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30 Mar 2020 at 01:46
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Bibliography on: Mesothelioma and Asbestos


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RJR: Recommended Bibliography 30 Mar 2020 at 01:46 Created: 

Mesothelioma and Asbestos

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

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

Citations The Papers (from PubMed®)

RevDate: 2020-03-27

Hoon SN, Fyfe K, Peddle-McIntyre CJ, et al (2020)

Randomised placebo-controlled cross-over study examining the role of anamorelin in mesothelioma (The ANTHEM study): rationale and protocol.

BMJ open respiratory research, 7(1):.

INTRODUCTION: Cachexia is common in malignant mesothelioma (MM); half of patients have malnutrition and low skeletal muscle mass. Malnourished patients have worse quality of life (QoL). Weight loss is strongly associated with poor survival. Anamorelin is an oral ghrelin receptor agonist that improves appetite, body weight and QoL in advanced cancer. The aim of this study is to examine the efficacy of anamorelin in improving appendicular skeletal muscle mass (ASM) and patient-reported outcomes in patients with MM with cachexia.

METHODS AND ANALYSIS: A single-centre, phase II, randomised, placebo-controlled cross-over pilot study with 28-day treatment periods and 3-day washout. Forty patients will be randomised. Primary outcome is change in ASM relative to height measured by dual energy X-ray absorptiometry at end of period 1. Secondary outcomes include cancer-specific and cachexia-related QoL, objective physical activity, dietary intake and adverse events. Eligible patients will have confirmed MM, Eastern Cooperative Oncology Group 0-2, expected survival >3 months and cachexia (defined as >5% weight loss in 6 months or body mass index <20 kg/m2 with weight loss >2%).

ETHICS AND DISSEMINATION: Ethical approval has been granted. Results will be reported in peer-reviewed publications.

TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (U1111-1240-6828).

RevDate: 2020-03-25

Neitzel RL, Sayler SK, Demond AH, et al (2020)

Measurement of asbestos emissions associated with demolition of abandoned residential dwellings.

The Science of the total environment, 722:137891 pii:S0048-9697(20)31404-2 [Epub ahead of print].

Many cities are revitalizing their urban cores through the demolition of abandoned residential dwellings (ARDs). However, data regarding the emissions of asbestos during such an operation are sparse. We measured airborne asbestos emissions from emergency demolitions (demolitions on structures deemed too dangerous to enter and remove asbestos) of ARDs in Detroit. High-flow air sampling was conducted during ARD demolitions. Air samples were analyzed using Phased Contrast Microscopy (PCM), and a subset using Transmission Electron Microscopy (TEM). One hundred and one air samples were collected on 25 emergency demolitions. Fifty-four of the 101 PCM samples (53%) exceeded the limit of detection (LOD). However, only 2 of 46 TEM samples (4%) exceeded the LOD for asbestos; these latter samples were from two different demolitions and each contained a single chrysotile asbestos fiber. Using conservative exposure assumptions and commonly-accepted risk estimation formulae, we estimated the lifetime risk of mesothelioma and lung cancer combined to be less than one case per one million people. Emissions of airborne asbestos during emergency (unabated) ARD demolition operations appear to be negligible. As a result, the associated health risk for asbestos-related disease is also negligible. Reconsideration of current regulatory mandates for asbestos abatement in ARDs may be warranted.

RevDate: 2020-03-24

Gray SG, L Mutti (2020)

Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives.

Translational lung cancer research, 9(Suppl 1):S100-S119.

At the clinical level the role of immunotherapy in cancer is currently at a pivotal point. Therapies such as checkpoint inhibitors are being approved at many levels in cancers such as non-small cell lung cancer (NSCLC). Mesothelioma is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Various clinical trials for checkpoint inhibitors have been conducted in this rare disease, and suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Most recently approved as a salvage therapy in mesothelioma was granted in Japan, regulatory approval for their use in the clinic elsewhere lags. In this article we review the current pertinent clinical trials of immunotherapies in malignant mesothelioma, discuss the current issues that may affect the clinical outcomes of such therapies and further evaluate potential candidate new avenues that may become future targets for immunotherapy in this cancer.

RevDate: 2020-03-24

Yoshikawa Y, Emi M, Nakano T, et al (2020)

Mesothelioma developing in carriers of inherited genetic mutations.

Translational lung cancer research, 9(Suppl 1):S67-S76.

Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the BAP1 cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the BAP1 gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on BAP1 as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of BAP1 and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of BAP1, rare missense variants were found in genes encoding lysine-specific histone methyltransferase SETD2 and SETDB1 and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.

RevDate: 2020-03-24

Carbone M, Gazdar A, JS Butel (2020)

SV40 and human mesothelioma.

Translational lung cancer research, 9(Suppl 1):S47-S59.

Simian virus 40 (SV40) is a DNA tumor virus capable of infecting and transforming human mesothelial (HM) cells in vitro. Hamsters injected intracardially to expose most tissue types to SV40 preferentially develop mesotheliomas. In humans, asbestos is the main cause of mesothelioma, and asbestos and SV40 are co-carcinogens in transforming HM cells in tissue culture and in causing mesothelioma in hamsters. Laser microdissection experiments conducted in the laboratory of Adi Gazdar demonstrated that SV40 was present specifically in the malignant mesothelioma cells and not in nearby stromal cells. Further experiments demonstrated that SV40 remains episomal in HM cells and astrocytes because of the production of a long antisense RNA that represses viral capsid protein production. Thus, the potent SV40 oncoprotein, T-antigen (Tag), is expressed, but because the capsid proteins are not produced, the cells are not lysed and, instead, become transformed. Together this evidence suggests that SV40 may contribute to the development of mesotheliomas in humans. However, epidemiological evidence to support this hypothesis is lacking. This chapter also summarizes the introduction of SV40, a monkey virus, into the human population as an unrecognized contaminant of early poliovaccines. In addition to mesotheliomas, SV40 now is linked with brain cancers, osteosarcomas, and lymphomas in humans. Explanations are provided for the apparent geographic variations in SV40 prevalence and for controversies about the role of SV40 in human cancer.

RevDate: 2020-03-24

Gaudino G, Xue J, H Yang (2020)

How asbestos and other fibers cause mesothelioma.

Translational lung cancer research, 9(Suppl 1):S39-S46.

Mesothelioma has long been associated with the exposure to asbestos, which was largely used in manufacturing activities. Toxicology studies in vitro and in vivo demonstrated that asbestos fibers were carcinogenic, and epidemiology studies revealed that asbestos exposure was paralleled by the increase in the incidence of mesothelioma and related mortality rates. More recently, the role of chronic inflammation and the molecular mechanisms involved in carcinogenesis by mineral fibers were elucidated following the discovery of the roles of HMGB1 and inflammasome. A change of paradigm was the discovery of a prevalence of mesotheliomas attributable to inherited mutations of cancer susceptibility genes. The discovery of BAP1 as a predisposition gene for the development of familial mesothelioma and other cancers implemented genome studies in patients with mesothelioma and routine clinical surveys in individuals at risk to identify germline mutations associated with cancers included in the BAP1 syndrome. A further progress in the approach to asbestos-related malignancy was the adoption of combined genetics and environmental analyses according to the model of gene-environment (GxE) interactions. This review aims at updating on the most recently discovered mechanisms of tumorigenesis and the pivotal role of GxE interactions.

RevDate: 2020-03-24

Alpert N, van Gerwen M, E Taioli (2020)

Epidemiology of mesothelioma in the 21st century in Europe and the United States, 40 years after restricted/banned asbestos use.

Translational lung cancer research, 9(Suppl 1):S28-S38.

Research has established a strong association between asbestos exposure and malignant mesothelioma, a deadly form of cancer. Since the early 1980's many countries have restricted or banned the production of asbestos, leading to a decline of occupational asbestos exposure in many industrialized countries. However, some countries continue to use asbestos, and worldwide rates of mesothelioma are still increasing. Because of the long latency between exposure and mesothelioma occurrence and the persistence of environmental exposure, incidence rates (IR) may decrease very slowly for several years ahead. In this review, we examine estimates of asbestos consumption before widespread asbestos regulations and the trends in incidence and mortality rates, as well as changes over time for the United States and Europe. In some countries with earlier asbestos restrictions, mesothelioma incidence has been in a modest decline over time. However, asbestos exposure is still a burden worldwide and legislative action is needed to obtain a full ban. The pattern of mesothelioma is shifting from a mostly male disease to a disease that affects females as well in substantial numbers. Studies on unknown sources of asbestos exposure, of other sources of natural exposure to asbestos and asbestos-like fibers, as well as of individual genetic susceptibility to asbestos fibers are needed.

RevDate: 2020-03-24

Carbone M (2020)

This special volume of mesothelioma is dedicated to my friend Adi Gazdar.

Translational lung cancer research, 9(Suppl 1):S1-S2.

RevDate: 2020-03-18

Goricar K, Kovac V, Dodic-Fikfak M, et al (2020)

Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases.

Radiology and oncology, 54(1):86-95 pii:/j/raon.2020.54.issue-1/raon-2020-0011/raon-2020-0011.xml.

Background Asbestos exposure is associated with increased risk of several diseases, including malignant mesothelioma (MM). Cell surface glycoprotein mesothelin is overexpressed in MM and serum soluble mesothelin-related peptides (SMRP) were already proposed as a diagnostic or prognostic biomarker in MM. However, interindividual variability in serum SMRP levels limits the clinical usefulness. Our primary objective was to investigate the influence of MSLN rs1057147 on serum SMRP levels in asbestos-exposed subjects and patients with asbestos-related diseases as well as on survival in MM. Subjects and methods Among 782 asbestos-exposed subjects and patients with asbestos-related diseases, 154 had MM. Serum SMRP levels were determined using sandwich enzyme-linked immunosorbent assay. All subjects were genotyped for MSLN rs1057147 polymorphism using competitive allele-specific polymerase chain reaction. Nonparametric tests, logistic and Cox regression were used in statistical analysis to compare different subject groups. Results MM patients had significantly higher SMRP levels than all other subjects (p < 0.001). Compared to wild-type MSLN rs1057147 genotype, both heterozygotes and carriers of two polymorphic alleles had significantly higher SMRP levels among subjects without MM (p < 0.001), but not in MM patients (p = 0.424). If genotype information was included, specificity of SMRP increased from 88.5% to 92.7% for the optimal cutoff value. Overall survival was significantly shorter in MM patients carrying at least one polymorphic rs1057147 allele (HR = 1.72, 95% CI = 1.15-2.55, p = 0.008). Conclusions MSLN genetic variability affects serum SMRP levels and was associated with shorter survival of MM patients. Combination of genetic and serum factors could therefore serve as a better diagnostic or prognostic biomarker in MM patients.

RevDate: 2020-03-18

Funahashi S, Okazaki Y, Akatsuka S, et al (2020)

Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice.

Free radical research [Epub ahead of print].

Exposure to asbestos fiber is central to mesothelial carcinogenesis. Recent sequencing studies on human and rodent malignant mesothelioma (MM) revealed frequently mutated genes, including CDKN2A, BAP1 and NF2. Crocidolite directly or indirectly catalyzes the generation of hydroxyl radicals, which appears to be the major driving force for mesothelial mutations. DNA base modification is an oxidative DNA damage mechanism, where 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the most abundant modification both physiologically and pathologically. Multiple distinct mechanisms work together to decrease the genomic level of 8-OHdG through the enzymatic activities of Mutyh, Ogg1 and Mth1. Knockout of one or multiple enzymes is not lethal but increases the incidence of tumors. Here, we used single knockout (KO) mice to test whether the deficiency of these three genes affects the incidence and prognosis of asbestos-induced MM. Intraperitoneal injection of 3 mg crocidolite induced MM at a fraction of 14.8% (4/27) in Mth1 KO, 41.4% (12/29) in Mutyh KO and 24.0% (6/25) in Ogg1 KO mice, whereas 31.7% (20/63) induction was observed in C57BL/6 wild-type (Wt) mice. The lifespan of female Mth1 KO mice was longer than that of female Wt mice (p = 0.0468). Whole genome scanning of MM with array-based comparative genomic hybridization revealed rare genomic alterations compared to MM in rats and humans. These results indicate that neither Mutyh deficiency nor Ogg1 deficiency promotes crocidolite-induced MM in mice, but the sanitizing nucleotide pool with Mth1 is advantageous in crocidolite-induced mesothelial carcinogenesis.

RevDate: 2020-03-18

Roggli VL, Carney JM, Sporn TA, et al (2020)

Talc and mesothelioma: mineral fiber analysis of 65 cases with clinicopathological correlation.

Ultrastructural pathology [Epub ahead of print].

Malignant mesothelioma is strongly associated with prior asbestos exposure. Recently there has been interest in the role of talc exposure in the pathogenesis of mesothelioma. We have analyzed lung tissue samples from a large series of malignant mesothelioma patients. Asbestos bodies were counted by light microscopy and mineral fiber concentrations for fibers 5 µm or greater in length were determined by scanning electron microscopy equipped with an energy dispersive spectrometer. The values were compared with 20 previously published controls. Among 609 patients with mesothelioma, talc fibers were detected in 375 (62%) and exceeded our control values in 65 (11%). Elevated talc levels were found in 48/524 men (9.2%) and 17/85 women (20%). Parietal pleural plaques were identified in 30/51 informative cases (59%) and asbestosis in 5/62 informative cases (8%). Commercial amphiboles (amosite and/or crocidolite) were elevated in 52/65 (80%) and noncommercial amphiboles (tremolite, actinolite or anthophyllite) in 41/65 (63%). Both were elevated in 34/65 (52%). Asbestos body counts by light microscopy were elevated in 53/64 informative cases (83%). A history of working in industries associated with asbestos exposure and increased mesothelioma risk was identified in 36/48 cases in men, and a history of exposure as household contacts of an occupationally exposed individual was identified in 12/17 cases in women. We conclude that among patients with mesothelioma, the vast majority have talc levels indistinguishable from background. Of the remaining 11% with elevated talc levels, the vast majority (80%) have elevated levels of commercial amphibole fibers.

RevDate: 2020-03-17

Emory TS, Maddox JC, RL Kradin (2020)

Malignant mesothelioma following repeated exposures to cosmetic talc: A case series of 75 patients.

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

BACKGROUND: Asbestos is the primary known cause of malignant mesothelioma. Some cosmetic talc products have been shown to contain asbestos. Recently, repeated exposures to cosmetic talc have been implicated as a cause of mesothelioma.

METHODS: Seventy-five individuals (64 females; 11 males) with malignant mesothelioma, whose only known exposure to asbestos was repeated exposures to cosmetic talcum powders, were reviewed in medical-legal consultation. Out of the 75 cases, 11 were examined for asbestiform fibers.

