 months, p < 0.001) and Australian cohorts (19.6 vs 11.1 months, p < 0.01). Survival in patients with BAP1 retained and treated with platinum/pemetrexed was similar as in those with best supportive care (BSC). There was a higher OS in BSC patients with BAP1 loss, but significant only in the Australian cohort (16.8 vs 8.3 months, p < 0.01).results CONCLUSION: BAP1 is a predictive biomarker for survival following first-line combination platinum/pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumour is a promising clinical tool for treatment stratification.

RevDate: 2022-04-26

Maghin F, Antonietti A, Cerri N, et al (2022)

Assessment protocol of mesothelioma and relevance of SEM-EDS analysis through a case studies of legal medicine of Brescia (Italy).

Legal medicine (Tokyo, Japan), 57:102076 pii:S1344-6223(22)00064-5 [Epub ahead of print].

INTRODUCTION: This study evaluates the assessment protocol that allows the correlation between the development of mesothelioma to a specific exposure, with particular focus on investigations with Scanning Electron Microscope with Energy Dispersion Spectroscopy.

METHODS: This retrospective study includes 80 subjects who died from mesothelioma in the period 2001-2019. A judicial autopsy was performed for each case to confirm cause of death and correlate the disease with specific asbestos exposure. In 28 cases investigations were carried out to determine the pulmonary load of the asbestos fibres and corpuscles in the lung tissue through microscopic investigations, in order to confirm the suspicion of occupational exposure.

RESULTS: Our data agree with the scientific literature reported, but it is interesting to underline how the present study uses a different systematic approach than others, which are mainly based on epidemiological and environmental studies without considering the lung content of fibres and corpuscles.

CONCLUSION: It would be desirable that the use of the microscopic analysis was introduced in the evaluation protocol: it should always be carried out if the suspicion of asbestos-related disease is raised and not only as a possible integration to the less expensive anamnestic evaluation, even more so if the work or personal history should be suggestive of exposure to asbestos fibres.

RevDate: 2022-04-24

Carbone M, Pass HI, Ak G, et al (2022)

Medical and surgical care of mesothelioma patients and their relatives carrying germline BAP1 mutations.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(22)00192-7 [Epub ahead of print].

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma; less frequently breast cancer, several types of skin carcinomas and other tumor types. Mesotheliomas in these patients are significantly less aggressive and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, significant medical, social and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life and is also cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges and our recommendations of how to best care for these patients and their family members, as well as the potential economic and psychosocial impact.

RevDate: 2022-04-24

Napoli F, Rapa I, Izzo S, et al (2022)

Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition.

Virchows Archiv : an international journal of pathology [Epub ahead of print].

The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS). In several cancer models, miR-215 and miR-375 have been shown to target TS, while information on these miRNAs in PM are still limited although suggest their role in epithelial to mesenchymal transition. Seventy-one consecutive PM tissues (4 biphasic, 7 sarcomatoid, and 60 epithelioid types) and 16 commercial and patient-derived PM cell lines were screened for TS, miR-215, and miR-375 expression. REN and 570B cells were selected for miR-215 and miR-375 transient transfections to test TS modulation. ZEB1 protein expression in tumor samples was also tested. Moreover, genetic profile was investigated by means of BAP1 and p53 immunohistochemistry. Expression of both miR-215 and miR-375 was significantly higher in epithelioid histotype. Furthermore, inverse correlation between TS protein and both miR-215 and miR-375 expression was found. Efficiently transfected REN and 570B cell lines overexpressing miR-215 and miR-375 showed decreased TS protein levels. Epithelioid PM with a mesenchymal component highlighted by reticulin stain showed significantly higher TS and ZEB1 protein and lower miRNA expression. A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM.

RevDate: 2022-04-21

Ziółkowska B, Cybulska-Stopa B, Papantoniou D, et al (2022)

Systemic treatment in patients with malignant pleural mesothelioma - real life experience.

BMC cancer, 22(1):432.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments.

METHODS: The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR).

RESULTS: In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47).

CONCLUSION: Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

RevDate: 2022-04-19

Jin MY, ZQ Jiang (2022)

[Research progress on the role of lncRNA in the occurrence and development of malignant mesothelioma].

Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases, 40(3):231-235.

Malignant mesothelioma (MM) is a long latency, poor prognosis and asbestos exposure related malignant disease. Long non-coding RNA (lncRNA) is a kind of RNA with a length of more than 200 nucleotides that does not encode protein. It plays an important role in epigenetic regulation, cell cycle regulation and cell differentiation regulation. Recent studies have shown that the abnormal expression or function of lncRNA is closely related to the diagnosis and prognosis of MM. In this paper, the lncRNA research on MM is reviewed to better understand the role of lncRNA in MM.

RevDate: 2022-04-18

Robinson BWS, Redwood AJ, J Creaney (2022)

How Our Continuing Studies of the Pre-clinical Inbred Mouse Models of Mesothelioma Have Influenced the Development of New Therapies.

Frontiers in pharmacology, 13:858557 pii:858557.

Asbestos-induced preclinical mouse models of mesothelioma produce tumors that are very similar to those that develop in humans and thus represent an ideal platform to study this rare, universally fatal tumor type. Our team and a number of other research groups have established such models as a stepping stone to new treatments, including chemotherapy, immunotherapy and other approaches that have been/are being translated into clinical trials. In some cases this work has led to changes in mesothelioma treatment practice and over the last 30 years these models and studies have led to trials which have improved the response rate in mesothelioma from less than 10% to over 50%. Mouse models have had a vital role in that improvement and will continue to play a key role in the future success of mesothelioma immunotherapy. In this review we focus only on these original inbred mouse models, the large number of preclinical studies conducted using them and their contribution to current and future clinical therapy for mesothelioma.

RevDate: 2022-04-15
CmpDate: 2022-04-15

Tran T, Egilman D, M Rigler (2020)

Response to Roggli et al. (2020) "Talc and mesothelioma: mineral fiber analysis of 65 cases with clinicopathological correlation".

Ultrastructural pathology, 44(3):314-315.

RevDate: 2022-04-12

Dawson AG, Kutywayo K, Mohammed SB, et al (2022)

Cytoreductive surgery with hyperthermic intrathoracic chemotherapy for malignant pleural mesothelioma: a systematic review.

Thorax pii:thoraxjnl-2021-218214 [Epub ahead of print].

INTRODUCTION: Cytoreductive surgery has been used a part of multimodality treatment in patients with malignant pleural mesothelioma (MPM). The residual microscopic disease that remains will lead to disease progression in the majority of patients. Delivery of hyperthermic intrathoracic chemotherapy at the time of surgery has been used to address this microscopic disease, however it's effect and place in the multimodality treatment sphere is unknown. The aim of this systematic review was to assess the effect of surgery and hyperthermic intrathoracic chemotherapy in patients with MPM on overall survival and disease-free interval.

METHODS: Ovid MEDLINE, Embase, Web of Science and the Cochrane Database of Systematic Reviews were searched from database inception through to June 2021. Studies reporting overall survival and/or disease-free interval in patients with MPM undergoing cytoreductive surgery with hyperthermic intrathoracic chemotherapy were considered. Study quality was assessed using the Newcastle-Ottawa Scale. A narrative review was performed.

RESULTS: Fifteen studies were eligible for inclusion comprising 598 patients. Surgery with hyperthermic intrathoracic chemotherapy was associated with a median overall survival and disease-free interval ranging from 11 to 75 months and 7.2 to 57 months, respectively. These appeared to be superior to patients not receiving hyperthermic intrathoracic chemotherapy (overall survival: 5-36 months and disease-free interval: 12.1-21 months). A higher dose of hyperthermic intrathoracic chemotherapy was associated with an improvement in overall survival compared with a lower dose: 18-31 months versus 6-18 months, respectively. The most common morbidity was atrial fibrillation followed by renal complications.

CONCLUSION: Surgery with hyperthermic intrathoracic chemotherapy offers a safe and effective therapy with an improvement in disease-free interval and overall survival, particularly when hyperthermic intrathoracic chemotherapy is administered at a higher dose.

PROSPERO REGISTRATION NUMBER: CRD42019129002.

RevDate: 2022-04-12

Berry TA, Belluso E, Vigliaturo R, et al (2022)

Asbestos and Other Hazardous Fibrous Minerals: Potential Exposure Pathways and Associated Health Risks.

International journal of environmental research and public health, 19(7): pii:ijerph19074031.

There are six elongate mineral particles (EMPs) corresponding to specific dimensional and morphological criteria, known as asbestos. Responsible for health issues including asbestosis, and malignant mesothelioma, asbestos has been well researched. Despite this, significant exposure continues to occur throughout the world, potentially affecting 125 million people in the workplace and causing thousands of deaths annually from exposure in homes. However, there are other EMPS, such as fibrous/asbestiform erionite, that are classified as carcinogens and have been linked to cancers in areas where it has been incorporated into local building materials or released into the environment through earthmoving activities. Erionite is a more potent carcinogen than asbestos but as it is seldom used for commercial purposes, exposure pathways have been less well studied. Despite the apparent similarities between asbestos and fibrous erionite, their health risks and exposure pathways are quite different. This article examines the hazards presented by EMPs with a particular focus on fibrous erionite. It includes a discussion of the global locations of erionite and similar hazardous minerals, a comparison of the multiple exposure pathways for asbestos and fibrous erionite, a brief discussion of the confusing nomenclature associated with EMPs, and considerations of increasing global mesothelioma cases.

RevDate: 2022-04-12

Henzi T, Diep KL, Oberson A, et al (2022)

Forchlorfenuron and Novel Analogs Cause Cytotoxic Effects in Untreated and Cisplatin-Resistant Malignant Mesothelioma-Derived Cells.

International journal of molecular sciences, 23(7): pii:ijms23073963.

Malignant mesothelioma (MM) is a currently incurable, aggressive cancer derived from mesothelial cells, most often resulting from asbestos exposure. The current first-line treatment in unresectable MM is cisplatin/pemetrexed, which shows very little long-term effectiveness, necessitating research for novel therapeutic interventions. The existing chemotherapies often act on the cytoskeleton, including actin filaments and microtubules, but recent advances indicate the 'fourth' form consisting of the family of septins, representing a novel target. The septin inhibitor forchlorfenuron (FCF) and FCF analogs inhibit MM cell growth in vitro, but at concentrations which are too high for clinical applications. Based on the reported requirement of the chloride group in the 2-position of the pyridine ring of FCF for MM cell growth inhibition and cytotoxicity, we systematically investigated the importance (cell growth-inhibiting capacity) of the halogen atoms fluorine, chlorine, bromine and iodine in the 2- or 3-position of the pyridine ring. The MM cell lines ZL55, MSTO-211H, and SPC212, and-as a control-immortalized Met-5A mesothelial cells were used. The potency of the various halogen substitutions in FCF was mostly correlated with the atom size (covalent radius); the small fluoride analogs showed the least effect, while the largest one (iodide) most strongly decreased the MTT signals, in particular in MM cells derived from epithelioid MM. In the latter, the strongest effects in vitro were exerted by the 2-iodo and, unexpectedly, the 2-trifluoromethyl (2-CF3) FCF analogs, which were further tested in vivo in mice. However, FCF-2-I and, more strongly, FCF-2-CF3 caused rapidly occurring strong symptoms of systemic toxicity at doses lower than those previously obtained with FCF. Thus, we investigated the effectiveness of FCF (and selected analogs) in vitro in MM cells which were first exposed to cisplatin. The slowly appearing population of cisplatin-resistant cells was still susceptible to the growth-inhibiting/cytotoxic effect of FCF and its analogs, indicating that cisplatin and FCF target non-converging pathways in MM cells. Thus, a combination therapy of cisplatin and FCF (analogs) might represent a new avenue for the treatment of repopulating chemo-resistant MM cells in this currently untreatable cancer.

RevDate: 2022-04-11

Tilsed CM, Casey TH, de Jong E, et al (2022)

Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy.

Frontiers in oncology, 12:849793.

With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.

RevDate: 2022-04-08

Nakashima K, Sakai Y, Hoshino H, et al (2022)

Sulfated Glycans Recognized by S1 Monoclonal Antibody can Serve as a Diagnostic Marker for Malignant Pleural Mesothelioma.

Lung [Epub ahead of print].

PURPOSE: Malignant pleural mesothelioma (MPM) is a malignant neoplasm of the pleura caused by asbestos exposure. For diagnosis of MPM, immunohistochemistry using multiple markers is recommended to rule out differential diagnoses, such as pulmonary adenocarcinoma. However, the specificity of currently used markers is not fully satisfactory. We previously developed a monoclonal antibody named S1, which recognizes 6-sulfo sialyl Lewis x, an L-selectin ligand expressed on high endothelial venules. During the screening process, we discovered that this antibody stained normal pleural mesothelium. This finding prompted us to hypothesize that the epitope recognized by S1 might serve as a new diagnostic marker for MPM.

METHODS: To test this hypothesis, we immunostained human MPM (n = 22) and lung adenocarcinoma (n = 25) tissues using S1 antibody.

RESULTS: 77.3% of MPM were S1 positive, and if limited to epithelioid type, the positivity rate was 100%, while that of lung adenocarcinoma was only 36.0%. Statistical analysis revealed a significant difference in the S1 positivity rate between each disease. Furthermore, immunohistochemistry using a series of anti-carbohydrate antibodies combined with glycosidase digestion revealed the structure of sulfated glycans expressed in MPM to be 6-sulfo sialyl N-acetyllactosamine attached to core 2-branched O-glycans.