RESULTS: All subjects had pathologically confirmed malignant mesothelioma. The mean age at diagnosis was 61 ± 17 years. The mean latency from exposure to diagnosis was 50 ± 13 years. The mean exposure duration was 33 ± 16 years. Four mesotheliomas (5%) occurred in individuals working as barbers/cosmetologists, or in a family member who swept the barber shop. Twelve (16%) occurred in individuals less than 45 years old (10 females; 2 males). Forty-eight mesotheliomas were pleural (40 females; 8 males), 23 were peritoneal (21 females; 2 males). Two presented with concomitant pleural and peritoneal disease. There was one pericardial, and one testicular mesothelioma. The majority (51) were of the epithelioid histological subtype, followed by 13 biphasic, 8 sarcomatoid, 2 lymphohistiocytoid, and 1 poorly differentiated. Of the 11 individuals whose nontumorous tissues were analyzed for the presence of asbestiform fibers, all showed the presence of anthophyllite and/or tremolite asbestos.

CONCLUSIONS: Mesotheliomas can develop following exposures to cosmetic talcum powders. These appear to be attributable to the presence of anthophyllite and tremolite contaminants in cosmetic talcum powder.

RevDate: 2020-03-14

Napolitano A, Antoine DJ, Pellegrini L, et al (2020)

Expression of Concern: HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients.

Clinical cancer research : an official journal of the American Association for Cancer Research, 26(6):1529.

RevDate: 2020-03-11

Viscardi G, Di Liello R, F Morgillo (2020)

How I treat malignant pleural mesothelioma.

ESMO open, 4(Suppl 2):.

Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected patients may benefit from aggressive surgical management, also as part of a multimodal approach. In advanced disease, the combination of pemetrexed and platinum remains the only established treatment, while efficacy evidence of second line chemotherapy is lacking. Thus, a deeper knowledge of biology of the disease and more effective treatments are urgently needed. Refer to specialised centres with multidisciplinary expertise is mandatory, as well as inclusion of patients in clinical trials is advisable whenever possible. In all stages of disease focus on symptoms control is paramount.

RevDate: 2020-03-06

Paajanen J, Laaksonen S, Kettunen E, et al (2020)

Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival.

Human pathology pii:S0046-8177(20)30048-4 [Epub ahead of print].

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, where the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. In order to study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival over five years (long-term survivals [LTS]) and compared the findings with 84 tumors from a reference group with average survival (RG). We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34,90%) and a tubulopapillary growth pattern (n = 30,70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49,61%) and solid growth pattern (n = 59,70%) were more frequent in RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (p < 0.001) and the presence of necrosis (p = 0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (p < 0.001) and presence of exophytic polypoid growth (p = 0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.

RevDate: 2020-03-05

Nowak AK, Brosseau S, Cook A, et al (2020)

Antiangiogeneic Strategies in Mesothelioma.

Frontiers in oncology, 10:126.

There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.

RevDate: 2020-03-03

Fan X, McLaughlin C, Robinson C, et al (2019)

Zeolites ameliorate asbestos toxicity in a transgenic model of malignant mesothelioma.

FASEB bioAdvances, 1(9):550-560 pii:FBA21079.

Malignant mesothelioma (MM) is an almost invariably fatal cancer caused by asbestos exposure. The toxicity of asbestos fibers is related to their physicochemical properties and the generation of free radicals. We set up a pilot study to investigate the potential of the zeolite clinoptilolite to counteract the asbestos carcinogenesis by preventing the generation of reactive nitrogen and oxygen radicals. In cell culture experiments, clinoptilolite prevented asbestos-induced cell death, reactive oxygen species production, DNA degradation, and overexpression of genes known to be up-regulated by asbestos. In an asbestos-induced transgenic mouse model of MM, mice were injected intraperitoneal injections with blue asbestos, with or without clinoptilolite, and monitored for 30 weeks. By the end of the trial all 13 mice injected with asbestos alone had reached humane end points, whereas only 7 of 29 mice receiving crocidolite and clinoptilolite reached a similar stage of disease. Post-mortem examination revealed pinpoint mesothelioma-like tumors in affected mice, and the absence of tumor formation in surviving mice. Interestingly, the macrophage clearance system, which was largely suppressed in asbestos-treated mice, exhibited evidence of increased phagocytosis in mice treated with asbestos and clinoptilolite. Our study suggests that inhibiting the asbestos-induced generation of reactive oxygen species and stimulating the macrophage system may represent a pathway to amelioration of asbestos-induced toxicity. Additional studies are warranted to explore the underlying mechanisms responsible for our observations.

RevDate: 2020-03-02

Reid G, Johnson TG, N van Zandwijk (2020)

Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.

Frontiers in oncology, 10:105.

microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.

RevDate: 2020-03-02

Testa JR, A Berns (2020)

Preclinical Models of Malignant Mesothelioma.

Frontiers in oncology, 10:101.

Rodent models of malignant mesothelioma help facilitate the understanding of the biology of this highly lethal cancer and to develop and test new interventions. Introducing the same genetic lesions as found in human mesothelioma in mice results in tumors that show close resemblance with the human disease counterpart. This includes the extensive inflammatory responses that characterize human malignant mesothelioma. The relatively fast development of mesothelioma in mice when the appropriate combination of lesions is introduced, with or without exposure to asbestos, make the autochthonous models particularly useful for testing new treatment strategies in an immunocompetent setting, whereas Patient-Derived Xenograft models are particularly useful to assess effects of inter- and intra-tumor heterogeneity and human-specific features of mesothelioma. It is to be expected that new insights obtained by studying these experimental systems will lead to new more effective treatments for this devastating disease.

RevDate: 2020-03-02

Kim K, Ko Y, Oh H, et al (2020)

MicroRNA-98 is a prognostic factor for asbestos-induced mesothelioma.

Journal of toxicology and environmental health. Part A [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a type of cancer characterized by a short survival time and poor prognosis. Malignant pleural mesothelioma is most frequently associated with exposure to asbestos and other elongated mineral fibers. The aim of this study was to examine molecular differences between asbestos-exposed and non-exposed MPM patients and assess prognostic significances of molecular factors. Clinical and genetic data were downloaded from Cancer Genome Atlas. To identify the molecular differences, Significant Analysis of Microarray method was used. Prognostic significances of differentially expressed genes were confirmed by using Kaplan-Meier curve with the Log-Rank test. Although mRNAs did not exhibit any significant differences between the two patient groups, nine miRNAs were found to be down-regulated in the asbestos-exposed group. The top five pathways most relevant to the selected miRNAs were extracted through pathway enrichment analysis. Survival analysis revealed that high expression of only hsa-miR-98 was significantly associated with poor prognosis in patients with asbestos-exposed MPM. Evidence suggests that management of the aggressiveness and progression of asbestos-induced MPM may require high levels of hsa-miR-98 due to its tumor-suppressive role. This study might be helpful in enhancing our understanding of the biological mechanisms underlying asbestos-induced MPM and for acquiring greater insights into targeted therapy.Abbreviations: FDR: false discovery rate; MM: malignant mesothelioma; MPM: malignant pleural mesothelioma; mRNA: messenger RNA; miRNA: microRNA; SAM: significance analysis of microarrays; TCGA: the cancer genome atlas.

RevDate: 2020-02-28

Drevinskaite M, Patasius A, Kevlicius L, et al (2020)

Malignant mesothelioma of the tunica vaginalis testis: a rare case and review of literature.

BMC cancer, 20(1):162 pii:10.1186/s12885-020-6648-3.

BACKGROUND: Malignant mesothelioma of the tunica vaginalis is a rare tumour which comprises less than 1% of all mesotheliomas.

CASE PRESENTATION: 69-years old patient with painful hard mass and hydrocele in the right scrotum to whom a right hydrocelectomy was performed. Any history of scrotal trauma or exposure to asbestos was not present. Excisional biopsy revealed a multinodular tumour with focal areas of necrosis and infiltrative growth. According to morphological and immunohistochemical findings, diagnosis of malignant biphasic mesothelioma of the tunica vaginalis testis was made. Two months after hydrocelectomy, right inguinal orchidectomy was performed. Post-surgical whole body CT scan revealed paraaortic and pararenal lymphadenopathy, likely to be metastatic. Adjuvant treatment with 6 cycles of cisplatin and pemetrexed was applied. After 3 cycles of chemotherapy, CT scan showed progression and the treatment was changed to gemcitabine 1 month after.

CONCLUSIONS: Although malignant mesothelioma of the tunica vaginalis is a rare malignancy, it poses a diagnostic challenge which can mimic common inguinal or scrotal diseases such as hydrocele. Despite aggressive surgical procedures or adjuvant therapies, the prognosis remains poor.

RevDate: 2020-02-21

Quetel L, Meiller C, Assié JB, et al (2020)

Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival.

Molecular oncology [Epub ahead of print].

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well-annotated with histologic, molecular and clinical data of patients. Targeted next generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioïd-like and sarcomatoïd-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2 and LATS2 were more frequent in non-epithelioid MPM and positively associated to the S.score. BAP1, NF2, TERT promoter, TP53 and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2 and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.

RevDate: 2020-02-21

Döngel İ, Akbaş A, Benli İ, et al (2019)

Comparison of serum biochemical markers in patients with mesothelioma and pleural plaques versus healthy individuals exposed to environmental asbestos.

Turk gogus kalp damar cerrahisi dergisi, 27(3):374-380.

Background: In this study, we aimed to compare serum biochemical markers in patients with malignant pleural mesothelioma and pleural plaques versus healthy individuals exposed to environmental asbestos.

Methods: Between September 01, 2010 and March 31, 2011, a total of 540 participants (354 males, 186 females; mean age 61.4 years; range, 35 to 89 years) were included in the study. The participants were divided into four groups as follows: (1) patients with pleural plaques (n=277); (2) healthy individuals with normal chest X-rays who were exposed to environmental asbestos (n=121); (3) healthy individuals with normal chest X-rays who were not exposed to environmental asbestos (n=118); and (4) patients with malignant pleural mesothelioma (n=24). Serum levels of carcinoembryonic antigen, cancer antigen 125, 15-3, 19-9, free T3, free T4, thyroidstimulating hormone, vitamin B12, folate, and ferritin were measured.

Results: Serum cancer antigen 125, 15-3, folic acid, vitamin B12, and ferritin levels were higher with lower free T3 levels in Group 4 than the other groups. The areas under the curve for cancer antigen 125 and 15-3 were 0.78 and 0.67, respectively in the differential diagnosis of mesothelioma from other pathologies (p<0.001 for both). Optimal limits of these biomarkers were 13.63 and 18.43 ng/mL, respectively with 83% and 75% sensitivity and 69% and 48% specificity, respectively.

Conclusion: The combination or individual use of serum cancer antigen 125, 15-3, folic acid, vitamin B12, and ferritin levels may be helpful for early diagnosis and treatment of malignant pleural mesothelioma.

RevDate: 2020-02-21

Sinha S, Swift AJ, Kamil MA, et al (2020)

The role of imaging in malignant pleural mesothelioma: an update after the 2018 BTS guidelines.

Clinical radiology pii:S0009-9260(19)30675-0 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a primary malignancy of the pleura and is associated with a poor outcome. The symptoms and signs of malignant mesothelioma present late in the natural history of the disease and are non-specific, making the diagnosis challenging and imaging key. In 2018, the British Thoracic Society (BTS) updated the guideline on diagnosis, staging, and follow-up of patients with MPM. These recommendations are discussed in this review of the current literature on imaging of MPM. It is estimated MPM will continue to cause serious morbidity and mortality in the UK late into the 21st century, and internationally, people continue to be exposed to asbestos. We aim to update the reader on current and future imaging strategies, which could aid early diagnosis of pleural malignancy and provide an update on staging and assessment of tumour response.

RevDate: 2020-02-21

Okazaki Y, Misawa N, Akatsuka S, et al (2020)

Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats.

Cancer science [Epub ahead of print].

The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite and actinolite types. Although few studies have been conducted, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7) and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, while the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a two-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, while anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, while anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Further, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in eight cases of rat MM [homozygous deletion (5/8) and loss of heterozygosity (3/8)] by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

RevDate: 2020-02-20

Loreto C, Lombardo C, Caltabiano R, et al (2020)

An in vivo immunohistochemical study on MacroH2A.1 in lung and lymph-node tissues exposed to an asbestiform fiber.

Current molecular medicine pii:CMM-EPUB-104697 [Epub ahead of print].

AIMS: The aim of this study was to investigate MacroH2A.1 immunoexpression in tissues of sheep exposed to FE.

BACKGROUND: The correlation between asbestiform fibers, lung cancer, pleural mesothelioma and other lung diseases is already well established as the pathophisiological respiratory mechanisms involved by inhalation of Fluoro-edenite (FE). The latter is represented by cell proliferation and inducing release of growth factors, cytokines and reactive oxygen and nitrite species, with DNA damage that cause chronic inflammation and carcinogenesis. MacroH2A.1, and histone variant, seems to play a role in sensing the metabolic state of the cell and linking it with chromatin. Physiologically, MacroH2A.1 is expressed at low levels in stem cells and it became upregulated during differentiation, preventing reprogramming of induced pluripotent stem cells and after nuclear transfer. In particular, MacroH2A.1 has been shown to explicate a potent antitumor mechanism in vivo as it results upregulated in senescent cells determining a permanent growth-arrest.

OBJECTIVE: Evaluate the possible role the histone variant in the organism response to deep insight the mechanisms of toxicity and the cellular response to FE.

METHODS: Lung and lymph nodes of exposed sheep were selected. Samples were processed for histological and immunihistochemical evaluations. Densitometric, morphometric and statistical analysis were conducted.

RESULTS: Tissue sections of FE exposed sheep demonstrated an overexpression of MacroH2A.1 vs unexposed samples. The data suggest an involvement of these molecule in the cellular response triggered by FE directed exposure.

CONCLUSION: In this contest, MacroH2A.1 overexpression supports its function as an epigenetic stabilizer that helps to establish and maintain differentiated states.

RevDate: 2020-02-17

Barbieri PG, Somigliana A, Chen Y, et al (2020)

Lung Asbestos Fibre Burden and Pleural Mesothelioma in Women with Non-occupational Exposure.

Annals of work exposures and health pii:5739326 [Epub ahead of print].

BACKGROUND: Malignant pleural mesothelioma (MPM) due to environmental and familial (domestic) asbestos exposure is well recognized. However, information on cumulative asbestos dose in subjects affected by MPM is limited.

OBJECTIVES: To evaluate the residual lung asbestos fibre and asbestos body burden in women with MPM with past environmental and/or familial asbestos exposure.

METHODS: We collected lung samples from autopsies regarding 15 non-occupationally asbestos-exposed MPM cases, divided in three groups: (i) familial exposure from the Fincantieri shipyards in Monfalcone (No. 7), (ii) environmental and familial asbestos exposure from the asbestos-cement plant Fibronit in Broni (No. 6), and (iii) environmental exposure from the Fibronit plant (No. 2). Asbestos body (AB) and fibres (AF) per gram of dry lung tissue were counted by optical and scanning electron microscopy, respectively, and expressed as geometric means and standard deviations (GM, GSD).

RESULTS: GM/GSD of AB counts were 6123/9.6 (Group 1), 13 800/10.4 (Group 2), and 8400/1.1 (Group 3); GM/GSD of AF were 0.6/2.1 (Group 1), 7.9/2.1 (Group 2), and 6.0/2.3 (Group 3) million. Pleural plaques were observed in 12 cases.

CONCLUSIONS: Exclusive familial exposure to asbestos determined cumulative doses close to those observed in moderate occupational exposure circumstances. Our results also suggest that combined environmental and familial exposures may cause unexpectedly high cumulative fibre doses.

RevDate: 2020-02-14

GBD 2016 Occupational Carcinogens Collaborators (2020)

Global and regional burden of cancer in 2016 arising from occupational exposure to selected carcinogens: a systematic analysis for the Global Burden of Disease Study 2016.

Occupational and environmental medicine, 77(3):151-159.

OBJECTIVES: This study provides a detailed analysis of the global and regional burden of cancer due to occupational carcinogens from the Global Burden of Disease 2016 study.

METHODS: The burden of cancer due to 14 International Agency for Research on Cancer Group 1 occupational carcinogens was estimated using the population attributable fraction, based on past population exposure prevalence and relative risks from the literature. The results were used to calculate attributable deaths and disability-adjusted life years (DALYs).

RESULTS: There were an estimated 349 000 (95% Uncertainty Interval 269 000 to 427 000) deaths and 7.2 (5.8 to 8.6) million DALYs in 2016 due to exposure to the included occupational carcinogens-3.9% (3.2% to 4.6%) of all cancer deaths and 3.4% (2.7% to 4.0%) of all cancer DALYs; 79% of deaths were of males and 88% were of people aged 55 -79 years. Lung cancer accounted for 86% of the deaths, mesothelioma for 7.9% and laryngeal cancer for 2.1%. Asbestos was responsible for the largest number of deaths due to occupational carcinogens (63%); other important risk factors were secondhand smoke (14%), silica (14%) and diesel engine exhaust (5%). The highest mortality rates were in high-income regions, largely due to asbestos-related cancers, whereas in other regions cancer deaths from secondhand smoke, silica and diesel engine exhaust were more prominent. From 1990 to 2016, there was a decrease in the rate for deaths (-10%) and DALYs (-15%) due to exposure to occupational carcinogens.

CONCLUSIONS: Work-related carcinogens are responsible for considerable disease burden worldwide. The results provide guidance for prevention and control initiatives.

RevDate: 2020-02-13

Töreyin ZN, Ghosh M, Göksel Ö, et al (2020)

Exhaled Breath Analysis in Diagnosis of Malignant Pleural Mesothelioma: Systematic Review.

International journal of environmental research and public health, 17(3): pii:ijerph17031110.

Malignant pleural mesothelioma (MPM) is mainly related to previous asbestos exposure. There is still dearth of information on non-invasive biomarkers to detect MPM at early stages. Human studies on exhaled breath biomarkers of cancer and asbestos-related diseases show encouraging results. The aim of this systematic review was to provide an overview on the current knowledge about exhaled breath analysis in MPM diagnosis. A systematic review was conducted on MEDLINE (PubMed), EMBASE and Web of Science databases to identify relevant studies. Quality assessment was done by the Newcastle-Ottawa Scale. Six studies were identified, all of which showed fair quality and explored volatile organic compounds (VOC) based breath profile using Gas Chromatography Coupled to Mass Spectrometry (GC-MS), Ion Mobility Spectrometry Coupled to Multi-capillary Columns (IMS-MCC) or pattern-recognition technologies. Sample sizes varied between 39 and 330. Some compounds (i.e, cyclohexane, P3, P5, P50, P71, diethyl ether, limonene, nonanal, VOC IK 1287) that can be indicative of MPM development in asbestos exposed population were identified with high diagnostic accuracy rates. E-nose studies reported breathprints being able to distinguish MPM from asbestos exposed individuals with high sensitivity and a negative predictive value. Small sample sizes and methodological diversities among studies limit the translation of results into clinical practice. More prospective studies with standardized methodologies should be conducted on larger populations.

RevDate: 2020-02-12

Habbel VSA, Mahler EA, Feyerabend B, et al (2020)

[Diffuse malignant peritoneal mesothelioma (DMPM) - a rare diagnosis].

Zeitschrift fur Gastroenterologie, 58(2):146-151.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare diagnosis, found more frequently in men than in women. Symptoms are unspecific abdominal disorders making that diagnosis difficult to set. Causes of DMPM are yet to be discovered in entirety. Asbestos exposure is the reason for approximately 7 % of all peritoneal mesotheliomas. Until the evaluation of systematic cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) DMPM was a fatal diagnosis with a median overall survival (OS) of 4-13 months. The prognosis of DMPM dramatically improved with implementation of CRS and HIPEC to an OS of 30-92 month nowadys. CRS and HIPEC were performed in this case.

RevDate: 2020-02-12

Singh R, Cherrie JW, Rao B, et al (2020)

Assessment of the future mesothelioma disease burden from past exposure to asbestos in ship recycling yards in India.

International journal of hygiene and environmental health, 225:113478 pii:S1438-4639(19)31001-6 [Epub ahead of print].

The recycling of end-of-life vessels is a complex activity that generates an enormous amount of hazardous waste, including asbestos-containing materials (ACM). Efforts by the Government of India to comply with national and international regulations and improved standard operating procedures are expected to lower the exposure risk of the workforce to hazardous substances, including asbestos. The current workers are likely to face lesser risks than did those exposed in the past. The present study assesses the health risks from past exposure of asbestos for those workers engaged in handling and removing ACM in ship recycling yards before environmentally sound recycling of obsolete ships was introduced in the early 2000s. Estimates were made of the number of workers exposed, and the intensity of exposure and these data were used to estimate the likely number of mesothelioma deaths in the future. It was estimated that nearly 15% of the total workforce engaged in ship recycling will suffer from mesothelioma which translates to about 4,513 mesothelioma deaths among the total of 31,000 workers estimated to be ever employed in the yards from 1994 till 2002. Recommendations are made for a practical approach to the safe handling of ACMs in Indian ship recycling yards.

RevDate: 2020-02-11

Ahmed ST, Barvo M, Kamath N, et al (2020)

Acute popliteal thrombus workup leads to discovery of primary peritoneal mesothelioma in the absence of any known asbestos exposure.

BMJ case reports, 13(2): pii:13/2/e232812.

A 75-year-old man presented to the emergency department with 1-day history of right lower limb pain and 3-month history of vague abdominal pain. In the emergency department a thrombus was discovered in the right popliteal artery. CT scan of the abdomen and pelvis revealed high-density material in the pelvis, multiple hypodensities on the liver, ascites with omental nodularity, and high-density material along the stomach wall. He underwent thrombectomy and was started on anticoagulation therapy. The core needle biopsy revealed primary omental mesothelioma. There was no history of any known asbestos exposure. He also had to undergo therapeutic paracentesis twice due to abdominal distension. Mesothelioma treatment of carboplatin and pemetrexed was started, and the patient is currently receiving this chemotherapy treatment regimen.

RevDate: 2020-02-11

Airoldi C, Ferrante D, Miligi L, et al (2020)

Estimation of Occupational Exposure to Asbestos in Italy by the Linkage of Mesothelioma Registry (ReNaM) and National Insurance Archives. Methodology and Results.

International journal of environmental research and public health, 17(3): pii:ijerph17031020.

The identification and monitoring of occupational cancer is an important aspect of occupational health protection. The Italian law on the protection of workers (D. Leg. 81/2008) includes different cancer monitoring systems for high and low etiologic fraction tumors. Record linkage between cancer registries and administrative data is a convenient procedure for occupational cancer monitoring. We aim to: (i) Create a list of industries with asbestos exposure and (ii) identify cancer cases who worked in these industries. The Italian National Mesothelioma Registry (ReNaM) includes information on occupational asbestos exposure of malignant mesothelioma (MM) cases. We developed using data from seven Italian regions a methodology for listing the industries with potential exposure to asbestos linking ReNaM to Italian National Social Security Institute (INPS) data. The methodology is iterative and adjusts for imprecision and inaccuracy in reporting firm names at interview. The list of asbestos exposing firms was applied to the list of cancer cases (all types associated or possibly associated with asbestos according to International Agency for Research on Cancer (IARC) monograph 100C) in two Italian regions for the indication of possible asbestos exposure. Eighteen percent of the cancer cases showed at least one work period in firms potentially exposing to asbestos, 48% of which in regions different from where the cases lived at diagnosis. The methodology offers support for the preliminary screening of asbestos exposing firms in the occupational history of cancer cases.

RevDate: 2020-02-10

Wylie AG, Korchevskiy A, Segrave AM, et al (2020)

Modeling mesothelioma risk factors from amphibole fiber dimensionality: mineralogical and epidemiological perspective.

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

Amphiboles are common rock-forming minerals but when they form asbestos, they are known carcinogens. Mesothelioma mortality among miners and millers per the unit of asbestiform amphibole exposure varies significantly across cohorts when asbestos exposure measurements are based on the membrane filter method. Because the cohorts were exposed to different occurrences of asbestiform amphibole, variance in mesothelioma potency (RM) among cohorts is likely due to differences in exposure characteristics not reflected by the membrane filter method. In this paper using both linear and nonlinear models we correlate RM from four mining and milling cohorts with two-dimensional parameters of the exposure. The parameters are based on the proportion of elongated minerals that are >5 μm in length from each occurrence that also have either (a) width ≤ 0.15 μm, or (b) width ≤ 0.25 μm. Based on the models we derived, it was possible to quantify RM for the occurrences of asbestiform amphibole associated with mesothelioma excess but for which epidemiologically based RM has not been published. It was demonstrated that modeled RM for amphibole occurrences in nonasbestiform habits are lower (fibrous glaucophane) or not significant (cleavage fragments). The results of the study can be used in a risk assessment of elongated mineral particles and have implications for public policy and regulations.

RevDate: 2020-02-09

Pais A, Pinto N, Cardoso J, et al (2020)

[Diffuse Intraparenchymal Mesothelioma: An Atypical Presentation].

Acta medica portuguesa, 33(2):143-146.

Pleural mesothelioma is a disease associated with exposure to asbestos. Although rare, it is the most common malignant pleural neoplasm. It is difficult to diagnose and it has a poor prognosis. We report the case of a 62-year-old male patient with a history of prolonged occupational exposure to asbestos, with dyspnea for minor exertion and productive cough, for several months. Imaging studies revealed extensive interstitial involvement with marked thickening of the interlobular and centrilobular septa and tenuous pleural involvement. Several differential diagnoses were considered such as, asbestosis, cryptogenic organizing pneumonia, desquamative interstitial pneumonia, pleuropulmonary metastases, and/or bronchopulmonary infection, but the histological and immunohistochemical results were compatible with pleural mesothelioma - a rare malignant neoplasm, with pleural origin, with a high mortality rate.

RevDate: 2020-02-08

Aoki K, N Saito (2020)

Biocompatibility and Carcinogenicity of Carbon Nanotubes as Biomaterials.

Nanomaterials (Basel, Switzerland), 10(2): pii:nano10020264.

With the development of nanotechnology in recent years, there have been concerns about the health effects of nanoparticles. Carbon nanotubes (CNTs) are fibrous nanoparticles with a micro-sized length and nano-sized diameter, which exhibit excellent physical properties and are widely studied for their potential application in medicine. However, asbestos has been historically shown to cause pleural malignant mesothelioma and lung cancer by inhalation exposure. Because carbon nanotubes are also fibrous nanotubes, some have raised concerns about its possible carcinogenicity. We have reported that there is no clear evidence of carcinogenicity by local and intravenous administration of multi-walled CNTs to cancer mice models. We firmly believe that CNTs can be a safe, new, and high-performance biomaterials by controlling its type, site of administration, and dosage.

RevDate: 2020-02-05

Cheng YY, Rath EM, Linton A, et al (2020)

The Current Understanding Of Asbestos-Induced Epigenetic Changes Associated With Lung Cancer.

Lung Cancer (Auckland, N.Z.), 11:1-11 pii:186843.

Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. Occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. This review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. Genomic mutations of DNA nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. The genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. Currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. Epigenetic DNA methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. Asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. These efforts hold the promise of non-invasive cancer diagnosis in the future. Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.

RevDate: 2020-02-01

Gaetani S, Monaco F, Alessandrini F, et al (2020)

Mechanism of miR-222 and miR-126 regulation and its role in asbestos-induced malignancy.

The international journal of biochemistry & cell biology pii:S1357-2725(20)30017-0 [Epub ahead of print].

MiR-222 and miR-126 are associated with asbestos exposure and the ensuing malignancy, but the mechanism(s) of their regulation remain unclear. We evaluated the mechanism by which asbestos regulates miR-222 and miR-126 expression in the context of cancer etiology. An 'in vitro' model of carcinogen-induced cell transformation was used based on exposing bronchial epithelium BEAS-2B cells to three different carcinogens including asbestos. Involvement of the EGFR pathway and the role of epigenetics have been investigated in carcinogen-transformed cells and in malignant mesothelioma, a neoplastic disease associated with asbestos exposure. Increased expression of miR-222 and miR-126 were found in asbestos-transformed cells, but not in cells exposed to arsenic and chrome. Asbestos-mediated activation of the EGFR pathway and macrophages-induced inflammation resulted in miR-222 upregulation, which was reversed by EGFR inhibition. Conversely, asbestos-induced miR-126 expression was affected neither by EGFR modulation nor inflammation. Rather than methylation of the miR-126 host gene EGFL7, epigenetic mechanism involving DNMT1- and PARP1-mediated chromatin remodeling was found to upregulate of miR-126 in asbestos-exposed cells, while miR-126 was downregulated in malignant cells. Analysis of MM tissue supported the role of PARP1 in miR-126 regulation. Therefore, activation of the EGFR pathway and the PARP1-mediated epigenetic regulation both play a role in asbestos-induced miRNA expression, associated with in asbestos-induced carcinogenesis and tumor progression.

RevDate: 2020-02-01

Fels Elliott DR, KD Jones (2020)

Diagnosis of Mesothelioma.

Surgical pathology clinics, 13(1):73-89.

Mesothelioma is a rare neoplasm that arises from mesothelial cells lining body cavities including the pleura, pericardium, peritoneum, and tunica vaginalis. Most malignant mesotheliomas occur in the chest and are frequently associated with a history of asbestos exposure. The diagnosis of malignant mesothelioma is challenging and fraught with pitfalls, particularly in small biopsies. This article highlights what the pathologist needs to know regarding the clinical and radiographic presentation of mesothelioma, histologic features including subtypes and variants, and recent advances in immunohistochemical markers and molecular testing.

RevDate: 2020-01-31

Ma S, Chee J, Fear VS, et al (2020)

Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome.