CONCLUSION: We propose that the S1 glycoepitope could serve as a new diagnostic marker for MPM.

RevDate: 2022-04-04

Cameron JK, Aitken J, Reid A, et al (2022)

Geographic distribution of malignant mesothelioma incidence and survival in Australia.

Lung cancer (Amsterdam, Netherlands), 167:17-24 pii:S0169-5002(22)00386-5 [Epub ahead of print].

OBJECTIVES: To understand the geographic distribution of and area-level factors associated with malignant mesothelioma incidence and survival in Australia.

MATERIALS AND METHODS: Generalised linear models and Bayesian spatial models were fitted using population registry data. Area-level covariates were socioeconomic quintile, remoteness category and state or territory. The maximised excess events test was used to test for spatial heterogeneity.

RESULTS: There was strong evidence of spatial differences in standardised incidence rates for malignant mesothelioma but survival was uniformly poor. Incidence rates varied by state or territory and were lower in remote areas. Patterns in the geographic distribution of modelled incidence counts for malignant mesothelioma differed substantially from patterns of standardised incidence rates.

CONCLUSIONS: Geographic variation in the modelled incidence counts of malignant mesothelioma demonstrates varying demand for diagnostic and management services. The long latency period for this cancer coupled with migration complicates any associations with patterns of exposure, however some of the geographic distribution of diagnoses can be explained by the location of historical mines and asbestos-related industries.

RevDate: 2022-04-03

Laaksonen S, Kettunen E, Sutinen E, et al (2022)

Pulmonary Asbestos Fiber Burden is Related to Patient Survival in Malignant Pleural Mesothelioma.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(22)00167-8 [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with poor prognosis and is strongly associated with occupational asbestos exposure. Given the importance of asbestos exposure in MPM pathogenesis, we retrospectively analyzed the types and concentrations of asbestos fibers within the lung tissues of patients with MPM and investigated their effects on all-cause mortality.

METHODS: We formed a national dataset of patients with MPM identified from the Finnish Cancer Registry and Statistics Finland. These data were merged with pulmonary asbestos fiber analysis results received from the Finnish Institute of Occupational Health.

RESULTS: We identified 590 patients with MPM that underwent pulmonary asbestos fiber analysis. The median asbestos concentration within dry lung tissue was 3.20 million fibers/gram (f/g) (range: 0-1700 million f/g). Crocidolite and anthophyllite were the most prevalent asbestos fiber types detected in lung tissue. The multivariable risk of death analyses, where changes over time were accounted for, revealed that total asbestos fiber concentration was associated with increased mortality. However, no difference in mortality was noted between different fiber types.

CONCLUSION: Our study revealed that pulmonary fiber concentrations correlated with the manner of asbestos usage. Anthophyllite was identified as the sole fiber in a sizable proportion of cases, supporting its independent role in the pathogenesis of MPM. Our findings suggest that asbestos fiber burden, but not fiber type, may have an impact on the prognosis of MPM.

RevDate: 2022-04-01

Idkedek M, Tahayneh KS, Abu-Akar F, et al (2022)

Case Report and Review of Literature: Familial Malignant Pleural Mesothelioma in a 39 Years Old Patient With an Inconclusive 18F-FDG PET/CT Result.

Frontiers in surgery, 9:819596.

Malignant pleural mesothelioma (MPM) is a rare yet aggressive neoplasm that was linked only to asbestos exposure for decades, although familial clusters were diagnosed with MPM without a known history of asbestos exposure most likely due to genetic susceptibility. Here, we describe a case of familial malignant mesothelioma in a 39 years old patient with a confirmed BAP1 mutation in addition to a known family history with the same mutation. The patient presented with progressive shortness of breath and recurrent pleural effusions and diagnosis was made through biopsies taken during uniportal Video-Assisted Thoracoscopic Surgery. After the inconclusive result of 18F-FDG PET/CT scan, subxiphoid uniportal Video-Assisted Thoracoscopic Surgery left pleural and laparoscopic peritoneal biopsies were obtained for staging and evaluating contralateral lung and peritoneal cavity. Finally, two important educational values should be acquired from this case: genetic predisposition and BAP1 tumor suppressor gene mutation might affect the age of presentation and overall prognosis of the disease. Also, 18F-FDG PET/CT scan may not be the best modality for staging and confirming the diagnosis of malignant pleural mesothelioma.

RevDate: 2022-03-31

Kindler HL, Novello S, Bearz A, et al (2022)

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

The Lancet. Oncology, 23(4):540-552.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab.

METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.

FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).

INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.

FUNDING: Bayer Healthcare Pharmaceuticals.

RevDate: 2022-03-28

Ierardi AM, Best EA, GM Marsh (2022)

Updated Italian cohort data continues to confirm lack of mesothelioma risk in pooled cohort of international cosmetic talc miners and millers.

Inhalation toxicology [Epub ahead of print].

OBJECTIVES: To assess potential mesothelioma risk following inhalation of cosmetic talc, we updated previous iterations of a pooled cohort analysis, post-study statistical power analysis, and confidence interval function analysis for a pooled cohort of international cosmetic talc miners/millers given new Italian cohort data.

METHODS: Five cohorts of cosmetic talc miners/millers were pooled. Expected numbers of mesotheliomas for each cohort were reported by the original authors. We based our post-study statistical power analysis on an a priori one-sided significance level of 0.05, and exact Poisson and approximate distribution probabilities. To evaluate the confidence interval function for the observed pooled mesothelioma standardized mortality ratios (SMRs), we calculated the probability for the upper 100(1-2α)% confidence limit that equals various SMRs of interest.

RESULTS: The pooled cohorts generated a total observation time of 135,524.38 person-years. Overall, 4.14 mesotheliomas were expected (mid-value estimate), though only one case of mesothelioma has been confirmed in the pooled cohort to date. We calculated 71% and 87% post-study power to detect a 2.5-fold or greater and a 3.0-fold or greater increase in mesothelioma, respectively. Our complimentary confidence interval function analysis demonstrated that the probability that the true mesothelioma SMR for the pooled cohort was at or above 2.0 or at or above 3.0 was 0.00235 and 0.00005, respectively.

CONCLUSIONS: Based on the updated results of our various analyses, the current epidemiological evidence from cosmetic talc miner/miller cohort studies continues to not support the hypothesis that the inhalation of cosmetic talc is associated with an increased risk of mesothelioma.

RevDate: 2022-03-27

Ejegi-Memeh S, Sherborne V, Harrison M, et al (2022)

Patients' and informal carers' experience of living with mesothelioma: A systematic rapid review and synthesis of the literature.

European journal of oncology nursing : the official journal of European Oncology Nursing Society, 58:102122 pii:S1462-3889(22)00030-8 [Epub ahead of print].

PURPOSE: Mesothelioma is a rare and incurable cancer linked to asbestos exposure. It primarily affects the pleura. This systematic rapid review aimed to identify what is known about the experience of living with mesothelioma, from the perspective of patients and their informal carers.

METHODS: Medline, PsycInfo, Scopus and the Cumulative Index to Nursing and Allied Health Literature were searched for empirical studies published between December 2008 and October 2020. Google Scholar was searched. The inclusion criteria stated that studies were peer-reviewed, reported the experience of living with mesothelioma from the perspective of patients and carers and written in English. The Mixed-Methods Appraisal Tool was used to assess quality. The review protocol is registered on PROSPERO: CRD42020204726.

RESULTS: Twenty-five studies met the inclusion criteria. Following data extraction, a narrative synthesis identified three themes: the impact on the individual; the impact on informal carers and relationships; and interactions with professionals and systems. The physical and psychological symptom burden of mesothelioma on patients' lives was reported as high. Both the qualitative and quantitative literature highlighted that patients and carers may have different needs throughout the mesothelioma journey. Differences included psychological experiences and preferences regarding the timing of information and support provision. Patients and carers expected their health care professionals to be knowledgeable about mesothelioma or refer to those who were. Health care professionals that were compassionate, honest and supportive also positively influenced the experience of patients and carers living with mesothelioma. A lack of communication or misinformation was damaging to the patient-healthcare professional relationship. Continuity of care, coordinated care and good communication between treatment centres were widely reported as important in the literature. Fragmented care was identified as detrimental to the patient experience, increasing anxiety in patients. However, relationships with professionals were not only important in terms of co-ordinating care. There was also evidence that good relationships with healthcare professionals were beneficial to coping with the mesothelioma diagnosis.

CONCLUSION: The volume of mesothelioma experience research has grown over the past decade. This has led to our growing understanding of the complex needs and experiences of mesothelioma patients and carers. However, this review identified several evidence gaps.

RevDate: 2022-03-25

Saito CA, Bussacos MA, Salvi L, et al (2022)

Sex-Specific Mortality from Asbestos-Related Diseases, Lung and Ovarian Cancer in Municipalities with High Asbestos Consumption, Brazil, 2000-2017.

International journal of environmental research and public health, 19(6): pii:ijerph19063656.

The aim of this study is to compare the mortality rates for typical asbestos-related diseases (ARD-T: mesothelioma, asbestosis, and pleural plaques) and for lung and ovarian cancer in Brazilian municipalities where asbestos mines and asbestos-cement plants had been operating (areas with high asbestos consumption, H-ASB) compared with in other municipalities. The death records for adults aged 30+ years were retrieved from multiple health information systems. In the 2000-2017 time period, age-standardized mortality rates (standard: Brazil 2010) and standardized rate ratios (SRR; H-ASB vs. others) were estimated. The SRRs for ARD-T were 2.56 for men (257 deaths in H-ASB municipalities) and 1.19 for women (136 deaths). For lung cancer, the SRRs were 1.33 for men (32,604 deaths) and 1.19 for women (20,735 deaths). The SRR for ovarian cancer was 1.34 (8446 deaths). Except for ARD-T and lung cancer in women, the SRRs were higher in municipalities that began using asbestos before 1970 than in municipalities that began utilizing asbestos from 1970 onwards. In conclusion, the mortality rates for ARD-T, and lung and ovarian cancer in municipalities with a history of asbestos mining and asbestos-cement production exceed those of the whole country. Caution is needed when interpreting the results of this ecological study. Analytical studies are necessary to document the impact of asbestos exposure on health, particularly in the future given the long latency of asbestos-related cancers.

RevDate: 2022-03-25

Stoppa G, Mensi C, Fazzo L, et al (2022)

Spatial Analysis of Shared Risk Factors between Pleural and Ovarian Cancer Mortality in Lombardy (Italy).

International journal of environmental research and public health, 19(6): pii:ijerph19063467.

BACKGROUND: Asbestos exposure is a recognized risk factor for ovarian cancer and malignant mesothelioma. There are reports in the literature of geographical ecological associations between the occurrence of these two diseases. Our aim was to further explore this association by applying advanced Bayesian techniques to a large population (10 million people).

METHODS: We specified a series of Bayesian hierarchical shared models to the bivariate spatial distribution of ovarian and pleural cancer mortality by municipality in the Lombardy Region (Italy) in 2000-2018.

RESULTS: Pleural cancer showed a strongly clustered spatial distribution, while ovarian cancer showed a less structured spatial pattern. The most supported Bayesian models by predictive accuracy (widely applicable or Watanabe-Akaike information criterion, WAIC) provided evidence of a shared component between the two diseases. Among five municipalities with significant high standardized mortality ratios of ovarian cancer, three also had high pleural cancer rates. Wide uncertainty was present when addressing the risk of ovarian cancer associated with pleural cancer in areas at low background risk of ovarian cancer.

CONCLUSIONS: We found evidence of a shared risk factor between ovarian and pleural cancer at the small geographical level. The impact of the shared risk factor can be relevant and can go unnoticed when the prevalence of other risk factors for ovarian cancer is low. Bayesian modelling provides useful information to tailor epidemiological surveillance.

RevDate: 2022-03-25

Spinazzè A, Consonni D, Borghi F, et al (2022)

Asbestos Exposure in Patients with Malignant Pleural Mesothelioma included in the PRIMATE Study, Lombardy, Italy.

International journal of environmental research and public health, 19(6): pii:ijerph19063390.

The PRIMATE study is an Italian translational research project, which aims to identify personalized biomarkers associated with clinical characteristics of malignant pleural mesothelioma (MPM). For this purpose, characteristics of MPM patients with different degrees of asbestos exposure will be compared to identify somatic mutations, germline polymorphism, and blood inflammatory biomarkers. In this framework, we assessed exposure to asbestos for 562 cases of MPM extracted from the Lombardy region Mesothelioma Registry (RML), for which a complete interview based on a standardized national questionnaire and histopathological specimens were available. Exposure assessment was performed: (1) through experts' evaluation (considered as the gold standard for the purpose of this study), according to the guidelines of the Italian National Mesothelioma Registry (ReNaM) and (2) using a job-exposure matrix (SYN-JEM) to obtain qualitative (ever/never) and quantitative estimates of occupational asbestos exposure (cumulative exposure expressed in fibers per mL (f/mL)). The performance of SYN-JEM was evaluated against the experts' evaluation. According to experts' evaluation, occupational asbestos exposure was recognized in 73.6% of men and 23.6% of women; furthermore, 29 men (7.8%) and 70 women (36.9%) had non-occupational exposure to asbestos. When applying SYN-JEM, 225 men (60.5%) and 25 women (13.2%) were classified as occupationally exposed, with a median cumulative exposure higher for men (1.7 f/mL-years) than for women (1.2 f/mL-years). The concordance between the two methods (Cohen's kappa) for occupational exposure assessment was 0.46 overall (0.41 in men, and 0.07 in women). Sensitivity was higher in men (0.73) than in women (0.18), while specificity was higher in women (0.88) than in men (0.74). Overall, both methods can be used to reconstruct past occupational exposure to asbestos, each with its own advantages and limitations.