Oncoimmunology, 9(1):1684714 pii:1684714.

Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines.

RevDate: 2020-01-31

Sneddon S, Rive CM, Ma S, et al (2020)

Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma.

Oncoimmunology, 9(1):1684713 pii:1684713.

Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM. We characterized the landscape of potential neoantigens from SNVs identified in 27 MM patients and performed whole transcriptome sequencing of cell populations from 18 patient-matched pleural effusions. IFNγ ELISpot was performed to detect a CD8+ T cell responses to predicted neoantigens in one patient. We detected a median of 68 (range 7-258) predicted neoantigens across the samples. Wild-type non-binding to mutant binding predicted neoantigens increased risk of death in a model adjusting for age, sex, smoking status, histology and treatment (HR: 33.22, CI: 2.55-433.02, p = .007). Gene expression analysis indicated a dynamic immune environment within the pleural effusions. TCR clonotypes increased with predicted neoantigen burden. A strong activated CD8+ T-cell response was identified for a predicted neoantigen produced by a spontaneous mutation in the ROBO3 gene. Despite the challenges associated with the identification of bonafide neoantigens, there is growing evidence that these molecular changes can provide an actionable target for personalized therapeutics in difficult to treat cancers. Our findings support the existence of candidate neoantigens in MM despite the low mutation burden of the tumor, and may present improved treatment opportunities for patients.

RevDate: 2020-01-28

Consonni D, C Mensi (2019)

Comment on the paper 'Boffetta et al. Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy. Ann Oncol 2018; 29(2): 484-489'.

Annals of oncology : official journal of the European Society for Medical Oncology, 30(2):340-341.

RevDate: 2020-01-28

Boffetta P, Righi L, Ciocan C, et al (2019)

Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy.

Annals of oncology : official journal of the European Society for Medical Oncology, 30(11):1844.

RevDate: 2020-01-24

Fernández-Rodríguez P, Martín-Marcuartu JJ, Acevedo Báñez I, et al (2020)

99mTc-HDP Bone Scintigraphy, SPECT/CT, and 18F-FDG PET/CT Diagnosis Imaging of Incidental Pleural Mesothelioma in a Patient With Biochemical Recurrences of Prostate Cancer: Is it Really a Coincidence?.

Clinical nuclear medicine [Epub ahead of print].

We present the case of a 69-year-old man with history of prostate carcinoma treated with prostatectomy and subsequently with external beam radiotherapy and hormone therapy because of biochemical recurrences. More than 10 years after the diagnosis, follow-up Tc-HDP bone scans and SPECT/CT images demonstrated an incidental diagnosis of osteoblastic pleural plaques that quickly evolve to mesothelioma. PET/CT achieved the definitive diagnosis by guiding the biopsy to the highest and most accessible focus of glucidic hypermetabolism. Our case report raises the association between prostate cancer patients treated with external beam radiotherapy and the development of pleural mesothelioma despite having no history of exposure to asbestos.

RevDate: 2020-01-22

Vimercati L, Cavone D, Mansi F, et al (2019)

Health impact of exposure to asbestos in polluted area of Southern Italy.

Journal of preventive medicine and hygiene, 60(4):E407-E418.

The three main sources of asbestos pollution in the city of Bari, Puglia, the former Fibronit asbestos factory, the Torre Quetta beach, the former Rossani barracks and the history of their reclamation are described. The results of cohort studies on factory workers and case-control studies on asbestos exposure to the resident population and the onset of mesothelioma are also reported. Finally, the data of the regional register of mesothelioma related to residents in the city of Bari and four new cases with environmental exposure due to the former Rossani barracks are presented.

RevDate: 2020-01-22

Peterson MK, Mohar I, Lam T, et al (2019)

Critical review of the evidence for a causal association between exposure to asbestos and esophageal cancer.

Critical reviews in toxicology, 49(7):597-613.

Esophageal cancers comprise about 1% of all cancers diagnosed in the US but are more prevalent in other regions of the world. Several regulatory agencies have classified asbestos as a known human carcinogen, and it is linked to multiple diseases and malignancies, including lung cancer and mesothelioma. In a 2006 review of the epidemiological literature, the Institute of Medicine (IOM) did not find sufficient evidence to demonstrate a causal relationship between asbestos exposure and esophageal cancer. To reevaluate this conclusion, we performed a critical review of the animal toxicological, epidemiological, and mechanism of action literature on esophageal cancer and asbestos, incorporating studies published since 2006. Although there is some evidence in the epidemiological literature for an increased risk of esophageal cancer in asbestos-exposed occupational cohorts, these studies generally did not control for critical esophageal cancer risk factors (e.g. smoking, alcohol consumption). Furthermore, data from animal toxicological studies do not indicate that asbestos exposure increases esophageal cancer risk. Based on our evaluation of the literature, and reaffirming the IOM's findings, we conclude that there is insufficient evidence to demonstrate a causal link between asbestos exposure and esophageal cancer.

RevDate: 2020-01-22

Oddone E, Bollon J, Nava CR, et al (2020)

Predictions of Mortality from Pleural Mesothelioma in Italy After the Ban of Asbestos Use.

International journal of environmental research and public health, 17(2): pii:ijerph17020607.

Even if the epidemic of malignant pleural mesothelioma (MPM) is still far from being over worldwide, the health effects of regulations banning asbestos can be evaluated in the countries that implemented them early. Estimates of MPM future burden can be useful to inform and support the implementation of anti-asbestos health policies all around the world. With this aim we described the trends of MPM deaths in Italy (1970-2014) and predicted the future number of cases in both sexes (2015-2039), with consideration of the national asbestos ban that was issued in 1992. The Italian National Statistical Institute (ISTAT) provided MPM mortality figures. Cases ranging from 25 to 89 years of age were included in the analysis. For each five-year period from 1970 to 2014, mortality rates were calculated and age-period-cohort Poisson models were used to predict future burden of MPM cases until 2039. During the period 1970-2014 a total number of 28,907 MPM deaths were observed. MPM deaths increased constantly over the study period, ranging from 1356 cases in 1970-1974 to 5844 cases in 2010-2014. The peak of MPM cases is expected to be reached in the period 2020-2024 (about 7000 cases). The decrease will be slow: about 26,000 MPM cases are expected to occur in Italy during the next 20 years (2020-2039). The MPM epidemic in Italy is far from being concluded despite the national ban implemented in 1992, and the peak is expected in 2020-2024, in both sexes. Our results are consistent with international literature.

RevDate: 2020-01-13

Borchert S, Suckrau PM, Wessolly M, et al (2019)

Screening of Pleural Mesothelioma Cell Lines for Kinase Activity May Identify New Mechanisms of Therapy Resistance in Patients Receiving Platin-Based Chemotherapy.

Journal of oncology, 2019:2902985.

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumor associated with a dismal prognosis. Multimodal therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons underlying the rather poor efficacy of platinum compounds remain largely unknown. Kinase activity might influence cellular response to these regimens.

Materials and Methods: For this exploratory study, we screened MPM cell lines (NCI-H2452, NCI-H2052, and MSTO-211H) differing in response to cisplatin and benign control fibroblasts (MRC-5) for overall phosphorylation patterns as well as kinase activity with respect to cellular response to cisplatin-based therapeutics. We analysed the cell lines for cellular kinases in a high-throughput manner using the highly innovative technique PamGene. Cell state analysis including apoptosis, necrosis, and cell viability was performed by using enzyme activity and fluorescent-based assays.

Results: Cisplatin alters cellular phosphorylation patterns affecting cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis. In cisplatin-responsive cell lines, phosphorylation of AKT1 and GSK3B was decreased but could not be influenced in cisplatin-resistant NCI-H2452 cells. Cisplatin-responsive cell lines showed increased phosphorylation levels of JNK1/2/3 but decreased phosphorylation in cisplatin-resistant NCI-H2452 cells.

Conclusion: Kinase phosphorylation and activity might play a crucial role in cellular response to cytostatic agents. Cisplatin influences phosphorylation patterns with distinct features in cisplatin-resistant cells. These alterations exert a significant impact on cell cycle, migration, adhesion, signal transduction, immune modulation, and apoptosis of the respective tumor cells. Based on our results, the induction of p38 or JNK1/3, or inhibition of AKT1 by, for example, BIA-6, might offer a positive synergistic effect by induction of an apoptotic response to cisplatin-based treatment, thus potentially enhancing the clinical outcome of MPM patients.

RevDate: 2020-01-13

Cox LA (Jr) (2019)

Nonlinear dose-time-response functions and health-protective exposure limits for inflammation-mediated diseases.

Environmental research, 182:109026 pii:S0013-9351(19)30823-0 [Epub ahead of print].

Why have occupational safety regulations in the United States not been more successful in protecting worker health from mesothelioma risks, while apparently succeeding relatively well in reducing silicosis risks? This paper briefly discusses biological bases for thresholds and nonlinearities in exposure-response functions for respirable crystalline silica (RCS) and asbestos, based on modeling a chronic inflammation mode of action (mediated by activation of the NLRP3 inflammasome, for both RCS and asbestos). It applies previously published physiologically based pharmacokinetic (PBPK) models to perform computational experiments illuminating how different time courses of exposure with the same time-weighted average (TWA) concentration affect internal doses in target tissues (lung for RCS and mesothelium for asbestos). Key conclusions are that (i) For RCS, but not asbestos, limiting average (TWA) exposure concentrations also tightly constrains internal doses and ability to trigger chronic inflammation and resulting increases in disease risks (ii) For asbestos, excursions (i.e., spikes in concentrations); and especially the times between them are crucial drivers of internal doses and time until chronic inflammation; and hence (iii) These dynamic aspects of exposure, which are not addressed by current occupational safety regulations, should be constrained to better protect worker health. Adjusting permissible average exposure concentration limits (PELs) and daily excursion limits (ELs) is predicted to have little impact on reducing mesothelioma risks, but increasing the number of days between successive excursions is predicted to be relatively effective in reducing worker risks, even if it has little or no impact on TWA average concentrations.

RevDate: 2020-01-10

Kim MK, Kim HW, Jang M, et al (2020)

LOX family and ZFPM2 as novel diagnostic biomarkers for malignant pleural mesothelioma.

Biomarker research, 8:1 pii:180.

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that develops in the pleural and outer layer of tissues surrounding the lungs. MPM is primarily caused by occupational exposure to asbestos and results in a poor prognosis. Effective therapeutics as well as early diagnostics for the MPM are still lacking. To identify potential diagnostic biomarkers for MPM, we performed bioinformatics analysis of public database.

Methods: Utilizing databases from Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO), we identified several potential candidates that could act as MPM biomarkers. We carried out additional molecular analyses of these potential markers using MPM patient tissue samples via quantitative polymerase chain reaction.

Results: We identified Lysyl oxidase (LOX), Lysyl oxidase homologs 1&2 (LOXL1& LOXL2) Zinc Finger Protein, FOG Family Member 2 (ZFPM2) as potential diagnostic biomarkers for MPM. In this study, we found that the LOX family and ZFPM2 showed comparable diagnostic ability to Fibulin-3 or mesothelin (MSLN) and would be better potential biomarkers than Sulfatase 1 (SULF1), Thrombospondin 2 (THBS2) and Cadherin 11 (CDH11).

Conclusions: LOX family and ZPFM2 were identified as novel MPM diagnostic biomarkers which could strengthen MPM clinical diagnostic capabilities.

RevDate: 2020-01-09

Ugelvig Petersen K, Pukkala E, Martinsen JI, et al (2020)

Cancer incidence among seafarers and fishermen in the Nordic countries.

Scandinavian journal of work, environment & health pii:3879 [Epub ahead of print].

Objectives Maritime workers may be exposed to several occupational hazards at sea. The aim of this study was to assess cancer incidence among seafarers and fishermen in the Nordic countries and identify patterns in morbidity in the context of existing studies in this field. Methods A cohort of 81 740 male seafarers and 66 926 male fishermen was established from census data on 15 million citizens in the five Nordic countries. Using personal identity codes, information on vital status and cancer was linked to members of the cohort from the national population and cancer registries for the follow-up period 1961-2005. Standardized incidence ratios (SIR) were calculated applying national cancer incidence rates for each country and pooling results. Results The overall incidence of cancer was increased among the male seafarers [SIR 1.22, 95% confidence interval (CI) 1.19-1.23]. Significant excesses were observed for multiple cancer sites among the seafarers, while results for the fishermen were mixed. Lip cancer incidence was increased among both maritime populations. For mesothelioma (SIR 2.17, 95% CI 1.83-2.56 seafarers) and non-melanoma skin cancer (SIR 1.23, 95% CI 1.14-1.32 seafarers), incidence was increased among the seafarers. Conclusion In our cohort, seafaring was associated with a higher overall incidence of cancer compared to the general population. While the majority of cancers could not be linked to specific occupational factors, increases in mesothelioma, lip and non-melanoma-skin cancer indicate previous exposure to asbestos, ultraviolet radiation and potentially also chemicals with dermal carcinogenic properties at sea.

RevDate: 2020-01-07

Klebe S, Leigh J, Henderson DW, et al (2019)

Asbestos, Smoking and Lung Cancer: An Update.

International journal of environmental research and public health, 17(1): pii:ijerph17010258.

This review updates the scientific literature concerning asbestos and lung cancer, emphasizing cumulative exposure and synergism between asbestos exposure and tobacco smoke, and proposes an evidence-based and equitable approach to compensation for asbestos-related lung cancer cases. This update is based on several earlier reviews written by the second and third authors on asbestos and lung cancer since 1995. We reevaluated the peer-reviewed epidemiologic studies. In addition, selected in vivo and in vitro animal studies and molecular and cellular studies in humans were included. We conclude that the mechanism of lung cancer causation induced by the interdependent coaction of asbestos fibers and tobacco smoke at a biological level is a multistage stochastic process with both agents acting conjointly at all times. The new knowledge gained through this review provides the evidence for synergism between asbestos exposure and tobacco smoke in lung cancer causation at a biological level. The evaluated statistical data conform best to a multiplicative model for the interaction effects of asbestos and smoking on the lung cancer risk, with no requirement for asbestosis. Any asbestos exposure, even in a heavy smoker, contributes to causation. Based on this information, we propose criteria for the attribution of lung cancer to asbestos in smokers and non-smokers.

RevDate: 2020-01-06

Cox LA (Jr) (2020)

Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples.

Critical reviews in toxicology [Epub ahead of print].

Can a single fiber of amphibole asbestos increase the risk of lung cancer or malignant mesothelioma (MM)? Traditional linear no-threshold (LNT) risk assessment assumptions imply that the answer is yes: there is no safe exposure level. This paper draws on recent scientific progress in inflammation biology, especially elucidation of the activation thresholds for NLRP3 inflammasomes and resulting chronic inflammation, to model dose-response relationships for malignant mesothelioma and lung cancer risks caused by asbestos exposures. The modeling integrates a physiologically based pharmacokinetics (PBPK) front end with inflammation-driven two-stage clonal expansion (I-TSCE) models of carcinogenesis to describe how exposure leads to chronic inflammation, which in turn promotes carcinogenesis. Together, the combined PBPK and I-TSCE modeling predict that there are practical thresholds for exposure concentration below which asbestos exposure does not cause chronic inflammation in less than a lifetime, and therefore does not increase chronic inflammation-dependent cancer risks. Quantitative examples using model parameter estimates drawn from the literature suggest that practical thresholds may be within about a factor of 2 of some past exposure levels for some workers. The I-TSCE modeling framework explains previous puzzling aspects of asbestos epidemiology, such as why age at first exposure is a better predictor of lifetime MM risk than exposure duration. It may be a valuable tool for risk analysts when LNT assumptions are not justified due to inflammation response thresholds mediating dose-response relationships.

RevDate: 2020-01-06

Colin DJ, Bejuy O, Germain S, et al (2019)

Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice.

Journal of visualized experiments : JoVE.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor arising in the mesothelium that covers the lungs, the heart, and the thoracic cavity. MPM development is mainly associated with asbestos. Treatments provide only modest survival since the median survival average is 9-18 months from the time of diagnosis. Therefore, more effective treatments must be identified. Most data describing new therapeutic targets were obtained from in vitro experiments and need to be validated in reliable in vivo preclinical models. This article describes one such reliable MPM orthotopic model obtained after injection of a human MPM cell line H2052/484 into the pleural cavity of immunodeficient athymic mice. Transplantation in the orthotopic site allows studying the progression of tumor in the natural in vivo environment. Positron emission tomography/computed tomography (PET/CT) molecular imaging using the clinical [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) radiotracer is the diagnosis method of choice for examining patients with MPM. Accordingly, [18F]FDG-PET/CT was used to longitudinally monitor the disease progression of the H2052/484 orthotopic model. This technique has a high 3R potential (Reduce the number of animals, Refine to lessen pain and discomfort, and Replace animal experimentation with alternatives) since the tumor development can be monitored non-invasively and the number of animals required could be significantly reduced. This model displays a high development rate, a rapid tumor growth, is cost-efficient and allows for rapid clinical translation. By using this orthotopic xenograft MPM model, researchers can assess biological responses of a reliable MPM model following therapeutic interventions.

RevDate: 2020-01-05

Lam WS, Creaney J, Chen FK, et al (2019)

A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma.

Lung cancer (Amsterdam, Netherlands), 140:87-92 pii:S0169-5002(19)30786-X [Epub ahead of print].

OBJECTIVES: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment.

MATERIALS AND METHODS: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients.

RESULTS: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes.

CONCLUSIONS: The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

RevDate: 2020-01-04

Hinkamp CA, Dalal SN, Butt Y, et al (2020)

Diffuse epithelioid malignant mesothelioma of the pleura presenting as a hydropneumothorax and vertebral body invasion.

BMJ case reports, 13(1): pii:13/1/e231987.

Malignant mesothelioma is an uncommon form of neoplastic transformation of the mesothelial cells that line the serosal surfaces of the body. It most commonly affects the pleura and is often associated with pleural effusions and pleural-based masses. The annual incidence in the United States is only 3300 cases, representing less than 0.3% of all cancers worldwide, although this is likely underestimated. We present a case of diffuse epithelioid malignant pleural mesothelioma in a patient with remote, short-term asbestos exposure complicated by recurrent left-sided hydropneumothoraces and pleural-based invasion of the T12 vertebral body, which represent two rare coexisting complications. This case illustrates the importance of maintaining a broad differential for hydropneumothorax, particularly as the risk factors may be decades removed and the degree of asbestos exposure to induce a malignant mesothelioma may be smaller than has been traditionally thought.

RevDate: 2020-01-02

Walters GI (2019)

Occupational exposures and idiopathic pulmonary fibrosis.

Current opinion in allergy and clinical immunology [Epub ahead of print].

PURPOSE OF REVIEW: A recent meta-analysis of data from international case-control studies reports a population attributable fraction of 16% for occupational factors in the cause of idiopathic pulmonary fibrosis (IPF). Smoking, genetic factors and other prevalent diseases only partly explain IPF, and so this review aims to summarize recent progress in establishing which occupational exposures are important in cause.

RECENT FINDINGS: IPF is a rare disease, although it is the commonest idiopathic interstitial pneumonia. Epidemiological study suggests that incidence of IPF is increasing, particularly in older men. There are significant associations with IPF and occupational exposures to organic dust, including livestock, birds and animal feed, metal dust, wood dust and silica/minerals. Estimates of effect vary between studies, and are influenced by the distribution of employment, study design and case definition. Inhalation of asbestos fibres is a known cause of usual interstitial pneumonia (as seen histologically in IPF), though there are significant linear relationships between asbestos consumption, and mortality from both IPF and mesothelioma, leading to the hypothesis that low-level asbestos exposure may cause IPF.

SUMMARY: Research must focus on exposure-response relationships between asbestos and other occupational inhaled hazards, and IPF. Funding bodies and policy makers should acknowledge the significant occupational burden on IPF.

RevDate: 2019-12-30

Totaro M, Giorgi S, Filippetti E, et al (2019)

[Asbestos in drinking water and hazards to human health: a narrative synthesis].

Igiene e sanita pubblica, 75(4):303-312.

The term asbestos refers to six unique fibrous minerals mostly used in the production of asbestos cement sheets and pipes. According to the World Health Organization and the International Agency for Research on Cancer (IARC), there exists at least &quot;sufficient evidence&quot; that all types of asbestos may cause cancer in humans (mesothelioma, lung cancer, laryngeal tumor and ovarian cancer). The only asbestos limit in drinking water is 7 million fiber/liter. This study is a narrative synthesis about the possible hazards to human health related to the presence of asbestos in drinking water. The various scientific studies and epidemiological reports examined highlight that there is an ongoing debate on the possible carcinogenic risk associated with asbestos exposure through ingestion. Nevertheless, considering the latency with which diseases caused by asbestos may emerge, control measures should be adopted.

RevDate: 2019-12-27

Vimercati L, Cavone D, Delfino MC, et al (2019)

Response to the "Letter to the Editor" by Gabor Mezei et al., Comments on Vimercati et al., 2019, "Asbestos exposure and malignant mesothelioma of the tunica vaginalis testis: a systematic review and the experience of the Apulia (Southern Italy) mesothelioma register".

Environmental health : a global access science source, 18(1):112 pii:10.1186/s12940-019-0553-8.

RevDate: 2019-12-27

Mezei G, Chang ET, Mowat FS, et al (2019)

Comments on Vimercati et al., 2019, "Asbestos exposure and malignant mesothelioma of the tunica vaginalis testis: a systematic review and the experience of the Apulia (southern Italy) mesothelioma register".

Environmental health : a global access science source, 18(1):111 pii:10.1186/s12940-019-0552-9.

RevDate: 2019-12-26

Kodama E, Kodama T, Ichikawa T, et al (2019)

18F-FDG Uptake of Localized Malignant Peritoneal Mesothelioma.

Clinical nuclear medicine [Epub ahead of print].

We present 2 cases of malignant peritoneal mesothelioma (MPM) characterized by a localized solid mass without ascites and showing F-FDG uptake. A 79-year-old man with a history of asbestos exposure suffered from an epithelioid MPM originating from the hepatoduodenal ligament with FDG uptake (SUVmax 16.8). Another 80-year-old man with esophageal cancer showed desmoplastic MPM of the small bowel mesentery with FDG uptake (SUVmax 4.0). Desmoplastic MPM is more aggressive and yields poorer prognosis compared with the epithelioid type. However, the present desmoplastic MPM case showed mild FDG uptake because of rich fibrosis.

RevDate: 2019-12-26

Pavlisko EN, Liu B, Green C, et al (2019)

Malignant Diffuse Mesothelioma in Women: A Study of 354 Cases.

The American journal of surgical pathology [Epub ahead of print].

We reviewed 354 cases of malignant diffuse mesothelioma (MM) in women from a database of 2858 histologically confirmed MM cases. There was a pleural predominance with 78% pleural MM and 22% peritoneal MM. The pleural tumors consisted of 72% epithelioid, 19% biphasic, and 9% sarcomatoid variant. The peritoneal tumors consisted of 82% epithelioid, 13% biphasic, and 5% sarcomatoid. The immunohistochemical profile was typical of what is well-accepted and previously described for MM. When examining tumor subtype and location, there was a trend toward epithelioid subtype and peritoneal location; however, this did not reach statistical significance. Age at the time of diagnosis ranged from 19 to 93 years with a mean of 60 years. The median age at time of diagnosis for pleural MM was 65 years and for peritoneal MM was 52 years. A further look at age and histologic subtype showed no statistically significant difference in age between MM subtypes. Survival was greatest for epithelioid variant, and this was magnified in the peritoneum. A majority of our cases were exposed to asbestos through a household contact. Asbestosis and parietal pleural plaque were present in 5% and 50% of cases with data, respectively. Fiber analysis data was available in 67 cases; 38 cases had elevated asbestos fiber burden, and tremolite was the most common asbestos fiber type detected. Commercial and noncommercial amphibole asbestos fibers were elevated in nearly equal numbers of cases.

RevDate: 2019-12-23

Chu GJ, van Zandwijk N, JEJ Rasko (2019)

The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy.

Frontiers in oncology, 9:1366.

Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials.

RevDate: 2019-12-18

Tomasetti M, Gaetani S, Monaco F, et al (2019)

Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy.

Frontiers in oncology, 9:1293.

Asbestos exposure leads to epigenetic and epigenomic modifications that, in association with ROS-induced DNA damage, contribute to cancer onset. Few miRNAs epigenetically regulated in MM have been described in literature; miR-126, however, is one of them, and its expression is regulated by epigenetic mechanisms. Asbestos exposure induces early changes in the miRNAs, which are reversibly expressed as protective species, and their inability to reverse reflects the inability of the cells to restore the physiological miRNA levels despite the cessation of carcinogen exposure. Changes in miRNA expression, which results from genetic/epigenetic changes during tumor formation and evolution, can be detected in fluids and used as cancer biomarkers. This article has reviewed the epigenetic mechanisms involved in miRNA expression in MM, focusing on their role as biomarkers of early diagnosis and therapeutic effects.

RevDate: 2019-12-17

Apostoli P, Boffetta P, Bovenzi M, et al (2019)

Position Paper on Asbestos of the Italian Society of Occupational Medicine.

La Medicina del lavoro, 110(6):459-485.

The Position Paper (PP) on asbestos of the Italian Society of Occupational Medicine (SIML) aims at providing a tool to the occupational physician to address current diagnostic criteria and results of epidemiological studies, and their consequences in terms of preventive and evaluation actions for insurance, compensation and litigation. The PP was based on an extensive review of the scientific literature and was compiled by a Working Group comprising researchers who have contributed to the international literature on asbestos-related diseases, as well as occupational physicians with extensive experience in the evaluation of risks and the medical surveillance of workers currently and formerly exposed to asbestos. The PP was drafted and reviewed between 2017 and 2018; its final version was prepared according to the guidelines of AGREE Reporting Checklist. All the members of the Working Group subscribed to the document, which was eventually approved by SIML's Executive Committee. The first section addresses industrial hygiene issues, such as methods for environmental monitoring, advantages and limitations of different microscopy techniques, the potential role of microfibers and approaches for retrospective assessment of exposure, in particular in epidemiological studies. The second section reviews the biological effects of asbestos with particular attention to the diagnostic aspects of asbestosis, pleural changes, mesothelioma and lung cancer. In the following section the criteria of causal attribution are discussed, together with different hypotheses on the form of the risk functions, with a comparison of the opinions prevalent in the literature. In particular, the models of the risk function for mesothelioma were examined, in the light of the hypothesis of an acceleration or anticipation of the events in relation to the dose. The last section discusses topics of immediate relevance for the occupational physician, such as health surveillance of former exposed and of workers currently exposed in remediation activities.

RevDate: 2019-12-17

Vernez D, Duperrex O, Herrera H, et al (2019)

Exposure to Amosite-Containing Ceiling Boards in a Public School in Switzerland: A Case Study.

International journal of environmental research and public health, 16(24): pii:ijerph16245069.

The measurement of an airborne concentration in Amosite fibers above 5035 F/m3 in a school prompted a retrospective quantitative health risk assessment. Dose estimates were built using air measurements, laboratory experiments, previous exposure data, and interviews. A dose response model was adapted for amosite-only exposure and adjusted for the life expectancy and lung cancer incidence in the Swiss population. The average yearly concentrations found were 52-320 F/m3. The high concentration previously observed was not representative of the average exposure in the building. Overall, the risk estimates for the different populations of the school were low and in the range of 2 × 10-6 to 3 × 10-5 for mesothelioma and 4 × 10-7 to 8 × 10-6 for lung cancer. The results evidenced however that children have to be considered at higher risk when exposed to asbestos, and that the current reference method and target values are of limited use for amphibole-only exposures. This study confirmed that quantitative health risk assessments and participatory approaches are powerful tools to support public decisions and build constructive communication between exposed people, experts, and policy-makers.

RevDate: 2019-12-13

Pellegrini I, Sibille A, Paulus A, et al (2019)

[How I manage... Malignant pleural mesothelioma in 2019].

Revue medicale de Liege, 74(12):627-632.

Malignant pleural mesothelioma is a rare disease originating from mesothelial cells of the pleura and is related to asbestos exposure. The tumor is generally extended at the time of diagnosis and the treatment consists of a systemic palliative therapy. Radical approach is limited to very selected patients and is performed in expert centers but without validated schema. Radiotherapy alone is mainly used in palliative intent. Platinum-based chemotherapy in association with pemetrexed is the frontline standard of care and provides a 12-month overall survival. The addition of bevacizumab, an antiangiogenic drug, shows an improvement in median survival. To date, there is no second-line treatment approved for this disease and therefore inclusion in trials is recommended. Currently, various studies are investigating target therapy, immunotherapy and intrapleural perioperative treatment.

RevDate: 2019-12-11

Kishimoto T, Fujimoto N, Ebara T, et al (2019)

Serum levels of the chemokine CCL2 are elevated in malignant pleural mesothelioma patients.

BMC cancer, 19(1):1204 pii:10.1186/s12885-019-6419-1.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a debilitating disease of the pleural cavity. It is primarily associated with previous inhalation of asbestos fibers. These fibers initiate an oxidant coupled inflammatory response. Repeated exposure to asbestos fibers results in a prolonged inflammatory response and cycles of tissue damage and repair. The inflammation-associated cycles of tissue damage and repair are intimately involved in the development of asbestos-associated cancers. Macrophages are a key component of asbestos-associated inflammation and play essential roles in the etiology of a variety of cancers. Macrophages are also a source of C-C motif chemokine ligand 2 (CCL2), and a variety of tumor-types express CCL2. High levels of CCL2 are present in the pleural effusions of mesothelioma patients, however, CCL2 has not been examined in the serum of mesothelioma patients.