RevDate: 2022-03-25

Anaya-Aguilar C, Bravo M, Magan-Fernandez A, et al (2022)

Prevention of Occupational Hazards Due to Asbestos Exposure in Dentistry. A Proposal from a Panel of Experts.

International journal of environmental research and public health, 19(6): pii:ijerph19063153.

Asbestos in all its forms is a Group 1 material agent with proven carcinogenic effects in the human being since 1977. Exposure to asbestos can be considered unsafe. The use of asbestos in the field of dentistry had a common use in the manufacture of dental prostheses in the 1960s and 1970s. Taking into account the long induction period of this agent and the plausibility for being a risk factor in dentistry, the objective of this study is to propose a plan for the prevention of occupational risks due to asbestos exposure in dentistry by means of the contribution of a panel of experts. An Expert Panel (EP) approach was used in which a group of nine experts identified and documented the use of asbestos in the dental profession. EP was created and followed the protocol in accordance with the EuropeAid Assessment Guidelines. As a result of this study, EP documented the common use and sources of asbestos in dentistry in prosthetic materials, dental dressings, and in the coating of casting cylinders. EP also created a consensus document on the priority measures for the Plan for the Prevention of Risks from Asbestos in Dentistry, based on previous reports from the European Commission Senior Labour Inspectors' Committee. The document concluded that obtainment of information, receiving specific training on the subject and performing epidemiological studies, and the proper risk assessments were the priority measures to adopt.

RevDate: 2022-03-25

Rovers S, Janssens A, Raskin J, et al (2022)

Recent Advances of Immune Checkpoint Inhibition and Potential for (Combined) TIGIT Blockade as a New Strategy for Malignant Pleural Mesothelioma.

Biomedicines, 10(3): pii:biomedicines10030673.

Malignant pleural mesothelioma (MPM) is a fatal cancer type that affects the membranes lining the lungs, and is causally associated with asbestos exposure. Until recently, the first-line treatment consisted of a combination of chemotherapeutics that only had a limited impact on survival, and had not been improved in decades. With the recent approval of combined immune checkpoint inhibition for MPM, promising new immunotherapeutic strategies are now emerging for this disease. In this review, we describe the current preclinical and clinical evidence of various immune checkpoint inhibitors in MPM. We will consider the advantages of combined immune checkpoint blockade in comparison with single agent checkpoint inhibitor drugs. Furthermore, recent evidence suggests a role for T cell immunoglobulin and ITIM domain (TIGIT), an inhibitory immunoreceptor, as a novel target for immunotherapy. As this novel immune checkpoint remains largely unexplored in mesothelioma, we will discuss the potential of TIGIT blockade as an alternative therapeutic approach for MPM. This review will emphasize the necessity for new and improved treatments for MPM, while highlighting the recent advances and future perspectives of combined immune checkpoint blockade, particularly aimed at PD-L1 and TIGIT.

RevDate: 2022-03-10

Nishida C, K Yatera (2022)

The Impact of Ambient Environmental and Occupational Pollution on Respiratory Diseases.

International journal of environmental research and public health, 19(5): pii:ijerph19052788.

Ambient pollutants and occupational pollutants may cause and exacerbate various lung and respiratory diseases. This review describes lung and respiratory diseases in relation to ambient pollutants, particularly particulate matter (PM2.5), and occupational air pollutants, excluding communicable diseases and indoor pollutants, including tobacco smoke exposure. PM2.5 produced by combustion is an important ambient pollutant. PM2.5 can cause asthma attacks and exacerbations of chronic obstructive pulmonary disease in the short term. Further, it not only carries a risk of lung cancer and death, but also hinders the development of lung function in children in the long term. It has recently been suggested that air pollution, such as PM2.5, is a risk factor for severe coronavirus disease (COVID-19). Asbestos, which causes asbestosis, lung cancer, and malignant mesothelioma, and crystalline silica, which cause silicosis, are well-known traditional occupational pollutants leading to pneumoconiosis. While work-related asthma (WRA) is the most common occupational lung disease in recent years, many different agents cause WRA, including natural and synthetic chemicals and irritant gases. Primary preventive interventions that increase awareness of pollutants and reduce the development and exacerbation of diseases caused by air pollutants are paramount to addressing ambient and occupational pollution.

RevDate: 2022-03-10

Serio G, Pezzuto F, Fortarezza F, et al (2022)

Mesothelioma and Colorectal Cancer: Report of Four Cases with Synchronous and Metachronous Presentation.

International journal of molecular sciences, 23(5): pii:ijms23052630.

There is evidence that asbestos could play a role in the carcinogenesis of digestive cancers. The presence of asbestos fibres in histological samples from gastric, biliary, colon cancers has been reported, but the mechanism is still controversial. It has been hypothesised that asbestos reaches these sites, especially through contaminated water; however, some experimental studies have shown that the inhaled fibres are mobile, so they can migrate to many organs, directly or via blood and lymph flow. We report four unusual cases of colorectal cancers in patients with a long history of asbestos exposure who also developed synchronous or metachronous mesothelioma. We evaluated the roles of BRCA associated protein-1 (BAP1) and cyclin-dependent kinase inhibitor 2A (CDKN2A) in colon cancer and mesothelioma to support the hypothesis that BAP-1 and CDKN2A are tumour suppressor genes involved in disease progression, recurrence, or death in both digestive cancers and mesothelioma. Potentially, these markers may be used as predictors of worse prognosis, but we also stress the importance of clinical surveillance of exposed patients because asbestos could induce cancer in any organ.

RevDate: 2022-03-10

Davis A, Ke H, Kao S, et al (2022)

An Update on Emerging Therapeutic Options for Malignant Pleural Mesothelioma.

Lung Cancer (Auckland, N.Z.), 13:1-12 pii:288535.

The treatment paradigm for malignant pleural mesothelioma (MPM) has changed little in the last 18 years. Radical intent treatment, consisting of surgical resection, radiotherapy and chemotherapy, has been offered to a highly select few; however, there is little randomised evidence to validate this approach. Prior to 2020 chemotherapy with platinum and an anti-folate was the only intervention with randomised evidence to demonstrate improved overall survival (OS) in MPM. No systemic therapy had been demonstrated to improve OS in the second line setting until 2020. The publication of the Checkmate 743 trial in 2021 demonstrated a survival benefit of combination immunotherapy over standard chemotherapy in newly diagnosed patients with MPM. This finding was shortly followed by the CONFIRM trial which demonstrates a modest but significant survival benefit of second line nivolumab versus placebo in patients having previously received standard chemotherapy. The results of these trials, recent biomarker directed therapy and chemotherapy adjuncts are discussed within this review. The integration of immunotherapy for the few patients in whom radical surgical therapy is intended is currently the subject of clinical trials and offers the prospect of improving outcomes in this rare but devastating disease.

RevDate: 2022-03-07

Rijavec E, Biello F, Barletta G, et al (2022)

Novel approaches for the treatment of unresectable malignant pleural mesothelioma: A focus on immunotherapy and target therapy (Review).

Molecular and clinical oncology, 16(4):89.

Malignant pleural mesothelioma (MPM) is considered a relatively uncommon disease but its incidence is increasing worldwide. Patients affected by MPM have a very severe prognosis and have been often occupationally and environmentally exposed to asbestos. In recent years, checkpoint inhibitors have dramatically revolutionized the paradigm for the treatment of several malignancies. Several efforts have also been made to improve the survival outcomes of patients with MPM and after decades, the standard-of-care systemic treatment for unresectable MPM, based on first-line combination chemotherapy with cisplatin and pemetrexed, has changed. In addition to checkpoint inhibitors, other types of treatments, such as molecularly targeted therapy have been evaluated. However, to date, the results of these investigations are not very encouraging. The aim of the present review is to provide a comprehensive overview of the most relevant data of clinical trials regarding recent treatment strategies of MPM with a particular focus on immunotherapeutic and targeted approaches.

RevDate: 2022-03-04
CmpDate: 2022-03-04

Freemantle GG, Chetty D, Olifant M, et al (2022)

Assessment of asbestos contamination in soils at rehabilitated and abandoned mine sites, Limpopo Province, South Africa.

Journal of hazardous materials, 429:127588.

Prior to its termination, asbestos mining in South Africa was centred on the large crocidolite fields of the present day Northern Cape, the amosite (grunerite)-crocidolite fields of Limpopo, and chrysotile fields of Mpumalanga provinces. The legacy of these activities continues to affect surrounding communities in contemporary South Africa. The asbestos fields of Limpopo host two important former mining areas at Penge and at the Bewaarkloof near Chuenespoort. A large abandoned site is located southeast of Penge at Weltevreden, where there is no evidence of any rehabilitation. Two former mines, Lagerdraai and Uitkyk, are rehabilitated sites in an extensive string of closed mines that operated in the southern Bewaarkloof. Samples from the abandoned and rehabilitated mine sites were studied using semi-quantitative X-ray powder diffraction (XRD) to determine asbestos contamination levels in soils, and to assess distribution patterns of asbestos mineral species in the surrounding soils. Only where below detection (typically 1-3 mass%) from XRD, samples were assessed optically. The Weltevreden site, with no observable rehabilitation efforts, contrasts with the rehabilitated sites at Lagerdraai and Uitkyk. The predominant asbestiform mineral species at each site were successfully identified, with underlying geological asbestos mineral distribution trends recognised in the soils at the Bewaarkloof. Trace amounts of asbestiform minerals were identified in soils downstream of the Weltevreden mine, as well as in surrounding hillsides. The results indicate that XRD is a potentially useful tool for benchmarking sites yet to be rehabilitated as well as monitoring the effectiveness of previous rehabilitation efforts. The method is also a suitable first-pass for target areas that may require more detailed, time-consuming, and costly analysis.

RevDate: 2022-02-28

Fortarezza F, Pezzuto F, Marzullo A, et al (2022)

Molecular Pathways in Peritoneal Mesothelioma: A Minireview of New Insights.

Frontiers in oncology, 12:823839.

Mesothelioma is a rare malignant neoplasm with poor survival. It mainly affects the pleura (90%) but can arise in all serous cavities: peritoneum (5-10%), pericardium and tunica vaginalis testis (<1%). The onset of pleural mesothelioma is strictly related to asbestos exposure with a long latency time. The causal link with asbestos has also been suggested for peritoneal mesothelioma, while the importance of exposure in the onset of pericardial and tunica vaginalis testis mesotheliomas is not well known. Mesothelioma remains an aggressive and fatal disease with a five-year mortality rate higher than 95%. However, new therapeutic approaches based on molecular-targeted and immunomodulatory therapies are being explored but have conflicting results. In this context, the identification of critical targets appears mandatory. Awareness of the molecular and physiological changes leading to the neoplastic degeneration of mesothelial cells and the identification of gene mutations, epigenetic alterations, gene expression profiles and altered pathways could be helpful for selecting targetable mechanisms and molecules. In this review, we aimed to report recent research in the last 20 years focusing on the molecular pathways and prognostic factors in peritoneal mesothelioma and their possible diagnostic and therapeutic implications.

RevDate: 2022-02-26

Štrbac D, V Dolžan (2022)

Novel and Future Treatment Options in Mesothelioma: A Systematic Review.

International journal of molecular sciences, 23(4): pii:ijms23041975.

Mesothelioma is a rare tumor, frequently associated with asbestos exposure, arising from pleura and peritoneum. Traditionally, diagnosis and treatment have been difficult in a clinical setting. The treatment is based on a trimodal approach involving surgery, chemotherapy, and radiotherapy. The introduction of chemotherapy improved the overall survival. However, the regimen of pemetrexed/cisplatin doublet has not been changed as a standard treatment since 2004. Novel combinations of ipilimumab and nivolumab have only been approved for clinical use in late 2020. The aim of this review was to systematically summarize findings on novel treatment options in mesothelioma. We searched available medical databases online, such as PubMed and Clinicaltrials.gov, to systematically review the literature on novel approaches in immunotherapy, vaccines, and Chimeric Antigen Receptor (CAR)-T cell therapy in mesothelioma. We manually screened 1127 articles on PubMed and 450 trials on ClinicalTrials.gov, and 24 papers and 12 clinical trials published in the last ten years were included in this review. Immunotherapy that was swiftly introduced to treat other thoracic malignancies was slow to reach desirable survival endpoints in mesothelioma, possibly due to limited patient numbers. Novel treatment approaches, such as CAR-T cell therapy, are being investigated. As the incidence of mesothelioma is still rising globally, novel treatment options based on a better understanding of the tumor microenvironment and the genetic drivers that modulate it are needed to support future precision-based therapies.

RevDate: 2022-02-25

Spinazzè A, Consonni D, Borghi F, et al (2022)

Development of a Crosswalk to Translate Italian Occupation Codes to ISCO-68 Codes.

Annals of work exposures and health pii:6535940 [Epub ahead of print].