METHODS: The present study was carried out with 50 MPM patients and 356 subjects who were possibly exposed to asbestos but did not have disease symptoms and 41 healthy volunteers without a history of exposure to asbestos. The levels of CCL2 in the serum of the study participants was determined using ELISA.

RESULTS: Levels of CCL2 were significantly elevated in the serum of patients with advanced MPM.

CONCLUSIONS: Our findings are consistent with the premise that the CCL2/CCR2 axis and myeloid-derived cells play an important role in MPM and disease progression. Therapies are being developed that target CCL2/CCR2 and tumor resident myeloid cells, and clinical trials are being pursued that use these therapies as part of the treatment regimen. The results of trials with patients with a similar serum CCL2 pattern as MPM patients will have important implications for the treatment of MPM.

RevDate: 2019-12-10

Ferrante D, Mirabelli D, Silvestri S, et al (2019)

Mortality and mesothelioma incidence among chrysotile asbestos miners in Balangero, Italy: A cohort study.

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

BACKGROUND: We studied cancer mortality and mesothelioma incidence in 974 male workers employed at least 6 months at the Balangero mine (Italy), the largest chrysotile mine in Western Europe, active from 1917 to 1985.

METHODS: Vital status as of 31 May 2013, causes of deaths and mesothelioma incidence from 1990 were ascertained. Past exposure to asbestos by working area and calendar period was estimated, based on historical data of fibers concentrations. Individual cumulative exposure was assessed by applying estimates to the job history of cohort members. Standardized mortality ratios (SMRs) for selected causes and standardized incidence ratios for malignant mesothelioma (MM) were calculated based on regional reference rates. Poisson regression analysis was used to study MM and lung cancer risk by latency, duration, and cumulative exposure.

RESULTS: Mortality was increased for all causes (SMR = 1.28; 95% confidence interval [CI] = 1.17-1.40), pleural cancer (SMR = 4.30; 95% CI = 1.58-9.37), asbestosis (SMR = 375.06; 95% CI = 262.68-519.23). An increase was also found for lung cancer (SMR = 1.14; 95% CI = 0.81-1.55) and peritoneal cancer (SMR = 3.25; 95% CI = 0.39-11.75). The risk of both pleural and peritoneal cancer mortality and of mesothelioma incidence increased with increasing cumulative exposure, duration, and latency. Poisson regression analyses showed an increase in mesothelioma risk with cumulative asbestos exposure and suggest a similar trend for lung cancer. Asbestosis mortality also increased with cumulative exposure.

CONCLUSIONS: Among Balangero chrysotile miners and millers, the occurrence of malignant and nonmalignant asbestos-related diseases was increased by exposure, with dose-response relation. The study confirms the carcinogenicity of chrysotile asbestos, in particular for pleural mesothelioma.

RevDate: 2019-12-10

Urso L, Cavallari I, Sharova E, et al (2019)

Metabolic rewiring and redox alterations in malignant pleural mesothelioma.

British journal of cancer pii:10.1038/s41416-019-0661-9 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in 18F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.

RevDate: 2019-12-09

Pfau JC, McNew T, Hanley K, et al (2019)

Autoimmune markers for progression of Libby amphibole lamellar pleural thickening.

Inhalation toxicology [Epub ahead of print].

Exposure to Libby Asbestiform Amphibole (LAA) is associated with asbestos-related diseases, including mesothelioma, pulmonary carcinoma, pleural fibrosis, and systemic autoimmune diseases. The pleural fibrosis can manifest as a rapidly progressing lamellar pleural thickening (LPT), which causes thoracic pain, dyspnea, and worsening pulmonary function tests (PFT). It is refractory to treatment and frequently fatal.Objective: Because of the immune dysfunction that has been described in the LAA-exposed population and the association of pleural manifestations with the presence of autoantibodies, this study tested whether specific immunological factors were associated with progressive LPT and whether they could be used as markers of progressive disease.Methods: Subjects were placed into three study groups defined as (1) progressive LPT, (2) stable LPT, (3) no LPT. Serum samples were tested for antinuclear autoantibodies, mesothelial cell autoantibodies, anti-plasminogen antibodies, IL1 beta, and IL17; which have all been shown to be elevated in mice and/or humans exposed to LAA.Results: Group 1 had significantly higher mean values for all of the autoantibodies, but not IL1 or IL-17, compared to the control Group 3. All three autoantibody tests had high specificity but low sensitivity, but ROC area-under-the-curve values for all three antibodies were over 0.7, statistically higher than a test with no value. When all LPT subjects were combined (Progressive plus Stable), no marker had predictive value for disease.Conclusion: The data support the hypothesis that progressive LPT is associated with immunological findings that may serve as an initial screen for progressive LPT.

RevDate: 2019-12-08

Consonni D, De Matteis S, Dallari B, et al (2019)

Impact of an asbestos cement factory on mesothelioma incidence in a community in Italy.

Environmental research pii:S0013-9351(19)30765-0 [Epub ahead of print].

BACKGROUND: Broni is a small town (9000 inhabitants) in the province of Pavia, Lombardy, north-west Italy, where the second largest Italian asbestos cement factory (Fibronit) was in operation between 1932 and 1993. Based on Lombardy Mesothelioma Registry (RML) data (2000-2011), we previously showed a high impact of asbestos exposure on malignant mesothelioma (MM) incidence among Fibronit workers, their families, and people living in Broni and in the nearby town of Stradella (11,000 residents). Given the great concern of the community, we have recently updated the data regarding 5 more years (2012-2016).

METHODS: From the RML database we extracted subjects who ever worked in Fibronit, their family members, ever residents in Broni, and subjects living in Stradella and nearby towns at the time of diagnosis. For each type of exposure we calculated standardized incidence ratios (SIR = observed/expected cases).

RESULTS: In the period 2000-2016 we registered 56 cases (2.52 expected, SIR = 22.2), 49 men (41 pleural, 8 peritoneal MM), 7 women (5 pleural, 2 peritoneal MM) with past occupational exposure in Fibronit. Among subjects never occupationally exposed and never exposed to extra-occupational sources unrelated to Fibronit, we counted 39 cases (4.24 expected, SIR = 9.2), 10 men (all pleural MM), 29 women (28 pleural, 1 peritoneal MM) in Fibronit workers' families, 91 pleural mesothelioma cases (7.43 expected, SIR = 12.2, 31 men, 60 women), ever residents in Broni, and 25 pleural mesothelioma cases (3.05 expected, SIR = 8.2, 6 men, 19 women) living in Stradella at the time of diagnosis. The overall number of excess cases was about 194 (211 against 17.24 expected). In the remaining adjacent (No. 8) and surrounding (No. 17) municipalities (32,000 people) there were 7 cases (1 men, 6 women, 8.85 expected).

CONCLUSION: The mesothelioma burden related to the asbestos cement factory is still high on factory workers, their families, and residents in Broni and Stradella towns.

RevDate: 2019-12-06

Johnson TG, Schelch K, Mehta S, et al (2019)

Corrigendum: Why Be One Protein When You Can Affect Many? The Multiple Roles of YB-1 in Lung Cancer and Mesothelioma.

Frontiers in cell and developmental biology, 7:293.

[This corrects the article DOI: 10.3389/fcell.2019.00221.].

RevDate: 2019-11-29

Mian I, Abdullaev Z, Morrow B, et al (2019)

Anaplastic lymphoma kinase (ALK) Gene Rearrangement in Children and Young Adults with Mesothelioma.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(19)33665-2 [Epub ahead of print].

INTRODUCTION: Children and young adults diagnosed with malignant mesothelioma may have unique genetic characteristics. In this study, we evaluated for the presence of the anaplastic lymphoma kinase (ALK) translocations in these patients.

METHODS: In a prospective study of mesothelioma natural history (MNH) (ClinicalTrials.gov number NCT01950572) we assessed for the presence of the ALK translocation in patients less than 40 years old, irrespective of site of disease. The presence of this translocation was assessed via fluorescence in-situ hybridization (FISH). If positive, both immunohistochemistry (IHC) and RNA sequencing (RNASeq) were performed on the tumor specimen.

RESULTS: Between September 2013 and December 2018, 373 patients were enrolled on the MNH study of which 32 patients were <40 years old at the time of their mesothelioma diagnosis. 25 patients had peritoneal, 5 pleural, 1 pericardial and 1 had bi-compartmental mesothelioma. Presence of an ALK translocation by FISH was seen in 2 of the 32 (6%) mesothelioma patients. Both patients, a 14 year old female and a 27 year old male, had peritoneal mesothelioma and neither had history of asbestos exposure, prior radiation or predisposing germline mutations. Neither had detectable ALK expression by IHC. RNAseq revealed the presence of an STRN fusion partner in the female patient but failed to identify any fusion protein in the male patient.

CONCLUSIONS: Young patients with peritoneal mesothelioma should be evaluated for the presence of ALK translocations. Presence of this translocation should be assessed by FISH and these patients could potentially benefit from tyrosine kinase inhibitors targeting ALK.

RevDate: 2019-11-26

Martinotti S, Patrone M, Moccia F, et al (2019)

Targeting Calcium Signalling in Malignant Mesothelioma.

Cancers, 11(12): pii:cancers11121839.

Calcium ions (Ca2+) are central in cancer development and growth, serving as a major signaling system determining the cell's fate. Therefore, the investigation of the functional roles of ion channels in cancer development may identify novel approaches for determining tumor prognosis. Malignant mesothelioma is an aggressive cancer that develops from the serosal surface of the body, strictly related to asbestos exposure. The treatment of malignant mesothelioma is complex and the survival outcomes, rather than the overall survival data are, to date, disappointedly daunting. Nevertheless, conventional chemotherapy is almost ineffective. The alteration in the expression and/or activity of Ca2+ permeable ion channels seems to be characteristic of mesothelioma cells. In this review, we explore the involvement of the Ca2+toolkit in this disease. Moreover, the established sensitivity of some Ca2+channels to selective pharmacological modulators makes them interesting targets for mesothelioma cancer therapy.

RevDate: 2019-12-06

Celsi F, Crovella S, Moura RR, et al (2019)

Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes.

Journal of toxicology and environmental health. Part A, 82(20):1088-1102.

Two of the major cancerous diseases associated with asbestos exposure are malignant pleural mesothelioma (MPM) and lung cancer (LC). In addition to asbestos exposure, genetic factors have been suggested to be associated with asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM were reported, to date the influence of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron (Fe) homeostasis are hallmarks of asbestos exposure affecting the pulmonary tissue, this study aimed at investigating the association between Fe-metabolism and inflammasome gene variants and susceptibility to develop LC or MPM, by comparing an asbestos-exposed population affected by LC with an "asbestos-resistant exposed population". A retrospective approach similar to our previous autopsy-based pilot study was employed in a novel cohort of autoptic samples, thus giving us the possibility to corroborate previous findings obtained on MPM by repeating the analysis in a novel cohort of autoptic samples. The protective role of HEPH coding SNP was further confirmed. In addition, the two non-coding SNPs, either in FTH1 or in TF, emerged to exert a similar protective role in a new cohort of LC exposed individuals from the same geographic area of MPM subjects. No association was found between NLRP1 and NLRP3 polymorphisms with susceptibility to develop MPM and LC. Further research into a specific MPM and LC "genetic signature" may be needed to broaden our knowledge of the genetic landscape attributed to result in MPM and LC.

RevDate: 2019-11-19

Cummings KJ, Becich MJ, Blackley DJ, et al (2019)

Workshop summary: Potential usefulness and feasibility of a US national mesothelioma registry.

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

BACKGROUND: The burden and prognosis of malignant mesothelioma in the United States have remained largely unchanged for decades, with approximately 3200 new cases and 2400 deaths reported annually. To address care and research gaps contributing to poor outcomes, in March of 2019 the Mesothelioma Applied Research Foundation convened a workshop on the potential usefulness and feasibility of a national mesothelioma registry.

METHODS: The workshop included formal presentations by subject matter experts and a moderated group discussion.

RESULTS: Workshop participants identified top priorities for a registry to be: (a) connecting patients with high-quality care and clinical trials soon after diagnosis and (b) making useful data and biospecimens available to researchers in a timely manner. Existing databases that capture mesothelioma cases are limited by factors such as delays in reporting, de-identification, and lack of exposure information critical to understanding as yet unrecognized causes of disease. National disease registries for amyotrophic lateral sclerosis in the United States, and for mesothelioma in other countries, provide examples of how a registry could be structured to meet the needs of patients and the scientific community.

CONCLUSIONS: Small-scale pilot initiatives should be undertaken to validate methods for rapid case identification, develop procedures to facilitate patient access to guidelines-based standard care and investigational therapies, and explore approaches to data-sharing with researchers. Ultimately, federal coordination and funding will be critical to the success of a national mesothelioma registry in improving mesothelioma outcomes and preventing future cases of this devastating disease.

RevDate: 2019-11-16

Eckert RL, Kandasamy S, Adhikary G, et al (2019)

The YAP1 signaling inhibitors, verteporfin and CA3, suppress the mesothelioma cancer stem cell phenotype.

Molecular cancer research : MCR pii:1541-7786.MCR-19-0914 [Epub ahead of print].

Mesothelioma is an aggressive cancer that has a poor prognosis. Tumors develop in the mesothelial lining of the pleural and peritoneal cavities in response to asbestos exposure. Surgical debulking followed by chemotherapy is initially effective, but this treatment ultimately selects for resistant cells that form aggressive and therapy resistant recurrent tumors. Mesothelioma cancer stem cells (MCS cells) are a highly aggressive subpopulation present in these tumors that are responsible for tumor maintenance and drug resistance. In the present manuscript, we examine the impact of targeting YAP1/TAZ/TEAD signaling in MCS cells. YAP1, TAZ and TEADs are transcriptional mediators of the Hippo signaling cascade that activate gene expression to drive tumor formation. We show that two YAP1 signaling inhibitors, verteporfin and CA3, attenuate the MCS cell phenotype. Verteporfin or CA3 treatment reduces YAP1/TEAD level/activity to suppress MCS cell spheroid formation, matrigel invasion, migration and tumor formation. These agents also increase MCS cell apoptosis. Moreover, constitutively-active YAP1 expression antagonizes inhibitor action, suggesting that loss of YAP1/TAZ/TEAD signaling is required for response to verteporfin and CA3. These agents are active against mesothelioma cells derived from peritoneal (epithelioid) and patient-derived pleural (sarcomatoid) mesothelioma, suggesting that targeting YAP1/TEAD signaling may be a useful treatment strategy. Implications: These studies suggest that inhibition of YAP1 signaling may be a viable approach to treating mesothelioma.

RevDate: 2019-11-15

Lorentz E, Despreaux T, Quignette A, et al (2019)

[Screening of occupational exposure to asbestos and silica by job-exposure matrix among patients with lung cancer and mesothelioma].