In occupational epidemiology, job coding is an important-but time-consuming-step in assigning exposure. We implemented a tool (i.e. a crosswalk) to translate occupation codes from the Italian (ISTAT-CIP-91, n = 6319 five-digit job codes) to the International Standard Classification of Occupations (ISCO-68, n = 1881 five-digit job codes). The former is currently used in Italy for various purposes (e.g. in the National Mesothelioma Registry). The latter has been used in several studies on occupational cancers because it facilitates communication of results to the scientific community and, most importantly, because some job exposure matrices (JEMs) are based on international codes. Three authors created a table containing the crosswalk structure, providing an interpretation for each of the ISTAT-CIP-91 codes job descriptions and then manually recoding them according to ISCO-68. Two other authors independently revised it. The performance of the final version was assessed by comparison with results obtained by manual ISCO-68 coding performed in two previous case-control studies on asbestos and mesothelioma. More specifically, the automatically obtained ISCO-68 codes were merged with a JEM (DOM-JEM). The resulting individual asbestos exposure estimates (ever versus never exposed) were compared to those originally obtained (using the same DOM-JEM) from manual translation of ISTAT-CIP-91 to ISCO-68 (considered as the 'gold standard'). In the first study, among 159 peritoneal mesothelioma cases (400 job codes), Cohen's kappa was 0.91, sensitivity 0.95, and specificity 0.96. In the second study, among 716 pleural mesothelioma cases and controls (4400 job codes) kappa was 0.86, sensitivity 0.94, and specificity 0.91. Performance was better among in women. For men, performance was lower among cases than among controls (kappa 0.70, sensitivity 0.95, specificity 0.72 versus kappa 0.87, sensitivity 0.97, and specificity 0.92). In conclusion, the proposed tool allowed a rapid translation of thousands of job codes with good to excellent accuracy. The table containing ISTAT-CIP-91 codes and job descriptions and the corresponding ISCO-68 codes and job descriptions is made publicly available and can be freely used for epidemiological analyses in Italy and international collaborations.

RevDate: 2022-02-25

Caraballo-Arias Y, Caffaro P, Boffetta P, et al (2022)

Quantitative Assessment of Asbestos Fibers in Normal and Pathological Pleural Tissue-A Scoping Review.

Life (Basel, Switzerland), 12(2): pii:life12020296.

BACKGROUND: pleural mesothelioma is a rare cancer in the general population, but it is more common in subjects occupationally exposed to asbestos. Studies with asbestos fiber quantification in pleural tissue are scarce: for this reason, we aimed at undertaking a scoping review to summarize the evidence provided by studies in which asbestos fibers were determined by electron microscopy (SEM or TEM) in human pleural tissues, whether normal or pathologic.

MATERIALS AND METHODS: A scoping review of articles that quantified asbestos fibers in human pleural tissue (normal or pathologic) by electron microscopy (SEM or TEM), in subjects with asbestos exposure (if any) was performed.

RESULTS: The 12 studies selected comprised 137 cases, out of which 142 samples were analyzed. Asbestos fibers were detected in 111 samples (78%) and were below the detectable limit in 31 samples (22%). The concentration of asbestos fibers detected in the positive samples was distributed from as low as 0.01 mfgdt (millions of fibers per gram of dry tissue) up to 240 mfgdt. However, the minimum concentration of fibers overlaps in the three types of tissues (normal pleura, pleural plaque, mesothelioma) in terms of magnitude; therefore, it is not possible to distinguish a definite pattern which differentiates one tissue from the other.

CONCLUSIONS: The studies included were heterogeneous as to the representativeness of the samples and analytical techniques; the possibility of false negatives must be considered. It would be desirable to systematically search for asbestos fibers to fill the knowledge gap about the presence of asbestos fibers in normal or pathological pleural tissue in order to better understand the development of the different pleural diseases induced by this mineral.

RevDate: 2022-02-25

Dalsgaard SB, Würtz ET, Hansen J, et al (2022)

A Cohort Study on Cancer Incidence among Women Exposed to Environmental Asbestos in Childhood with a Focus on Female Cancers, including Breast Cancer.

International journal of environmental research and public health, 19(4): pii:ijerph19042086.

OBJECTIVES: To examine the risk of cancer in former school children exposed to environmental asbestos in childhood with a focus on female cancers, including breast cancer.

METHODS: We retrieved a cohort of females (n = 6024) attending four schools located in the neighborhood of a large asbestos cement plant in Denmark. A reference cohort was frequency-matched 1:9 (n = 54,200) in sex and five-year age intervals. Using Danish registries, we linked information on historical employments, relatives' employments, cancer, and vital status. We calculated standardized incidence rates (SIRs) for all and specific cancers, comparing these rates with the reference cohort. Hazard ratios were calculated for selected cancers adjusted for occupational and familial asbestos exposure.

RESULTS: For cancer of the corpus uteri (SIR 1.29, 95% CI 1.01-1.66) and malignant mesothelioma (SIR 7.26, 95% CI 3.26-16.15), we observed significantly increased incidences. Occupationally, asbestos exposure had a significantly increased hazard ratio for cancer in the cervix, however, a significantly lower risk of ovarian cancer. The overall cancer incidence was similar to that of the reference cohort (SIR 1.02, 95% CI 0.96-1.07). The risk of cancer of the lung was increased for those exposed to occupational asbestos, those with family members occupationally exposed to asbestos and for tobacco smokers.

CONCLUSIONS: In our study, environmental asbestos exposure in childhood is associated with an increased risk of cancer of the corpus uteri and malignant mesothelioma in women.

RevDate: 2022-02-25

Shah R, Klotz LV, J Glade (2022)

Current Management and Future Perspective in Pleural Mesothelioma.

Cancers, 14(4): pii:cancers14041044.

Pleural mesothelioma is an aggressive malignancy arising from pleural mesothelial cell lining, predominantly associated with prior exposure to asbestos. The ban on asbestos use has led to its lower incidence in many countries, but globally the disease burden is expected to rise. Therefore, well-planned research is needed to develop more effective, tolerable and affordable drugs. The development of novel treatment has been too slow, with only two regimens of systemic therapy with robust phase 3 data approved formally to date. The treatment scenario for resectable disease remains controversial. However, recent developments in the understanding of disease and clinical trials have been encouraging, and may add better treatment options in the coming years. In this review, we discuss the current treatment options for pleural mesothelioma and shed light on some recent studies and ongoing trials.

RevDate: 2022-02-25

Foddis R, Franzini M, Bonotti A, et al (2022)

Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?.

Diagnostics (Basel, Switzerland), 12(2): pii:diagnostics12020311.

Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) analysis showed that the best Area Under Curve (AUC) value resulted from the combined index b/f (0.679, 95% CI: 0.582-0.777). Combining the b-/f-GGT activity with the levels of serum mesothelin-related protein (SMRP; another promising MPM biomarker) improved the diagnostic accuracy, increasing the AUC value to 0.875 (95% CI: 0.807-0.943, p = <0.0001). Since MPM has a specific pattern of GGT enzymatic activity, we could hypothesize that GGT fractions play different specific biochemical roles. The improvement in the diagnostic power given by the combination of these two biomarkers confirms that the strategy of biomarkers combination might be a better approach for MPM diagnosis.

RevDate: 2022-02-24

Lond B, Quincey K, Apps L, et al (2022)

The experience of living with mesothelioma: A meta-ethnographic review and synthesis of the qualitative literature.

Health psychology : official journal of the Division of Health Psychology, American Psychological Association pii:2022-34222-001 [Epub ahead of print].

OBJECTIVE: Mesothelioma is a life limiting cancer caused by previous exposure to asbestos. Due to the continued use of asbestos products internationally, the condition presents an increasing risk to global health with case numbers peaking in industrially developed nations. With the cancer reducing patient well-being, this study aimed to synthesizes the qualitative findings of studies exploring the experiences of patients living with mesothelioma to generate new conceptual insights and guide therapeutic care.

METHOD: Thirteen databases were systematically searched: Academic Search Premier, BioMed Central, British Nursing Database, CINAHL Plus, Cochrane Library, Europe PubMed Central, MEDLINE, PsycARTICLES, PsycINFO, Science Direct, Scopus, Social Care Online, and Web of Science, between August and September 2020. Included articles were subject to quality appraisal using CASP checklists, and their respective findings analyzed using a metaethnographic form of qualitative data synthesis.

RESULTS: Twenty-two articles met the inclusion criteria, and the data synthesis produced three themes: (1) "complex trauma"; (2) "psycho-behavioral coping strategies"; and (3) "external sources of support." Combined, these themes form a novel conceptual framework and awareness of the patient experience that presents the lived trauma of disease alongside a patients coping processes and support pathways.

CONCLUSION: Robust therapeutic support is needed to address the psychosocial and existential burden shouldered by people with mesothelioma. Therapies that promote sentiments of acceptance, hope, and benefit finding are proposed alongside initiatives that foster patient empowerment and meaning, and further promote patient choice in deciding end-of-life care. Recommendations for future research are also made. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

RevDate: 2022-02-12

van Kooten JP, Belderbos RA, von der Thüsen JH, et al (2022)

Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.

Thorax pii:thoraxjnl-2021-217709 [Epub ahead of print].

INTRODUCTION: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993.

MATERIALS AND METHODS: Patients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry. Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR). Treatment pattern and Kaplan-Meier overall survival analyses were performed.

RESULTS: In total, 12 168 patients were included in the study. For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between -9.4% and -1.8%, p<0.01). Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01). From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%). Overall, 62.2% of patients received no antitumour treatment. The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%). The median overall survival improved from 7.3 (1993-2003) to 8.9 (2004-2011) and 9.3 months from 2012 to 2018 (p<0.001).

CONCLUSION: The peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups. The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time. The majority of patients do not receive treatment though and prognosis is still poor.

RevDate: 2022-02-10

Louw A, van Vliet C, Peverall J, et al (2022)

Analysis of early pleural fluid samples in patients with mesothelioma: A case series exploration of morphology, BAP1, and CDKN2A status with implications for the concept of mesothelioma in situ in cytology.

Cancer cytopathology [Epub ahead of print].

BACKGROUND: The concept of mesothelioma in situ has been revisited and is a new World Health Organization diagnostic entity. The definition centers on ancillary techniques used in pleural mesothelioma (PM) assessment. At the authors' institution, most PM diagnoses are made on cytologic specimens. Effusion samples obtained before definitive PM diagnosis were interrogated using BRCA1-associated protein 1 gene (BAP1), cyclin-dependent kinase inhibitor 2A gene (CDKN2A) and cytologic evaluation to assess whether early or possible in situ disease could be characterized.

METHODS: All cases of PM diagnosed between January 2008 and December 2019 were identified at a tertiary referral center. Patients who had a pleural fluid sample collected 24 months before the diagnosis were selected, numbering 8 in total. The cytomorphology of each sample was reviewed; and, retrospectively, BAP1 immunohistochemistry (IHC) and CDKN2A fluorescence in situ hybridization (FISH) were performed on initial and diagnostic samples.

RESULTS: The initial samples were deemed benign in 5 cases and atypical mesothelial proliferations in 3 cases. A spectrum of apparently normal to atypical cytomorphologic changes was identified. BAP1 loss was present in 6 of 8 initial cases, whereas CDKN2A homozygous deletion was identified in 1 of 7 initial cases. Either abnormality was identified in 7 of 8 initial samples.

CONCLUSIONS: Detectable abnormalities of BAP1 IHC and CDKN2A FISH were present in pleural fluid specimens before the development of cytomorphologic features diagnostic of PM. This is the largest series to date describing cytology samples early in the course of PM development, thereby highlighting a possible cytological equivalent for mesothelioma in situ.

RevDate: 2022-02-07

Endo I, Amatya VJ, Kushitani K, et al (2021)

Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1.

Frontiers in oncology, 11:795467.

Malignant mesothelioma is a tumor with a poor prognosis, mainly caused by asbestos exposure and with no adequate treatment yet. To develop future therapeutic targets, we analyzed the microarray dataset GSE 29370 of malignant mesothelioma and reactive mesothelial hyperplasia, downloaded from the Gene Expression Omnibus (GEO) database. We identified insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) as one of the significantly upregulated genes in malignant mesothelioma. IGF2BP3 functions as an oncoprotein in many human cancers; however, to our knowledge, this is the first study on the biological function of IGF2BP3 in malignant mesothelioma cells. The knockdown of IGF2BP3 in malignant mesothelioma cells resulted in the suppression of cell proliferation with an increase in the proportion of cells in the G1 phase of the cell cycle. Furthermore, knockdown of IGF2BP3 inhibited cell migration and invasion. We focused on the cell cycle assay to investigate the role of IGF2BP3 in cell proliferation in malignant mesothelioma. Among the various proteins involved in cell cycle regulation, the expression of p27 Kip1 (p27) increased significantly upon IGF2BP3 knockdown. Next, p27 siRNA was added to suppress the increased expression of p27. The results showed that p27 knockdown attenuated the effects of IGF2BP3 knockdown on cell proliferation and G1 phase arrest. In conclusion, we found that IGF2BP3 promotes cell proliferation, a critical step in tumorigenesis, by suppressing the expression of p27 in malignant mesothelioma.

RevDate: 2022-02-04
CmpDate: 2022-02-04

Zhang F, Yuan X, Sun H, et al (2021)

A nontoxic dose of chrysotile can malignantly transform Met-5A cells, in which microRNA-28 has inhibitory effects.

Journal of applied toxicology : JAT, 41(11):1879-1892.

Chrysotile, which is classified as a class I carcinogen by the International Agency for Research on Cancer (IARC), has extensive application in the industry and can lead to lung or other cancers. However, whether chrysotile causes malignant mesothelioma and its molecular mechanism remain debatable. Thus, this study aimed to demonstrate the mesothelioma-inducing potential of chrysotile at the mesothelial cellular level and the function of microRNA-28 in malignantly transformed mesothelial MeT-5A cells. MeT-5A cells malignantly transformed by a nontoxic dose of chrysotile were named Asb-T, and miR-28 expression was downregulated in Asb-T cells. Restoration of miR-28 expression inhibited the proliferation, migration and invasion of Asb-T cells. We verified that IMPDH is a putative target of miR-28. The expression of IMPDH was significantly higher in Asb-T MeT-5A cells than in control cells, whereas the opposite trend was observed with miR-28 overexpression. Additionally, inhibition of IMPDH had similar effects as miR-28 overexpression. After miR-28 was elevated or IMPDH was inhibited, Ras activation was reduced, and its downstream pathways (the Erk and Akt signalling pathways) were inhibited. Surprisingly, the content of miR-28 in the blood of mesothelioma patients was higher than that in control subjects. Overall, nontoxic doses of chrysotile can cause malignant transformation of MeT-5A cells. Moreover, miR-28 inhibits the proliferation, migration and invasion of Asb-T MeT-5A cells, negatively regulates the expression of IMPDH through the Ras signalling pathway and may be an important therapeutic target.

RevDate: 2022-02-03

Repo P, Staskiewicz A, Sutinen E, et al (2022)

BAP1 germline variants in Finnish patients with malignant mesothelioma.

Lung cancer (Amsterdam, Netherlands), 165:102-107 pii:S0169-5002(22)00029-0 [Epub ahead of print].

OBJECTIVES: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM.

MATERIALS AND METHODS: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing.

RESULTS: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor.

CONCLUSION: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.

RevDate: 2022-02-03
CmpDate: 2022-02-03

Korchevskiy AA, AG Wylie (2021)

Dimensional determinants for the carcinogenic potency of elongate amphibole particles.

Inhalation toxicology, 33(6-8):244-259.

CONTEXT: Carcinogenic properties of particulates depend, among other factors, on dimensional characteristics that affect their ability to reach sensitive tissue, to be removed or retained, and to interact with the cells.

OBJECTIVE: To model mesothelioma and lung cancer potency of amphibole particles based on their dimensional characteristics and mineral habit (asbestiform vs. nonasbestiform) utilizing epidemiological data and detailed size information.

METHODS: The datasets from recently created depository of dimensional information of elongate mineral particles were used to correlate mesothelioma and lung cancer potency with the fraction of particles in a specific size range and the ratio of length and width in different powers. In addition, the cancer potency factors were estimated and compared for 30 asbestiform, 15 nonasbestiform, and 10 mixed datasets.

RESULTS: For particles longer than 5 µm, the highest correlation with mesothelioma potency was achieved for width <0.22 µm, and with lung cancer <0.28 µm. The statistical power of the correlation was observed to lose significance at a maximum width of 0.6-0.7 µm. Mesothelioma potency correlated with length in the power of 1.9 divided by width in the power of 2.97, lung cancer potency with length in the power of 0.4 divided by width in the power of 1.17. The predicted cancer potencies of asbestiform, nonasbestiform, and mixed categories were significantly different.

CONCLUSION: While additional studies in this direction are warranted, this paper should serve as an additional confirmation for the role of fiber dimensions in the carcinogenicity of amphibole elongate mineral particles (EMPs).

RevDate: 2022-02-01

LeMasters G, Lockey JE, Hilbert TJ, et al (2022)

Mortality of workers employed in refractory ceramic fiber manufacturing: An update.

Journal of applied toxicology : JAT [Epub ahead of print].

This study evaluates the possible association between refractory ceramic fibers (RCF) exposure and all causes of death. Current and former employees (n=1,119) hired from 1952-1999 at manufacturing facilities in New York (NY) state and Indiana were included. Work histories and quarterly plant-wide sampling from 1987-2015 provided cumulative fiber exposure (CFE) estimates. The full cohort was evaluated as well as individuals with lower and higher exposure, <45 and >45 fiber-months/cc. The Life-Table-Analysis-System was used for all standardized mortality estimates (SMR). Person-years at risk accumulated from start of employment until 12/31/2019 or date of death. There was no significant association with all causes, all cancers, or lung cancer in any group. In the higher exposed there was a significant elevation in both malignancies of the "urinary organs" (SMR=3.59, 95% CI 1.44, 7.40), and "bladder or other urinary site" (SMR=4.04, 95% CI 1.10, 10.36) which persisted in comparison to regional mortality rates from NY state and Niagara County. However, six of the nine workers with urinary cancers were known smokers. In the lower exposed there was a significant elevation in malignancies of the lymphatic and hematopoietic system (SMR=2.54, 95% CI 1.27, 4.55) and leukemia (SMR=4.21, 95% CI 1.69, 8.67). There was one pathologically unconfirmed mesothelioma death. A second employee currently living with a pathologically confirmed mesothelioma was identified, but the SMR was non-significant when both were included in the analyses. The association of these two mesothelioma cases with RCF exposure alone is unclear because of potential past exposure to asbestos.

RevDate: 2022-01-31

Le HT, Dinh HT, TT Ngo (2022)

Asbestos Dust Concentrations and Health Conditions of Workers at Asbestos - Cement Corrugated Sheets Production Manufacturers in Vietnam: A national-wide assessment.

International journal of occupational safety and ergonomics : JOSE [Epub ahead of print].

This study examined contemporary concentrations of asbestos dust during production and health conditions of workers at Asbestos - Cement Corrugated Sheets Production Manufacturers in Vietnam. A nationwide survey was conducted on 28 factories (with 206 air samples) and 2459 workers. Asbestos fiber dust and the health status of workers were assessed. Results showed that 108/206 (52.4%) samples had asbestos fiber dust. The average concentration of asbestos fibers was 0.19±0.14 fibers/ml. The percentage of workers with thickened pleural lesions/pleural calcification nodules was low. More studies are needed to evaluate the effectiveness of biomarkers in preventing the onset of lung cancer and mesothelioma in workers.

RevDate: 2022-01-31

Zolondick AA, Gaudino G, Xue J, et al (2021)

Asbestos-induced chronic inflammation in malignant pleural mesothelioma and related therapeutic approaches-a narrative review.

Precision cancer medicine, 4:.

Objective: The aim of this review is addressing the mechanisms of asbestos carcinogenesis, including chronic inflammation and autophagy-mediated cell survival, and propose potential innovative therapeutic targets to prevent mesothelioma development or improve drug efficacy by reducing inflammation and autophagy.

Background: Diffuse malignant pleural mesothelioma is an aggressive cancer predominantly related to chronic inflammation caused by asbestos exposure. Millions of individuals have been exposed to asbestos or to other carcinogenic mineral fibers occupationally or environmentally, resulting in an increased risk of developing mesothelioma. Overall patient survival rates are notably low (about 8-14 months from the time of diagnosis) and mesothelioma is resistant to existing therapies. Additionally, individuals carrying inactivating germline mutations in the BRCA-associated protein 1 (BAP1) gene and other genes are predisposed to developing cancers, prevalently mesothelioma. Their risk of developing mesothelioma further increases upon exposure to asbestos. Recent studies have revealed the mechanisms and the role of inflammation in asbestos carcinogenesis. Biomarkers for asbestos exposure and malignant mesothelioma have also been identified. These findings are leading to the development of novel therapeutic approaches to prevent or delay the growth of mesothelioma.

Methods: Review of full length manuscripts published in English from January 1980 to February 2021 gathered from PubMed.gov from the National Center of Biotechnology Information and the National Library of Medicine were used to inform this review.

Conclusion: Key regulators of chronic inflammation mediate asbestos-driven mesothelial cell transformation and survival through autophagic pathways. Recent studies have elucidated some of the key mechanisms involved in asbestos-induced chronic inflammation, which are largely driven by extracellular high mobility group box 1 (HMGB1). Upon asbestos exposure, mesothelial cells release HMGB1 from the nucleus to the cytoplasm and extracellular space, where HMGB1 initiates an inflammatory response. HMGB1 translocation and release also activates autophagy and other pro-survival mechanisms, which promotes mesothelioma development. HMGB1 is currently being investigated as a biomarker to detect asbestos exposure and to detect mesothelioma development in its early stage when therapy is more effective. In parallel, several approaches inhibiting HMGB1 activities have been studied and have shown promising results. Moreover, additional cytokines, such as IL-1β and TNF-α are being targeted to interfere with the inflammatory process that drives mesothelioma growth. Developing early detection methods and novel therapeutic strategies is crucial to prolong overall survival of patients with mesothelioma. Novel therapies targeting regulators of asbestos-induced inflammation to reduce mesothelioma growth may lead to clinical advancements to benefit patients with mesothelioma.

RevDate: 2022-01-28

Yue L, Luo Y, Jiang L, et al (2022)

PCBP2 knockdown promotes ferroptosis in malignant mesothelioma.

Pathology international [Epub ahead of print].

Malignant mesothelioma (MM) is still increasing worldwide. The pathogenesis depends on asbestos-induced iron accumulation, which eventually leads to ferroptosis-resistance of mesothelial cells via somatic mutations. Poly (rC)-binding proteins 1 and 2 (PCBP1/2) are recently recognized cytosolic Fe(II) chaperones. Here we studied the role of PCBP1/2 in rat/human mesothelial and MM cells as well as rat/human MM specimens. Normal peritoneal mesothelial cells in rats exhibited PCBP1 but not PCBP2 immunopositivity whereas primary/immortalized mesothelial cells showed PCBP1/2 immunopositivity. Rat MM specimens induced by intraperitoneal injection of chrysotile, including in situ lesion, revealed PCBP1/2 immunopositivity (90% for both) in the nucleus and cytoplasm with a tendency of higher expression in epithelioid subtype. Knockdown of PCBP2 but not PCBP1 significantly decreased both TfR1 and FTH expression in MM cells with inhibition of proliferation, indicating stagnation of intracellular iron transport. Erastin, a cysteine-deprivation type ferroptosis inducer, decreased the expression of both PCBP1/2 in MM cells. Furthermore, PCBP2 knockdown significantly increased the sensitivity of MM cells to erastin-induced ferroptosis with increased catalytic Fe(II). In conclusion, PCBP2 works for ferroptosis-resistance not only during mesothelial carcinogenesis but also in MM, which warrants further investigation as a novel therapeutic target.

RevDate: 2022-01-28

Kelsey K (2022)

Epigenetics, environment and epidemiology: an interview with Karl Kelsey.

Epigenomics [Epub ahead of print].

In this interview, Professor Karl Kelsey speaks with Storm Johnson, Commissioning Editor for Epigenomics, on his work to date in the field of environmental epigenomics and epidemiology. Dr Karl Kelsey, MD, MOH is a Professor of Epidemiology and Pathology and Laboratory Medicine at Brown University. He is the Founding Director of the Center for Environmental Health and Technology and Head of the Environmental Health Section at the Department of Epidemiology. Dr Kelsey is interested in the application of laboratory-based biomarkers in environmental disease, with experience in chronic disease epidemiology and tumor biology. The goals of his work include a mechanistic understanding of individual susceptibility to exposure-related cancers. In addition, his laboratory is interested in tumor biology, investigating somatic alterations in tumor tissue from the patients who have developed exposure-related cancers. This work involves the use of an epidemiologic approach to characterize epigenetic and genetic alteration of genes in the causal pathway for malignancy. Active work includes several studies of individual susceptibility to cancer. Dr Kelsey's laboratory mainly investigates susceptibility to smoking-related lung cancer and studies multi-racial and ethnic populations. In addition, the laboratory is also involved with the study of inherited susceptibility to brain tumors and pancreatic cancer. Major case control studies that are ongoing in the laboratory include studies designed to understand inherited and acquired susceptibility in head and neck cancers. The laboratory is also involved in a case control study of asbestos-associated mesothelioma, arsenic exposure, cigarette smoking and bladder cancer. Considerable work is being devoted to understanding the mechanisms of action of both asbestos and arsenic including their ability to affect promoter methylation and gene silencing in carcinogenesis. Recent laboratory studies includes an interest in using newly developed DNA methylation biomarkers to probe immune profiles from archived blood. Dr Kelsey received his MD from the University of Minnesota and Masters of Occupational Health from Harvard University.

RevDate: 2022-01-26

Tao XG, Curriero FC, Chee EM, et al (2022)

Updated Standardized Mortality Ratio Evaluation of Disease Risks of Shipyard Workers Exposed to Low Dose Ionizing Radiation.

Journal of occupational and environmental medicine pii:00043764-900000000-97652 [Epub ahead of print].

OBJECTIVE: To examine the risk of diseases among industrial workers with low and fractionated radiation exposures.

METHOD: 372,047 US male shipyard radiation and non-radiation workers were followed for 54 years and compared to US males using Standardized Mortality Ratio (SMR) method.

RESULTS: SMRs for both radiation and non-radiation workers had lower risks of death from all causes (0.74; 95% Confidence interval (CI) 0.74-0.75 and 0.77; 95% Cl 0.77-0.78, respectively) and from all cancers (0.92; 95% CI 0.91-0.93 and 0.90; 95% CI 0.89-0.91, respectively) compared to US males. Asbestos-related diseases including pleural cancers, mesothelioma, and asbestosis, but not lung cancers, were statistically higher in both radiation and non-radiation workers compared to the US males.

CONCLUSION: US shipyard male radiation and non-radiation workers did not show any elevated mortality risks that might be associated with radiation exposure.

RevDate: 2022-01-26

Kok PS, Forde PM, Hughes B, et al (2022)

Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial.

BMJ open, 12(1):e057663 pii:bmjopen-2021-057663.

INTRODUCTION: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial.

METHODS AND ANALYSIS: This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma.

ETHICS AND DISSEMINATION: The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.

DRUG SUPPLY: AstraZeneca.

PROTOCOL VERSION: CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.