Revue des maladies respiratoires pii:S0761-8425(19)30331-6 [Epub ahead of print].

INTRODUCTION: In the context of underreporting of occupational diseases, the aim was to study the validity of silica and asbestos job-exposure matrices in screening occupational exposure in the field of thoracic oncology.

METHODS: Fifty patients hospitalized with primitive lung cancer or mesothelioma in a university hospital center in the Hauts-de-Seine department of France were included between November 2016 and September 2017. For each patient 1/the job history was collected, from which data was entered single-blindly into the job-exposure matrices by a resident in occupational medicine, 2/a questionnaire (Q-SPLF) was completed similarly, and 3/the patients also had a consultation with a chief resident in occupational medicine, considered the gold standard. The main outcome was the diagnostic performance of the matrices. The Q-SPLF diagnostic performance was also studied.

RESULTS: The asbestos and silica matrices had sensitivities of 100%, specificities of respectively 76.1% and 87.8%, the positive likelihood ratios were at 4.19 [2.5-6] and 8.17 [3.8-10], and the negative likelihood ratios were at 0. The Q-SPLF diagnostic performance was comparable to that of the matrices.

CONCLUSIONS: The matrices and the questionnaire have a great diagnostic performance which seems interesting for a use as a screening tool for occupational exposures. These results have yet to be confirmed by large-scale studies.

RevDate: 2019-11-13

Alblin M, P Gustavsson (2019)

A silent epidemic: occupational exposure limits are insufficiently protecting individual worker health.

In an editorial in an earlier issue of this journal, Johanson & Tinnerberg (1) expressed serious and well-founded concern over the large number of future occupational cancer cases that will result if exposures for a number of substances are not reduced below the so-called "binding occupational exposure limit values" (BOELV) issued by the EU (2). The balance between what is perceived as possible to comply with and the foreseeable health gain when setting BOELV is further discussed in a letter to the Editor by Cherrie (3). This debate raises several important aspects of how to protect workers from cancer as well as other potentially lethal diseases. Herewith, we discuss some of these aspects. One problem in setting OEL is that levels that are considered safe may not be seen as feasible when accounting for technological and societal aspects. The EU has recognized this problem by distinguishing between so-called "indicative" (health-based) and legally binding OEL (4). However, a BOELV that does not protect from a high risk for severe health effects is not adequate. Both Johanson & Tinnerberg and Cherrie point to respirable crystalline silica (RCS) as an example: While the EU's Scientific Committee on Occupational Exposure Limits (SCOEL) recommended an OEL <0.05 (5) in order to protect workers reasonably well against negative health effects, the EU decided on a BOELV of 0.1 mg/m 3for RCS (2). The US Occupational Health and Safety administration (OSHA) has come to a different conclusion and decided on an OEL of 0.05 mg/m 3(6). The EU has presented an extensive risk assessment for RCS developed within the SHEcan project (7). We argue that a BOELV at 0.1 is insufficient and partly may be due to misinterpretations of the SHEcan report. The report estimates the future number of lung cancer cases attributable to occupational exposure to RCS in the EU up to 2069. Four scenarios are discussed: (i) a baseline scenario, essentially predicting future numbers of cases without further regulatory action, (ii) a BOELV of 0.2 mg/m3 with 99% compliance, (iii) a BOELV of 0.1 mg/m 3with 99% compliance, and (iv) a BOELV of 0.05 mg/m 3with 99% compliance. The estimations are based on an assumption of a latency period of 10-50 years from reduction of exposure until cancer risk drops. This assumption, in itself reasonable from present evidence, has the consequence that there is virtually no difference in projected annual future cases between the four scenarios for ≥40 years. The reduction in exposure in scenarios ii-iv comes into effect first only in the year 2050 (see figure 4.1 on p49 in ec.europa.eu/social/BlobServlet?docId=10161&langId=en). An assumption of 99% compliance with the BOELV in scenarios ii-iv has a dramatically stronger effect on the projected number of cases than the OEL itself: Even if the OEL was doubled to 0.2 mg/m 3the number of attributable cancer registrations in 2060 would be reduced by 70% just from the assumption of almost full compliance. The additional number of attributable cancer registrations that are prevented when an OEL of 0.1 (scenario iii) is compared to an OEL of 0.05 (scenario iv) under an assumption of almost full compliance is comparatively small (7, p123). The reason for this strong effect of a 99% compliance is that exposure often will exceed the OEL. The report may lead to the misconception that an OEL of 0.05 mg/m 3has little benefit over an OEL of 0.1 mg/m 3, especially if the cases saved are expressed as lives saved per year over the entire 60-year period. For Sweden and other countries where OEL already have legal status, the introduction of BOELV would have no legal implications. The SHEcan report shows that occupational exposure to silica will cause in all 440 000 cancer cases between 2010 and 2069 in the EU if nothing further is done (scenario i). This number must be reduced even if it will take time until preventive measures have full effect. An analogy with asbestos is obvious: it is well known that reductions in the mesothelioma rate were seen first only many decades after asbestos was banned - yet no one would argue that it was not worth reducing asbestos exposure for this reason. The report assumes an annual 7% decrease in silica exposure levels until the period 2020-2029 even if no further regulatory action is taken. This is a very questionable assumption that went unconfirmed in a recent French report (8) that gave no evidence for reduced exposure to RCS in the French construction sector during the last decade. This indicates that even the very high number of 440 000 attributable cancer registrations is underestimated by the report, to which, in addition, should be added the number of chronic obstructive pulmonary disease and kidney disease cases, for which a much shorter latency period until risk drops is likely. The concepts "maximum tolerable risk" and "acceptable risk" have been developed for exposure to genotoxic carcinogens, for which no exposure level could be considered safe. A life-time extra number of four cases per 1000 exposed workers over a 40-year working life has been suggested as a maximum tolerable risk, and four cases per 100 000 exposed workers as an acceptable risk, both in Germany and in the Netherlands (9, 10). These figures can be transformed to the individual life-time risk of contracting cancer from the exposure as 4/1000, corresponding to 0.4% individual risk. While these limits are not absolute and can be discussed, it is of interest to apply them to the case of RCS. The risk associated with an OEL of 0.1 mg/m 3for RCS is associated with risks far higher than "maximum tolerable", ie, 0,4%. The US OSHA estimated that exposing 1000 workers for 45 years at 0.1 mg/m3 would result in 33 extra lung cancer deaths as life-time risk, corresponding to an individual risk of 3.3% (6), exceeding the maximum tolerable risk nearly 10-fold. Since the EU Directive concerns cancer, the report did not consider other health effects, which is necessary for a general risk assessment. The US OSHA estimated there would be another 85 deaths from non-malignant lung disease (8.5%) and, roughly estimated, 39 deaths from renal disease (3.9%) that should be added to this toll. This adds up to an individual excess death risk of 15%, which by far clearly exceeds what is generally seen as the maximum tolerable risk of 0.4%! Still, this is a conservative estimate, which includes neither excess deaths from myocardial infarction that occur from 0.025 mg/m 3and up (11) nor excess autoimmune disease, eg, rheumatoid arthritis and other autoimmune diseases (12, 13). In support of Johanson & Tinnerberg (1), we argue that the lifetime excess death risk for silica-exposed workers is totally incompatible with fundamental workers' rights of health and safety. This aspect, which must be safeguarded by the OSH society, will be even more important when working life is prolonged and when exposure conditions may be more diverse, ie, workers with high exposure and excessive risk may be too few to impact the disease burden in society but in that group the burden may still be extreme. In our view, the assumption of 99% compliance is unrealistic and it is necessary to lower the OEL. In addition, leaving the BOELV at 0.1 mg/m3 means this will continue for the future, a silent epidemic that is deeply unethical to ignore. References 1. Johanson G, Tinnerberg H. Binding occupational exposure limits for carcinogens in the EU - good or bad? Scand J Work Environ Health 2019 May;45(3):213-4. https://doi.org/10.5271/sjweh.3825. 2. Directive EU. (EU) 2019/130 of the European parliament and of the council of 16 January 2019. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32019L0130. 3. Cherrie JW. Binding occupational exposure limits for carcinogens in the EU - necessary but not sufficient to reduce risk. Scand J Work Environ Health 2019 Jul;45(4):423-4. https://doi.org/10.5271/sjweh.3836. 4. SCOEL. SCOEL's involvement in setting Occupational Exposure Limits: Webpage accessed 2019-10-23. Available from: http://ec.europa.eu/social/BlobServlet?docId=3879&langId=en. 5. SCOEL. Recommendation from the Scientific Committee on Occupational Exposure Limits for Silica, Crystalline (respirable dust). SCOEL/SUM/94. November 2003. Available from: http://ec.europa.eu/social/BlobServlet?docId=3803&langId=en. 6. OSHA. Occupational Exposure to Respriable Crystalline Silica. Federal Register/vol 81, no 58/Friday, March 25, 2016/ Rules and Regulations. Occupational Safety and Health, Department of Labour, Administration (Docket No. OSHA-2010-0034) RIN 1218/AB70. OSHA 2016. Available from: https://www.govinfo.gov/content/pkg/FR-2016-03-25/pdf/2016-04800.pdf. 7. Cherrie JW, Gorman Ng M, Searl A, Shafrir A, van Tongeren M et al. Health, socio-economic and environmental aspects of possible amendments to the EU Directive on the protection of workers from the risks related to exposure to carcinogens and mutagens at work. Respirable crystalline silica. IOM Research Project: P937/8, May 2011. Available from: https://ec.europa.eu/social/BlobServlet?docId=10161&langId=en). 8. ANSES. Agence nationale de sécurité sanitaire alimentation, environnement, et du travail (ANSES). Dangers, expositions et risques relatifs à la silice cristalline. Avis de l'Anses Raports d'expertise collective (Saisine no 2015-SA-0236). Avril 2019. Èdition scientifique. ANSES English summary: Available from: https://www.anses.fr/en/content/exposure-crystalline-silica-poses-high-risks-worker-health 9. Federal Institute for Occupational safety and Health. The risk-based concept for carcinogenic substances developed by the Committee for Hazardous Substances. Federal Institute for Occupational safety and Health (BAuA), Dortmund, Germany, 2013. Available from: www.baua.de/dok/3581564 10. Health Council of the Netherlands. Guidelines for the calculation of occupational cancer risk values. Health Council of the Netherlands, 2012. Available from: www.healthcouncil.nl/documents/advisory-reports/2012/10/26/guideline-for-the-calculation-of-occupational-cancer-risk-values. 11. Liu Y, Zhou Y, Hnizdo E, Shi T, Steenland K, He X et al. Total and Cause-Specific Mortality Risk Associated With Low-Level Exposure to Crystalline Silica: A 44-Year Cohort Study From China. Am J Epidemiol 2017 Aug;186(4):481-90. https://doi.org/10.1093/aje/kwx124. 12. Stolt P, Källberg H, Lundberg I, Sjögren B, Klareskog L, Alfredsson L; EIRA study group. Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis 2005 Apr;64(4):582-6. https://doi.org/10.1136/ard.2004.022053. 13. Parks CG, Conrad K, Cooper GS. Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect 1999 Oct;107 Suppl 5:793-802.

RevDate: 2019-11-12

Larson TC, Williamson L, VC Antao (2019)

Follow-Up of the Libby, Montana Screening Cohort: A 17-Year Mortality Study.

Journal of occupational and environmental medicine [Epub ahead of print].

OBJECTIVE: To evaluate mortality patterns among participants in a community-based screening program for asbestos-related disease.

METHODS: We calculated standardized mortality ratios (SMRs) and stratified results by exposure group (three occupational exposure groups, household contacts and residents without occupational asbestos exposure) and by radiographic abnormality presence.

RESULTS: All-cause mortality (15.8%; 1,429/8,043) was statistically lower than expected. Asbestosis was statistically elevated in all exposure groups. Lung cancer was moderately associated with vermiculite miner/miller employment. Mesothelioma was elevated in that same exposure group and among residents. Systemic autoimmune disease mortality was also elevated. Radiographic parenchymal abnormalities were associated with lung cancer mortality.

CONCLUSION: In addition to asbestos-related mortality in occupational exposure groups, this initial mortality follow-up of this cohort also shows elevated mortality for some asbestos-related causes in non-occupational exposure groups.

RevDate: 2019-11-12

Finkelstein MM, C Meisenkothen (2019)

Malignant Mesothelioma Among Employees of a Connecticut Factory That Manufactured Friction Materials Using Chrysotile Asbestos: An Update.

Annals of work exposures and health pii:5622757 [Epub ahead of print].

There is an ongoing argument about the potency of chrysotile asbestos to cause malignant mesothelioma. Authors of chrysotile risk assessments have relied upon the results of an epidemiologic study, published in 1984, to state that there were no mesotheliomas found among workers at a Connecticut friction products plant. McDonald reported the first two cases in 1986. In 2010, we reported the work histories and pathologic reports of five individuals from the Connecticut plant who were diagnosed with mesothelioma. Despite this, a review of the health effects of chrysotile published in 2018 continued to state that there were no cases of mesothelioma from this plant. We report here two new cases that were diagnosed after the publication of our previous report, bringing the current total to nine cases. We also discuss the results of previously unpublished air sampling data from the plant. Chrysotile, mainly from Canada, was the only asbestos fiber type used until 1957 when some anthophyllite was added in making paper discs and bands. Beyond this original description of the anthophyllite usage from McDonald, there is a dearth of information about the amount of anthophyllite used in the plant, the frequency of its use, and the specific departments where it was used. For over 30 years in the published literature, this factory has alternatively been described as a 'chrysotile' or 'predominantly chrysotile' factory. While it is clear that some anthophyllite was used in the factory (in addition to 400 pounds of crocidolite in the laboratory), given the volume, frequency, and processes using chrysotile, it still seems satisfactory to describe this cohort as a predominantly, but not exclusively, chrysotile-exposed cohort.

RevDate: 2019-11-08

van Gerwen M, Alpert N, Flores R, et al (2019)

An overview of existing mesothelioma registries worldwide, and the need for a US Registry.

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

The association between asbestos exposure, mainly in occupational settings, and malignant mesothelioma has been well established; this has prompted several countries to establish mesothelioma epidemiologic surveillance programs often at the request of national agencies. This review compares currently existing mesothelioma registries worldwide to develop a concept model for a US real-time case capture mesothelioma registry. Five countries were identified with a mesothelioma specific registry, including Italy, France, UK, Australia, and South Korea. All, except the UK, used interviews to collect exposure data. Linkage with the national death index was available or was in future plans for all registries. The registries have limited information on treatment, quality of life, and other patient-centered outcomes such as symptoms and pain management. To thoroughly collect exposure data, "real-time" enrollment is preferable; to maximize the capture of mesothelioma cases, optimal coverage, and a simplified consent process are needed.

RevDate: 2019-12-02

Gwenzi W (2020)

Occurrence, behaviour, and human exposure pathways and health risks of toxic geogenic contaminants in serpentinitic ultramafic geological environments (SUGEs): A medical geology perspective.