RevDate: 2022-01-24

Voloaca OM, Clench MR, Koellensperger G, et al (2022)

Elemental Mapping of Human Malignant Mesothelioma Tissue Samples Using High-Speed LA-ICP-TOFMS Imaging.

Analytical chemistry [Epub ahead of print].

This is the first report of the use of laser ablation-inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS) to analyze human malignant pleural mesothelioma (MPM) samples at the cellular level. MPM is an aggressive, incurable cancer associated with asbestos exposure, with a long latency and poor overall survival. Following careful optimization of the laser fluence, the simultaneous ablation of soft biological tissue and hard mineral fibers was possible, allowing the spatial detection of elements such as Si, Mg, Ca, and Fe, which are also present in the glass substrate. A low-dispersion LA setup was employed, which provided the high spatial resolution necessary to identify the asbestos fibers and fiber fragments in the tissue and to characterize the metallome at the cellular level (a pixel size of 2 μm), with a high speed (at 250 Hz). The multielement LA-ICP-TOFMS imaging approach enabled (i) the detection of asbestos fibers/mineral impurities within the MPM tissue samples of patients, (ii) the visualization of the tissue structure with the endogenous elemental pattern at high spatial resolution, and (iii) obtaining insights into the metallome of MPM patients with different pathologies in a single analysis run. Asbestos and other mineral fibers were detected in the lung and pleura tissue of MPM patients, respectively, based on their multielement pattern (Si, Mg, Ca, Fe, and Sr). Interestingly, strontium was detected in asbestos fibers, suggesting a link between this potential toxic element and MPM pathogenesis. Furthermore, monitoring the metallome around the talc deposit regions (characterized by elevated levels of Al, Mg, and Si) revealed significant tissue damage and inflammation caused by talc pleurodesis. LA-ICP-TOFMS results correlated to Perls' Prussian blue and histological staining of the corresponding serial sections. Ultimately, the ultra-high-speed and high-spatial-resolution capabilities of this novel LA-ICP-TOFMS setup may become an important clinical tool for simultaneous asbestos detection, metallome monitoring, and biomarker identification.

RevDate: 2022-01-21

Senek M, Robertson S, Darlison L, et al (2022)

Malignant pleural mesothelioma patients' experience by gender: findings from a cross-sectional UK-national questionnaire.

BMJ open respiratory research, 9(1):.

OBJECTIVES: Malignant mesothelioma is an aggressive malignancy of mesothelial surfaces, most commonly those of the pleura. The aim of this study was to understand, using a national questionnaire, the gendered care experiences of patients with malignant pleural mesothelioma (MPM).Patients were asked about their experience of the diagnostic process, about information clarity, health care professionals' knowledge, general practitioner support and overall satisfaction with care received.

SETTING: Recruitment of patients was carried out in three UK countries (England, Wales and Scotland) via mesothelioma clinical nurse specialists.

PARTICIPANTS: In total, 503 patients completed the questionnaire. 460 had MPM, the remainder had other types of mesothelioma. In accord with the study protocol, only the MPM patients were included in this study.Primary and secondary measures were: (1) time from symptom to diagnosis, (2) satisfaction with the diagnosis and treatment, and (3) quality of life and well-being.

RESULTS: There were gender differences in time from symptom to diagnosis. The time from symptom to diagnosis was significantly longer for women than men (median=152 days vs men=92 days, p=0.01). Lack of a verified source of exposure to asbestos was a hindrance to private treatment access for women (95% of those that access private treatment are men). Patients were five times more likely to be satisfied if they thought that the doctors knew enough about their condition (OR=4.4, p=0.001) and nearly three times more likely to be satisfied if information was presented in a sensitive way (OR=2.8,p=0.01).

CONCLUSIONS: This study has several implications for clinical practice. Our findings suggest that the diagnostic time in women might be reduced by reviewing diagnostic processes including occupational history taking, and by revising the occupational risk of mesothelioma categorisation.

RevDate: 2022-01-26
CmpDate: 2022-01-26

Sunitha S, Shah AH, Gami A, et al (2021)

Thigh mass in a patient with malignant pleural mesothelioma: Metastasis at an unusual site.

Indian journal of pathology & microbiology, 64(4):834-836.

Soft tissue tumors are a highly heterogeneous group of lesions with varied clinical presentation. The majority is primary tumors and metastatic tumors are very rare. Malignant pleural mesothelioma presenting as a soft tissue mass at a distant site is even rarer and can cause diagnostic challenges both clinically and pathologically. We report a case of malignant pleural mesothelioma presenting as a soft tissue mass in the left thigh. A 59-year-old man, non-smoker, working in a cement factory since 30 years presented with complains of difficulty in walking since 1½ months. Review of his previous medical records revealed malignant pleural mesothelioma, which was diagnosed 9 months before. He had denied chemotherapy and was on Ayurvedic medication. The lesion involved the adjacent intercostal muscles. Few enlarged lymph nodes were noted in mediastinal and cervical regions. Biopsy of left supraclavicular and right cervical lymph nodes showed metastases. Metastasis from malignant pleural mesothelioma to the thigh was confirmed by immunohistochemistry. The tumor was positive for CK5/6, CK7, Calretinin and vimentin and immunonegative for CEA, Napsin A and TTF 1.

RevDate: 2022-01-18

Armato SG, Nowak AK, Francis RJ, et al (2021)

Imaging in pleural mesothelioma: A review of the 15th International Conference of the International Mesothelioma Interest Group.

Lung cancer (Amsterdam, Netherlands), 164:76-83 pii:S0169-5002(21)00636-X [Epub ahead of print].

Imaging of mesothelioma plays a role in all aspects of patient management, including disease detection, staging, evaluation of treatment options, response assessment, pre-surgical evaluation, and surveillance. Imaging in this disease impacts a wide range of disciplines throughout the healthcare enterprise. Researchers and clinician-scientists are developing state-of-the-art techniques to extract more of the information contained within these medical images and to utilize it for more sophisticated tasks; moreover, image-acquisition technology is advancing the inherent capabilities of these images. This paper summarizes the imaging-based topics presented orally at the 2021 International Conference of the International Mesothelioma Interest Group (iMig), which was held virtually from May 7-9, 2021. These topics include an update on the mesothelioma staging system, novel molecular targets to guide therapy in mesothelioma, special considerations and potential pitfalls in imaging mesothelioma in the immunotherapy setting, tumor measurement strategies and their correlation with patient survival, tumor volume measurement in MRI and CT, CT-based texture analysis for differentiation of histologic subtype, diffusion-weighted MRI for the assessment of biphasic mesothelioma, and the prognostic significance of skeletal muscle loss with chemotherapy.

RevDate: 2022-01-15

Sculco M, La Vecchia M, Aspesi A, et al (2022)

Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.

European journal of cancer (Oxford, England : 1990), 163:44-54 pii:S0959-8049(21)01304-6 [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.

AIM: This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.

METHODS: NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair.

RESULTS: We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat).

CONCLUSIONS: Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.

RevDate: 2022-01-11

Dalsgaard SB, Würtz ET, Hansen J, et al (2021)

Cancer Incidence and Risk of Multiple Cancers after Environmental Asbestos Exposure in Childhood-A Long-Term Register-Based Cohort Study.

International journal of environmental research and public health, 19(1): pii:ijerph19010268.

OBJECTIVES: To examine the asbestos-associated cancer incidence and the risk of multiple cancers in former school children exposed to environmental asbestos in childhood.

METHODS: A cohort of 12,111 former school children, born 1940-1970, was established using 7th grade school records from four schools located at a distance of 100-750 m in the prevailing wind direction from a large asbestos-cement plant that operated from 1928 to 1984 in Aalborg, Denmark. Using the unique Danish personal identification number, we linked information on employments, relatives' employments, date of cancer diagnosis, and type of cancer and vital status to data on cohortees extracted from the Supplementary Pension Fund Register (employment history), the Danish Cancer Registry, and the Danish Civil Registration System. We calculated standardized incidence rates (SIRs) for asbestos-associated cancers, all cancers, and multiple cancers using rates for a gender and five-year frequency-matched reference cohort.

RESULTS: The overall incidence of cancer was modestly increased for the school cohort (SIR 1.07, 95% confidence interval (CI) 1.02-1.12) compared with the reference cohort. This excess was driven primarily by a significantly increased SIR for malignant mesothelioma (SIR 8.77, 95% CI 6.38-12.05). Former school children who had combined childhood environmental and subsequent occupational exposure to asbestos had a significantly increased risk of lung cancer. Within this group, those with additional household exposure by a relative had a significantly increased SIR for cancer of the pharynx (SIR 4.24, 95% CI 1.59-11.29). We found no significant difference in the number of subjects diagnosed with multiple cancers between the two cohorts.

CONCLUSIONS: Our study confirms the strong association between environmental asbestos exposure and malignant mesothelioma and suggests that environmental asbestos exposure in childhood may increase the overall cancer risk later in life.

RevDate: 2022-01-11

Binazzi A, Di Marzio D, Verardo M, et al (2021)

Asbestos Exposure and Malignant Mesothelioma in Construction Workers-Epidemiological Remarks by the Italian National Mesothelioma Registry (ReNaM).

International journal of environmental research and public health, 19(1): pii:ijerph19010235.

Notwithstanding the ban in 1992, asbestos exposure for workers in the construction sector in Italy remains a concern. The purpose of this study is to describe the characteristics of malignant mesothelioma (MM) cases recorded by the Italian registry (ReNaM) among construction workers. Incident mesothelioma cases with a definite asbestos exposure have been analyzed. Characteristics of cases and territorial clusters of crude rates of MM in construction workers have been described, as well as the relation between asbestos use before the ban and the historical trend of workforce in the construction sector in Italy. ReNaM has collected 31,572 incident MM cases in the period from 1993 to 2018 and asbestos exposure has been assessed for 24,864 (78.2%) cases. An occupational exposure has been reported for 17,191 MM cases (69.1% of subjects with a definite asbestos exposure). Among them, 3574 had worked in the construction sector, with an increasing trend from 15.8% in the 1993-98 period to 23.9% in 2014-2018 and a ubiquitous territorial distribution. The large use of asbestos in construction sector before the ban makes probability of exposure for workers a real concern still today, particularly for those working in maintenance and removal of old buildings. There is a clear need to assess, inform, and prevent asbestos exposure in this sector.

RevDate: 2022-01-10

Crovella S, Revelant A, Muraro E, et al (2021)

Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study.

Frontiers in oncology, 11:784081.

Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.

RevDate: 2022-01-07

Tai SY, Wu J, Lee LJ, et al (2021)

How Malignant Mesothelioma Was Coded in Mortality Data in Taiwan During Years When the Specific ICD Code Was Not Available?.

Clinical epidemiology, 13:1135-1140 pii:339956.

Purpose: Malignant mesothelioma (MM) is associated with past exposure to asbestos and the latency period ranged from 20 to 40 years. Asbestos consumption reached a peak in the 1980s in Taiwan, and the MM mortality is expected to increase since 2000s. However, no specific code for MM was available before the International Classification of Disease, Tenth Revision (ICD-10), which was launched in 2008 in Taiwan. We examined how MM was coded in mortality data in Taiwan during the years when the ICD, Ninth Revision (ICD-9) was used.

Patients and Methods: Double-coded mortality data (each death coded according to both ICD-10 and ICD-9 codes) for the period 2002-2008 were obtained for analysis. Detection rates (similar to sensitivity) and confirmation rates (similar to positive predictive value) for various potential proxy ICD-9 codes for MM were calculated.

Results: For 113 deaths, for which the underlying cause of death was ICD-10 code C45 (MM), 14 corresponding ICD-9 codes were used. Four ICD-9 codes constituted 77% (87/113) of all MM deaths. The detection rate for code 199 (malignant neoplasm [MN] without specification of site) was 37% (42/113), that for code 163 (MN of pleura) was 18% (20/113), that for code 162 (MN of trachea, bronchus, and lung) was 12% (14/113), and that for code 173 (other MN of skin) was 10% (11/113). The confirmation rates for codes 199, 163, 162, and 173 were 0.9% (42/4759), 14.3% (20/140), 0.03% (14/51,778), and 1.5% (11/717), respectively.

Conclusion: ICD-9 codes 199, 163, 162, and 173 were most commonly used for MM deaths in Taiwan during the years before the ICD-10 introduction. However, when we used only ICD-9 code 163, which was most commonly used as a surrogate measure of MM in mortality studies during the ICD-9 era, we could detect only one-fifth of MM deaths in Taiwan.

RevDate: 2022-01-05

Orozco Morales ML, Rinaldi CA, de Jong E, et al (2022)

PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective.

iScience, 25(1):103571 pii:S2589-0042(21)01541-8.

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumors displayed a transcriptional signature consistent with increased activity of nuclear receptors PPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent, dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro anti-tumor effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.

RevDate: 2021-12-30
CmpDate: 2021-12-30

Lysaniuk B, Cely-García MF, Giraldo M, et al (2021)

Using GIS to Estimate Population at Risk Because of Residence Proximity to Asbestos Processing Facilities in Colombia.

International journal of environmental research and public health, 18(24):.

The recent enactment of the law banning asbestos in Colombia raises a significant number of challenges. The largest factories that have historically processed asbestos include five asbestos-cement facilities located in the cities of Sibaté (Cundinamarca), Cali (Valle del Cauca), and Barranquilla (Atlántico), and Manizales (Caldas), which has two, as well as a friction products facility in Bogotá D.C. An asbestos chrysotile mine has also operated in Colombia since 1980 in Campamento (Antioquia). In the framework of developing the National Asbestos Profile for Colombia, in this study, we estimated the population residing in the vicinity of asbestos processing plants or the mine and, therefore, potentially at risk of disease. Using a geographic information system, demographic data obtained from the last two general population censuses were processed to determine the number of people living within the concentric circles surrounding the asbestos facilities and the mine. In previous studies conducted in different countries of the world, an increased risk of asbestos-related diseases has been reported for people living at different distance bands from asbestos processing facilities. Based on these studies, circles of 500, 1000, 2000, 5000, and 10,000 m radii, centered on the asbestos processing facilities and the mine that operated in Colombia, were combined with the census data to estimate the number of people living within these radii. Large numbers of people were identified. It is estimated that in 2005, at the country level, 10,489 people lived within 500 m of an asbestos processing facility or mine. In 2018, and within a distance of 10,000 m, the number of people was 6,724,677. This information can aid public health surveillance strategies.

RevDate: 2021-12-29

Okazaki Y (2021)

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

Pathology international [Epub ahead of print].

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

RevDate: 2021-12-28

Kottek M, ML Yuen (2021)

Public health risks from asbestos cement roofing.

American journal of industrial medicine [Epub ahead of print].

There is no identified risk-free threshold exposure to asbestos. Based on epidemiology and toxicology, asbestos fiber dimensions have been implicated in causing asbestos-related diseases. Phase-contrast microscopy provides only a limited index of exposure to fiber dimensions implicated in mesothelioma induction. Installed asbestos-containing materials (ACMs) create an ongoing risk of intense exposure during natural disasters and remodeling, along with low-level exposure arising from the continual emission of airborne asbestos into the environment arising from weathering of installed ACM. Epidemiological studies have demonstrated a risk of disease associated with proximity to asbestos cement roofing (ACR), while ongoing environmental emissions of asbestos from installed ACR have also been demonstrated. Owing to the limitations of the available data, a precautionary approach is warranted; asbestos-free roofing materials should be used in new construction and existing ACR should be removed at the earliest opportunity.

RevDate: 2021-12-28

Forte IM, Indovina P, Montagnaro S, et al (2021)

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

Viruses, 13(12): pii:v13122458.

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

RevDate: 2021-12-24

Klebe S, Hocking AJ, Soeberg M, et al (2021)

The Significance of Short Latency in Mesothelioma for Attribution of Causation: Report of a Case with Predisposing Germline Mutations and Review of the Literature.

International journal of environmental research and public health, 18(24): pii:ijerph182413310.

Malignant mesothelioma is a tumour of the serosal membranes, related to asbestos exposure. Median latency is in the order of 40 years in various registries, but small numbers of cases with shorter latencies have long been reported and often dismissed as unrelated to asbestos exposure. However, emerging data regarding the significance of inherited mutations leading to a predisposition to mesothelioma suggest that the causative effect of asbestos may be associated with shorter latencies in a subset of patients. Here, we describe a male patient with germline mutations in RAD51 and p53 who developed peritoneal mesothelioma 8.5 years after well-documented asbestos exposure and discuss the current literature on the subject. Mesothelioma in situ is now a WHO-accepted diagnosis, but preliminary data reveal a potential lead time of 5 or more years to invasive disease, and this is also a factor which may affect the recording of latency (and potentially survival) in the future.

RevDate: 2021-12-24

Abukar A, Wipplinger M, Hariharan A, et al (2021)

Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A.

Cells, 10(12): pii:cells10123543.

Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its mRNA editing. RBM8A protein expression was higher in mesothelioma compared to mesothelial cells. Silencing RBM8A changed splicing patterns in mesothelial and mesothelioma cells but drastically reduced viability only in mesothelioma cells. In the tissues of asbestos-exposed mice, editing of Rbm8a mRNA was associated with increased protein immunoreactivity, with no change in mRNA levels. Increased adenosine deaminase acting on dsRNA (ADAR)-dependent editing of Alu elements in the RBM8A 3'UTR was observed in mesothelioma cells compared to mesothelial cells. Editing stabilized protein expression. The unedited RBM8A 3'UTR had a stronger interaction with Musashi (MSI) compared to the edited form. The silencing of MSI2 in mesothelioma or overexpression of Adar2 in mesothelial cells resulted in increased RBM8A protein levels. Therefore, ADAR-dependent editing contributes to maintaining elevated RBM8A protein levels in mesothelioma by counteracting MSI2-driven downregulation. A wider implication of this mechanism for the translational control of protein expression is suggested by the editing of similarly structured Alu elements in several other transcripts.

RevDate: 2021-12-24

Gharib AF, Alaa Eldeen M, Khalifa AS, et al (2021)

Assessment of Glutathione Peroxidase-1 (GPX1) Gene Expression as a Specific Diagnostic and Prognostic Biomarker in Malignant Pleural Mesothelioma.

Diagnostics (Basel, Switzerland), 11(12): pii:diagnostics11122285.

Malignant pleural mesothelioma (MPM) is a malignant tumor of the mesothelial lining of the thorax. It has been related to frequent exposure to asbestos. Diagnosis of malignant pleural mesothelioma is considered a criticizing problem for clinicians. Early diagnosis and sufficient surgical excision of MPM are considered the cornerstone success factors for the management of early MPM. Glutathione peroxidase-1 (GPX1) is an intracellular protein found to be extensively distributed in all cells, and it belongs to the GPX group. In the current study, we included ninety-eight patients with MPM that underwent surgery at the Zagazig University Hospital in Egypt. We assessed GPX1 gene expression level as it was thought to be related to pathogenicity of cancer in a variety of malignant tumors. We observed a significant elevation in GPX1-mRNA levels in MPM relative to the nearby normal pleural tissues. It was found to be of important diagnostic specificity in the differentiation of MPM from normal tissues. Moreover, we studied the survival of patients in correlation to the GPX1 expression levels and we reported that median overall survival was about 16 months in patients with high GPX1 expression levels, while it was found to be about 40 months in low GPX1 levels.

RevDate: 2021-12-15

Hajj GNM, Cavarson CH, Pinto CAL, et al (2021)

Malignant pleural mesothelioma: an update.

Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia, 47(6):e20210129 pii:S1806-37132021000600500.

Malignant mesotheliomas are rare types of cancers that affect the mesothelial surfaces, usually the pleura and peritoneum. They are associated with asbestos exposure, but due to a latency period of more than 30 years and difficult diagnosis, most cases are not detected until they reach advanced stages. Treatment options for this tumor type are very limited and survival ranges from 12 to 36 months. This review discusses the molecular physiopathology, current diagnosis, and latest therapeutic options for this disease.

RevDate: 2021-12-15

Frontini F, Bononi I, Torreggiani E, et al (2021)

Circulating microRNA-197-3p as a potential biomarker for asbestos exposure.

Scientific reports, 11(1):23955.

Asbestos is considered the main cause of diseases in workers exposed to this mineral in the workplace as well as an environmental pollutant. The association between asbestos and the onset of different diseases has been reported, but asbestos exposure specific biomarkers are not known. MicroRNAs (miRNAs) are small, single-strand, non-coding RNAs, with potential value as diagnostic, prognostic, and predictive markers in liquid biopsies. Sera collected from workers ex-exposed to asbestos (WEA) fibers were compared with sera from healthy subjects (HS) of similar age, as liquid biopsies. The expression of the circulating miRNA 197-3p was investigated employing two different highly analytical PCR methods, i.e. RT-qPCR and ddPCR. MiR-197-3p levels were tested in sera from WEA compared to HS. MiR-197-3p tested dysregulated in sera from WEA (n = 75) compared to HS (n = 62). Indeed, miR-197-3p was found to be 2.6 times down-regulated in WEA vs. HS (p = 0.0001***). In addition, an inverse correlation was detected between miR-197-3p expression level and cumulative asbestos exposure, being this miRNA down-regulated 2.1 times in WEA, with high cumulative asbestos exposure, compared to WEA with low exposure (p = 0.0303*). Circulating miR-197-3p, found to be down regulated in sera from WEA, is proposed as a new potential biomarker of asbestos exposure.

RevDate: 2021-12-13

Johnson BW, Takahashi K, YY Cheng (2021)

Preclinical Models and Resources to Facilitate Basic Science Research on Malignant Mesothelioma - A Review.

Frontiers in oncology, 11:748444.

Malignant mesothelioma is an aggressive cancer with poor prognosis, predominantly caused by human occupational exposure to asbestos. The global incidence of mesothelioma is predicted to increase as a consequence of continued exposure to asbestos from a variety of sources, including construction material produced in the past in developed countries, as well as those currently being produced in developing countries. Mesothelioma typically develops after a long latency period and consequently it is often diagnosed in the clinic at an advanced stage, at which point standard care of treatment, such as chemo- and radio-therapy, are largely ineffective. Much of our current understanding of mesothelioma biology, particularly in relation to disease pathogenesis, diagnosis and treatment, can be attributed to decades of preclinical basic science research. Given the postulated rising incidence in mesothelioma cases and the limitations of current diagnostic and treatment options, continued preclinical research into mesothelioma is urgently needed. The ever-evolving landscape of preclinical models and laboratory technology available to researchers have made it possible to study human disease with greater precision and at an accelerated rate. In this review article we provide an overview of the various resources that can be exploited to facilitate an enhanced understanding of mesothelioma biology and their applications to research aimed to improve the diagnosis and treatment of mesothelioma. These resources include cell lines, animal models, mesothelioma-specific biobanks and modern laboratory techniques/technologies. Given that different preclinical models and laboratory technologies have varying limitations and applications, they must be selected carefully with respect to the intended objectives of the experiments. This review therefore aims to provide a comprehensive overview of the various preclinical models and technologies with respect to their advantages and limitations. Finally, we will detail about a highly valuable preclinical laboratory resource to curate high quality mesothelioma biospecimens for research; the biobank. Collectively, these resources are essential to the continued advancement of precision medicine to curtail the increasing health burden caused by malignant mesothelioma.

RevDate: 2021-12-13

Marazioti A, Krontira AC, Behrend SJ, et al (2021)

KRAS signaling in malignant pleural mesothelioma.

EMBO molecular medicine [Epub ahead of print].

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.

RevDate: 2021-12-07

Sohn EJ (2021)

Bioinformatic Analysis of Potential Biomarker for hsa-miR-196b-5p in Mesothelioma.

Genetic testing and molecular biomarkers [Epub ahead of print].

Purpose: Malignant pleural mesothelioma is a rare neoplasia with a poor prognosis, and the majority of patients have advanced disease at the time of presentation. Exposure to asbestos is the most important risk factor for malignant pleural mesothelioma. Materials and Methods: To determine the cytotoxicity of geldanamycin in mesothelioma H28 cells, the MTT assay was used. To determine changes in microRNA (miRNA) expression in geldanamycin-treated H28 cells, miRNA microarray analysis was performed. To determine the function of miR-196b-5p, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of miR-196b-5p targets predicted by miRwalk. Results: Our data showed that geldanamycin treatment reduced H28 cell viability in a dose-dependent manner. MicroRNA array showed that expression of hsa-miR-196b-5p was downregulated in geldanamycin-treated H28 cells. Geldanamycin regulated miRNAs with roles in processes such as aging, angiogenesis, apoptosis, cell cycle, cell differentiation, cell proliferation, DNA repair, and secretion. Survival analysis showed that low expression of hsa-miR-196b-5p was significantly associated with a better outcome in mesothelioma patients. Expression of miR-196b-5p was also significantly associated with the developmental stages of mesothelioma. To narrow down the target genes of miR-196b-5p, we determined the overlap between the predicted target genes of miR-196b-5p and downregulated mRNAs in ovarian cancer based on the Gene Expression Omnibus dataset GSE12345. PDE1A, LAMA4, and PAPPA were identified as both miR-196b-5p targets and downregulated genes in GSE12345 and were thus considered targets of miR-196b-5p. Gene-miRNA expression correlation analysis showed that PDE1A, LAMA4, and PAPPA expression was negatively correlated with miR-196b-5p expression. Conclusions: We suggest that geldanamycin is potentially useful as an anticancer effect for the treatment of mesothelioma via regulating miR-196b-5p. Furthermore, miR-196b-5p may be a potential biomarker for mesothelioma.

RevDate: 2021-12-03

Popat S, Baas P, Faivre-Finn C, et al (2021)

Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

RevDate: 2021-11-29

Chen Z, Song S, Yang C, et al (2021)

Lipid Profiling in Malignant Mesothelioma Reveals Promising Signatures for Diagnosis and Prognosis: A Plasma-Based LC-MS Lipidomics Study.

Clinica chimica acta; international journal of clinical chemistry pii:S0009-8981(21)00414-9 [Epub ahead of print].

BACKGROUND AND AIM: Malignant mesothelioma (MM), being a rare and aggressive carcinoma, can barely be cured. Incidence of this cancer will keep climbing up in the next few decades since its major carcinogen, asbestos, is still in use in many countries. Unfortunately, prognosis of MM is unsatisfactory principally due to poor early diagnosis as a result of its long latency period and ambiguous symptoms. Lipids are known to contribute to cellular structure, signaling, and energy storage, and are widely reported to be related with tumorigenesis. Therefore, we aim to discover novel lipid biomarkers by plasma-based lipidomics that may improve MM diagnosis.

METHODS: Plasma samples from 25 MM patients and 32 healthy controls (HCs) were collected and analysed using a high-throughput liquid chromatography-mass spectrometry (LC-MS). Univariate and multivariate analyses were subsequently performed to visualize the separation trend between two groups and to screen for differential feature ions. Ions were annotated using LipidSearch 4.2 and their enriched pathways were detected on LIPEA. Receiver operating curves (ROC) were used for analysing each annotated lipid's diagnostic value. Survival analyses were performed to investigate each lipid's prognostic value.

RESULTS: In supervised partial least squares discriminant analysis (PLS-DA), clear separation between MM and HC groups was observed. A total of 34 differential lipids were annotated, among which 5 upregulated and 29 downregulated. Levels of plasma triacylglycerols (TGs) were higher in smoking versus non-smoking patients, and lower in female versus male patients. The top six lipids possessing highest diagnostic value included two phosphatidylethanolamines (PEs), two phosphatidylcholines (PCs) and two ceramides. Moreover, elevated circulating TG levels were associated with poorer survival, whereas increased monohexosylceramide (Hex1Cer) might be beneficial.

CONCLUSIONS: Our study revealed differentially expressed lipid patterns in MM and HC. PC, PE, and ceramides showed outstanding diagnostic performance, while TG and Hex1Cer exhibited significant prognostic values. Nevertheless, more studies should verify these trends as well as further investigating underlying mechanisms.

RevDate: 2021-11-29

De Sario M, Bauleo L, Magnani C, et al (2021)

L'impatto dell'esposizione occupazionale ad amianto sul tumore del polmone in Italia.

Epidemiologia e prevenzione, 45(5):353-367.

OBJECTIVES: to perform a meta-analysis of cohort studies on lung cancer mortality in occupational sectors exposed to asbestos, particularly in the construction sector, and to use data from Italian cohorts exposed to asbestos to estimate the number of lung cancer cases attributable to asbestos in Italy.

METHODS: systematic literature review and estimation of lung cancer deaths and cases attributable to asbestos in Italian cohorts and from the Italian National Register of Malignant Mesothelioma (ReNaM).

SETTING AND PARTICIPANTS: the literature search was conducted in Medline and Embase (Ovid), including papers published from 1999 to May 2019. The following sectors were considered most exposed to asbestos: asbestos-cement, rolling-stock, shipyards, dockyards, glass workers, insulators, asphalt roll production workers, industrial ovens, miners. Moreover, the construction sector was included.

MAIN OUTCOME MEASURES: the standardized mortality ratio (SMR) was estimated from the meta-analysis of the literature review. The ratio lung cancer to mesothelioma attributable cases was estimated by occupational sector from the Italian cohorts. For the construction sector, the ratio lung cancer to mesothelioma cases was estimated within the exposed workers estimated by CAREX (1990-1993). The ratios were applied to the mesothelioma cases registered at the ReNaM for the 2010-2015 period, to obtain a national estimate of lung cancer cases attributable to occupational exposure to asbestos.

RESULTS: the meta-analytical SMR for lung cancer in men varied between 1.05 (asphalt roll) and 2.36 (insulation). The mean risk for all sectors was 1.37 in men and 1.60 in women. It increased in cohorts with latency higher than 20 years. Significant risks were observed in asbestos-cement (both genders), construction, and mining sectors. There was a mean of 1.1, 2.7, and 2.8 lung cancer deaths per mesothelioma death in the cement-asbestos, harbour, and construction sectors, respectively. The impact in terms of lung cancer cases estimated at the national level was equal to 3,814 cases between 2010 and 2015.

CONCLUSIONS: to provide an overall assessment of the impact of the occupational asbestos exposure, it is important to consider lung cancer cases, in addition to malignant mesotheliomas. This study was able to estimate the impact of asbestos on lung cancer in Italy 25 years after the ban of this occupational carcinogen, with the largest contribution in terms of attributable cases coming from the construction sector. It is urgent to implement adequate information and prevention strategies, health surveillance of workers, and the appropriate legal framework for insurance purposes.

RevDate: 2021-11-29

Kawamoto Y, Kure S, Katayama H, et al (2021)

Cytological assessment of desmoplastic malignant pleural mesothelioma in an autopsy case.

Journal of Nippon Medical School = Nippon Ika Daigaku zasshi [Epub ahead of print].

INTRODUCTION: Desmoplastic malignant pleural mesothelioma (DMPM) is a sarcoma type mesothelioma, comprising about 5% of malignant pleural mesotheliomas. Although effusion cytology is commonly used as the primary diagnostic approach for mesothelioma, this may not be useful for DMPM due to its desmoplastic nature and bland cellular atypia. We hereby report a case of DMPM diagnosed through autopsy along with its cytological features that have not been described previously.

CASE PRESENTATION: A male in his 60s with a history of occupational asbestos exposure was referred to our hospital with right chest pain. Chest computed tomography scan showed right pleural effusion. Thirteen months later, the patient died of respiratory failure. In autopsy, the scrape-imprint smear and the pleural effusions cytology were performed. The scrape-imprint smear samples exhibited spindle cells with mild nuclear atypia and grooves with fibrous stroma. In the pleural effusion cytology, spindle cells having mild nuclear atypia and grooves with loose epithelial connections were observed. Histological examination of the right pleura showed spindle cells proliferating with dense collagen fibers, as seen in cytological samples, thus rendering the diagnosis of DMPM. Diagnosis was confirmed by fluorescence in situ hybridization.

CONCLUSION: Cytological procedures, such as pleural effusion cytology and scrape-imprinting method, may be useful as an ancillary tool in the diagnosis of rare tumors such as DMPM.

RevDate: 2021-11-27

Kelarji AB, Alshutaihi MS, Ghazal A, et al (2021)

Correction to: A rare case of benign multicystic peritoneal mesothelioma misdiagnosed as hydatid cyst found in the liver parenchyma and abdomen cavity of a male with asbestos exposure.

BMC gastroenterology, 21(1):447.

RevDate: 2021-11-27

Filetti V, Loreto C, Falzone L, et al (2021)

Diagnostic and Prognostic Value of Three microRNAs in Environmental Asbestiform Fibers-Associated Malignant Mesothelioma.

Journal of personalized medicine, 11(11): pii:jpm11111205.

Fluoro-edenite (FE) is an asbestiform fiber identified in Biancavilla (Sicily, Italy). Environmental exposure to FE has been associated with a higher incidence of malignant mesothelioma (MM). The present study aimed to validate the predicted diagnostic significance of hsa-miR-323a-3p, hsa-miR-101-3p, and hsa-miR-20b-5p on a subset of MM patients exposed to FE and matched with healthy controls. For this purpose, MM tissues vs. nonmalignant pleura tissues were analyzed through droplet digital PCR (ddPCR) to evaluate differences in the expression levels of the selected miRNAs and their MM diagnostic potential. In addition, further computational analysis has been performed to establish the correlation of these miRNAs with the available online asbestos exposure data and clinic-pathological parameters to verify the potential role of these miRNAs as prognostic tools. ddPCR results showed that the three analyzed miRNAs were significantly down-regulated in MM cases vs. controls. Receiver operating characteristic (ROC) analysis revealed high specificity and sensitivity rates for both hsa-miR-323a-3p and hsa-miR-20b-5p, which thus acquire a diagnostic value for MM. In silico results showed a potential prognostic role of hsa-miR-101-3p due to a significant association of its higher expression and increased overall survival (OS) of MM patients.

RevDate: 2021-11-27

Cersosimo F, Barbarino M, Lonardi S, et al (2021)

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms.

Cancers, 13(22): pii:cancers13225664.

Several studies have reported that cellular and soluble components of the tumor microenvironment (TME) play a key role in cancer-initiation and progression. Considering the relevance and the complexity of TME in cancer biology, recent research has focused on the investigation of the TME content, in terms of players and informational exchange. Understanding the crosstalk between tumor and non-tumor cells is crucial to design more beneficial anti-cancer therapeutic strategies. Malignant pleural mesothelioma (MPM) is a complex and heterogenous tumor mainly caused by asbestos exposure with few treatment options and low life expectancy after standard therapy. MPM leukocyte infiltration is rich in macrophages. Given the failure of macrophages to eliminate asbestos fibers, these immune cells accumulate in pleural cavity leading to the establishment of a unique inflammatory environment and to the malignant transformation of mesothelial cells. In this inflammatory landscape, stromal and immune cells play a driven role to support tumor development and progression via a bidirectional communication with tumor cells. Characterization of the MPM microenvironment (MPM-ME) may be useful to understand the complexity of mesothelioma biology, such as to identify new molecular druggable targets, with the aim to improve the outcome of the disease. In this review, we summarize the known evidence about the MPM-ME network, including its prognostic and therapeutic relevance.

RevDate: 2021-11-27

Ramundo V, Zanirato G, E Aldieri (2021)

The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma.

International journal of molecular sciences, 22(22): pii:ijms222212216.

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.

RevDate: 2021-11-27

Javadi J, Görgens A, Vanky H, et al (2021)

Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion.

Biomolecules, 11(11): pii:biom11111606.

Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are released by all cells into the extracellular matrix and body fluids, where they play important roles in intercellular communication and matrix remodeling in various pathological conditions. Malignant pleural mesothelioma (MPM) is a primary tumor of mesothelial origin, predominantly related to asbestos exposure. The detection of MPM at an early stage and distinguishing it from benign conditions and metastatic adenocarcinomas (AD) is sometimes challenging. Pleural effusion is often the first available biological material and an ideal source for characterizing diagnostic and prognostic factors. Specific proteins have previously been identified as diagnostic markers in effusion, but it is not currently known whether these are associated with vesicles or released in soluble form. Here, we study and characterize tumor heterogeneity and extracellular vesicle diversity in pleural effusion as diagnostic or prognostic markers for MPM. We analyzed extracellular vesicles and soluble proteins from 27 pleural effusions, which were collected and processed at the department of pathology and cytology at Karolinska University Hospital, representing three different patient groups, MPM (n = 9), benign (n = 6), and AD (n = 12). The vesicles were fractionated into apoptotic bodies, microvesicles, and exosomes by differential centrifugation and characterized by nanoparticle tracking analysis and Western blotting. Multiplex bead-based flow cytometry analysis showed that exosomal markers were expressed differently on EVs present in different fractions. Further characterization of exosomes by a multiplex immunoassay (Luminex) showed that all soluble proteins studied were also present in exosomes, though the ratio of protein concentration present in supernatant versus exosomes varied. The proportion of Angiopoietin-1 present in exosomes was generally higher in benign compared to malignant samples. The corresponding ratios of Mesothelin, Galectin-1, Osteopontin, and VEGF were higher in MPM effusions compared to those in the benign group. These findings demonstrate that relevant diagnostic markers can be recovered from exosomes.

RevDate: 2021-11-25

Nowak AK, Chin WL, Keam S, et al (2021)

Immune checkpoint inhibitor therapy for malignant pleural mesothelioma.

Lung cancer (Amsterdam, Netherlands), 162:162-168 pii:S0169-5002(21)00599-7 [Epub ahead of print].

Mesothelioma is a rare and universally fatal cancer linked to exposure to asbestos. Until recently, standard of care treatment was chemotherapy; a treatment resulting in a minimal survival extension, and not improved upon for almost twenty years. However, the advent of cancer immunotherapy - and in particular the immune checkpoint inhibitor class of drugs - has resulted in recently approved new treatment options, with more currently under investigation. Here, we review clinical trials of both single agent and combination checkpoint inhibitors in mesothelioma, plus studies investigating their combination with chemotherapy. We also describe current advances in biomarker identification regarding prediction of patient response to checkpoint inhibitors. Finally, we assess the probable future direction of the field; including where current and developing technologies are likely to lead - in terms of both biomarker discovery and treatment options.

RevDate: 2021-11-24

Novelli F, Bononi A, Wang Q, et al (2021)

BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos.

Proceedings of the National Academy of Sciences of the United States of America, 118(48):.

Carriers of heterozygous germline BAP1 mutations (BAP1 +/-) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1 +/- cells secrete increased amounts of HMGB1, and that BAP1 +/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.

RevDate: 2021-11-17

Dodge DG, Engel AM, Prueitt RL, et al (2021)

US EPA's TSCA risk assessment approach: a case study of asbestos in automotive brakes.

Inhalation toxicology [Epub ahead of print].

The United States Environmental Protection Agency (US EPA) is currently refining its approach for risk assessments conducted under the amended Toxic Substances Control Act (TSCA), largely based on recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM). We identified several issues with the current TSCA risk assessment approach that were not addressed by NASEM in its recommendations. Here, we demonstrate these issues with a case study of the 'Risk Evaluation for Asbestos, Part 1: Chrysotile Asbestos,' which US EPA released in December 2020. In this evaluation, US EPA found that occupational and some consumer uses of automotive brakes and clutches that contain asbestos result in unreasonable risks. These risks were calculated from estimated exposures during brake work and an inhalation unit risk (IUR) developed for chrysotile asbestos. We found that US EPA overestimated risk as a result of unrealistic inputs to both the exposure and toxicity components of the risk equation, and because the Agency did not fully consider relevant epidemiology and toxicity evidence in its systematic review. Our evaluation demonstrates areas in which the TSCA risk assessment approach could be improved to result in risk evaluations that are supported by the available scientific evidence.

RevDate: 2021-11-14

Sidhu C, Louw A, YC Gary Lee (2021)

Malignant Pleural Mesothelioma: Updates for Respiratory Physicians.

Clinics in chest medicine, 42(4):697-710.

RevDate: 2021-11-15

Çakılkaya P, Sørensen RR, Jürgensen HJ, et al (2021)

The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target.

International journal of molecular sciences, 22(21): pii:ijms222111452.

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients' asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.

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RJR Experience and Expertise

Researcher

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.

Educator

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.

Administrator

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.

Technologist

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.

Publisher

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.

Speaker

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.

Facilitator

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.

Designer

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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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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