The Science of the total environment, 700:134622.

Serpentinitic ultramafic geological environments (SUGEs) contain toxic geogenic contaminants (TGCs). Yet comprehensive reviews on the medical geology of SUGEs are still lacking. The current paper posits that TGCs occur widely in SUGEs, and pose human health risks. The objectives of the review are to: (1) highlight the nature, occurrence and behaviour of TGCs associated with SUGEs; (2) discuss the human intake pathways and health risks of TGCs; (4) identify the key risk factors predisposing human health to TGCs particularly in Africa; and (5) highlight key knowledge gaps and future research directions. TGCs of human health concern in SUGEs include chrysotile asbestos, toxic metals (Fe, Cr, Ni, Mn, Zn, Co), and rare earth elements. Human intake of TGCs occur via inhalation, and ingestion of contaminated drinking water, wild foods, medicinal plants, animal foods, and geophagic earths. Occupational exposure may occur in the mining, milling, sculpturing, engraving, and carving industries. African populations are particularly at high risk due to: (1) widespread consumption of wild foods, medicinal plants, untreated drinking water, and geophagic earths; (2) weak and poorly enforced environmental, occupational, and public health regulations; and (3) lack of human health surveillance systems. Human health risks of chrysotile include asbestosis, cancers, and mesothelioma. Toxic metals are redox active, thus generate reactive oxygen species causing oxidative stress. Dietary intake of iron and geophagy may increase the iron overload among native Africans who are genetically predisposed to such health risks. Synergistic interactions among TGCs particularly chrysotile and toxic metals may have adverse human health effects. The occurrence of SUGEs, coupled with the several risk factors in Africa, provides a unique and ideal setting for investigating the relationships between TGCs and human health risks. A conceptual framework for human health risk assessment and mitigation, and future research direction are highlighted.

RevDate: 2019-11-29

Boyles MSP, Poland CA, Raftis J, et al (2019)

Assessment of the physicochemical properties of chrysotile-containing brake debris pertaining to toxicity.

Inhalation toxicology, 31(8):325-342.

Grinding and drilling of chrysotile asbestos-containing brake pads during the 20th century led to release of chrysotile, resulting in varying levels of workplace exposures of mechanics. Despite exposures, excess risk of mesothelioma remains in doubt. Objectives: The toxicity of particulates is primarily derived through a combination of physicochemical properties and dose and as such this study aimed to determine properties of asbestos-containing brake debris (BD) which may influence pathogenicity and potential of mesothelioma. Materials and Methods: Chrysotile-containing brake pads were ground - to reflect occupational activities, aerosolized, and size-fractionated to isolate respirable fractions. Analysis of morphology, biodurability, surface charge, and interactions with macrophages were undertaken. Results: The respirable fraction of BD contained ∼15-17% free chrysotile fibers thereby constituting a small but relevant potential long fiber dose. Acellular biodurability studies showed rapid dissolution and fragmentation of chrysotile fibers that was consistent for pure chrysotile control and BD samples. Conclusions: The long, free, respirable chrysotile fibers were present in BD, yet were of low bio-durability; incubation in artificial lysosomal fluid led to destruction of free fibers.

RevDate: 2019-11-05

Waldron T (2019)

ERA Merewether - And asbestos.

Journal of medical biography [Epub ahead of print].

After a succession of posts and studying for the Bar, Edward Merewether joined the Medical Inspectorate of Factories in 1927. Not long thereafter he was asked to undertake a study of the effects of asbestos exposure on the lungs. His results showed that asbestos workers had a significant risk of developing pulmonary fibrosis and this resulted in the promulgation of regulations to limit exposure. Some years later, Merewether showed that asbestos workers also had a higher than expected risk of developing lung cancer, but on this occasion there was no further protective legislation, and the association was not generally accepted until some years later. Merewether's name is inextricably linked with the risks of asbestos exposure but after his death the importance of his efforts was often played down by those who wished to show that the government had not acted quickly enough, or vigorously enough to control the hazard. The contention of this paper is that these criticisms are not justified and that Merewether acted to the best of his ability, given the conditions and knowledge current at the time he was working.

RevDate: 2019-12-05

Świątkowska B (2019)

[The occurrence of asbestos-related diseases among former employees of asbestos processing plants in Poland].

Medycyna pracy, 70(6):723-731.

BACKGROUND: Despite the fact that asbestos is no longer used in production in Poland, there are still new cases of asbestos-related diseases among workers previously exposed to asbestos dust. This situation is related to the specificity of the biological activity of this mineral; the health consequences of asbestos can manifest not only during the exposure but also many years after exposure cessation. The aim of the analysis was to assess the occurrence of occupational diseases among people exposed to asbestos dust, who were examined under the Amiantus program.

MATERIAL AND METHODS: The research material consisted of the program cards filled by the doctors conducting the examinations as well as radiological images stored on the International Labour Organization form. The analysis covered 8049 people, including 37% of women surveyed in the years 2000-2017.

RESULTS: In the group of former employees of asbestos processing plants, the occupational disease was diagnosed in 1993 people (25%), including 584 women (19%). The most common was asbestosis (76% of occupational diseases) and pleural disease (17%). Malignant neoplasms accounted for 7% of all cases in this group. The analysis showed an increase in the incidence of respiratory system diseases along with the age of the surveyed persons, their seniority at asbestos processing plants and an increase in cumulative exposure. The chest radiographs revealed radiological changes among 75% of the examined cases, whereas the changes entitling to diagnose asbestosis, according to the criteria applicable in Poland, occurred in 23% of the workers. The adoption of international criteria would increase the incidence of asbestosis as an occupational disease by 19% in the study group.

CONCLUSIONS: The increase in the percentage of people with a diagnosed occupational disease provides evidence for the worsening health status of the former workers as well as a good detection of asbestos-related diseases among employees exposed to asbestos dust in the past. The results of the analysis indicate the need for undertaking a discussion in Poland on the implementation of international criteria for the diagnosis of asbestosis. Med Pr. 2019;70(6):723-31.

RevDate: 2019-11-01

Wörthmüller J, Salicio V, Oberson A, et al (2019)

Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin.

International journal of molecular sciences, 20(21): pii:ijms20215391.

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells' growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

RevDate: 2019-10-31

Musk AWB, Reid A, Olsen N, et al (2019)

The Wittenoom legacy.

International journal of epidemiology pii:5610558 [Epub ahead of print].

The Wittenoom crocidolite (blue asbestos) mine and mill ceased operating in 1966. The impact of this industry on asbestos-related disease in Western Australia has been immense. Use of the employment records of the Australian Blue Asbestos Company and records of the Wittenoom township residents has permitted two cohorts of people with virtually exclusive exposure to crocidolite to be assembled and studied. Follow-up of these two cohorts has been conducted through data linkage with available hospital, mortality and cancer records. The evolution of asbestos-related disease has been recorded and, with the establishment of exposure measurements, quantitative exposure-response relationships have been estimated. There has been an ongoing epidemic of mortality from lung cancer and malignant mesothelioma and, less so, from asbestosis. Wittenoom crocidolite was used extensively in asbestos-cement products in Western Australia. As a result, the state has recorded a higher malignant-mesothelioma mortality rate than in any other Australian state and in any defined general population in the world. Thus, the legacy of Wittenoom has extended beyond the mine and the town, and is still evident more than 50 years after the closure of the mine.

RevDate: 2019-12-04

Cinausero M, Rihawi K, Cortiula F, et al (2019)

Emerging therapies in malignant pleural mesothelioma.

Critical reviews in oncology/hematology, 144:102815.

Malignant pleural mesothelioma (MPM) is a rare cancer of the pleural surfaces frequently related to asbestos exposure. It is characterized by a poor prognosis even for patients treated with trimodality therapy, including surgery, chemotherapy and radiotherapy. Moreover, the majority of patients are not candidates for surgery due to disease advanced stage or medical comorbidities. For these patients, the survival rate is even lower and few therapeutic options are currently available. Nevertheless, many interesting novel approaches are under investigation, among which immunotherapy represents one of the most promising emerging strategies. In this review, we will discuss the role of new therapeutic options, particularly immunotherapy, and present the results of the most important and promising clinical trials.

RevDate: 2019-10-31

Minami K, Jimbo N, Tanaka Y, et al (2019)

Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report.

Virchows Archiv : an international journal of pathology pii:10.1007/s00428-019-02674-x [Epub ahead of print].

Malignant pleural mesothelioma (MPM), associated with unfavorable outcomes, is closely associated with asbestos exposure. Early detection and treatment are critical to prolong survival of patients with MPM because of the rapid progression and resistance to treatment. The recently defined malignant mesothelioma in situ (MIS) has been gaining increasing attention with advances in genome-based methods including fluorescence in situ hybridization (FISH) as well as immunohistochemistry. We herein report the case of a MIS in a 73-year-old male with a history of asbestos exposure presenting with massive pleural effusion in the right thoracic cavity. Video-assisted thoracoscopic surgery with pleural biopsy of the right side revealed a single layer of atypical mesothelial cells without invasive lesions by hematoxylin and eosin staining. However, these mesothelial cells exhibited a loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry and homozygous deletion of CDKN2A (p16) by FISH, leading to the diagnosis of MIS.

RevDate: 2019-11-15

Reynolds CJ, Minelli C, Darnton A, et al (2019)

Mesothelioma mortality in Great Britain: how much longer will dockyards dominate?.

Occupational and environmental medicine, 76(12):908-912.

OBJECTIVES: We aimed to investigate whether there has been a geographic shift in the distribution of mesothelioma deaths in Great Britain given the decline of shipbuilding and progressive exposure regulation.

METHODS: We calculated age-adjusted mesothelioma mortality rates and estimated rate ratios for areas with and without a dockyard. We compared spatial autocorrelation statistics (Moran's I) for age-adjusted rates at local authority district level for 2002-2008 and 2009-2015. We measured the mean distance of the deceased's postcode to the nearest dockyard at district level and calculated the association of average distance to dockyard and district mesothelioma mortality using simple linear regression for men, for 2002-2008 and 2009-2015.

RESULTS: District age-adjusted male mortality rates fell during 2002-2015 for 80 of 348 districts (23%), rose for 267 (77%) and were unchanged for one district; having one or more dockyards in a district was associated with rates falling (OR=2.43, 95% CI 1.22 to 4.82, p=0.02). The mortality rate ratio for men in districts with a dockyard, compared with those without a dockyard was 1.41 (95% CI 1.35 to 1.48, p<0.05) for 2002-2008 and 1.18 (95% CI 1.13 to 1.23, p<0.05) for 2009-2015. Spatial autocorrelation (measured by Moran's I) decreased from 0.317 (95% CI 0.316 to 0.319, p=0.001) to 0.312 (95% CI 0.310 to 0.314, p=0.001) for men and the coefficient of the association between distance to dockyard and district level age-adjusted male mortality (per million population) from -0.16 (95% CI -0.21 to -0.10, p<0.01) to -0.13 (95% CI -0.18 to -0.07, p<0.01) for men, when comparing 2002-2008 with 2009-2015.

CONCLUSION: For most districts age-adjusted mesothelioma mortality rates increased through 2002-2015 but the relative contribution from districts with a dockyard fell. Dockyards remain strongly spatially associated with mesothelioma mortality but the strength of this association appears to be falling and mesothelioma deaths are becoming more dispersed.

RevDate: 2019-10-27

Fortin M, Cabon E, Berbis J, et al (2019)

Diagnostic Value of Computed Tomography Imaging Features in Malignant Pleural Mesothelioma.

Respiration; international review of thoracic diseases pii:000503239 [Epub ahead of print].

BACKGROUND: Medical history, thoracentesis, and imaging features are usually the first steps in the investigation of a possible malignant pleural effusion (MPE). Unfortunately, the diagnostic yield of thoracentesis in this situation is suboptimal even if the procedure is repeated, especially in the context of malignant pleural mesothelioma (MPM). The next step for confirming the diagnosis, if clinically appropriate, is thoracoscopy, but not all patients are fit to undergo this procedure, so the diagnosis is then based on the medical history and imaging features only.

OBJECTIVES: Our objective was to evaluate the diagnostic value of the medical history and imaging features in MPM.

METHODS: We reviewed the imaging and medical charts of 92 patients with a final diagnosis of MPE included in our prospective medical thoracoscopy database. The clinical characteristics and imaging features of patients with primary MPE were compared with those of patients with secondary MPE.

RESULTS: Male sex (82 vs. 59%, p = 0.02), asbestos exposure (58 vs. 10%, p < 0.001), and mediastinal (68 vs. 33%, p = 0.04), diaphragmatic (75 vs. 31%, p = 0.001) and circumferential pleural thickening (55 vs. 19% p = 0.001) were significantly more frequent in MPM patients. In a multivariate linear regression model, only asbestos exposure (OR 11.2; 95% CI 3.4-36.9) and circumferential pleural thickening (OR 4.7; 95% CI 1.6-13.9) were significantly associated with a diagnosis of MPM.

CONCLUSION: In situations where it is impossible to obtain adequate pleural samples to differentiate MPM from a secondary pleural malignancy, the combination of circumferential pleural thickening and a history of asbestos exposure may be sufficient to make a clinical diagnosis.

RevDate: 2019-11-14

Alcala N, Mangiante L, Le-Stang N, et al (2019)

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

EBioMedicine, 48:191-202.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options.

METHODS: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples.

FINDINGS: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series.

INTERPRETATION: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.

RevDate: 2019-11-29

Johnson TG, Schelch K, Mehta S, et al (2019)

Why Be One Protein When You Can Affect Many? The Multiple Roles of YB-1 in Lung Cancer and Mesothelioma.

Frontiers in cell and developmental biology, 7:221.

Lung cancers and malignant pleural mesothelioma (MPM) have some of the worst 5-year survival rates of all cancer types, primarily due to a lack of effective treatment options for most patients. Targeted therapies have shown some promise in thoracic cancers, although efficacy is limited only to patients harboring specific mutations or target expression. Although a number of actionable mutations have now been identified, a large population of thoracic cancer patients have no therapeutic options outside of first-line chemotherapy. It is therefore crucial to identify alternative targets that might lead to the development of new ways of treating patients diagnosed with these diseases. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) could serve as one such target. Recent studies also link this protein to many inherent behaviors of thoracic cancer cells such as proliferation, invasion, metastasis and involvement in cancer stem-like cells. Here, we review the regulation of YB-1 at the transcriptional, translational, post-translational and sub-cellular levels in thoracic cancer and discuss its potential use as a biomarker and therapeutic target.

RevDate: 2019-11-20

Nowak AK, PM Forde (2019)

Immunotherapy trials in mesothelioma - promising results, but don't stop here.

Nature reviews. Clinical oncology, 16(12):726-728.

RevDate: 2019-10-23

Munot MN, Utpat KV, Desai UD, et al (2019)

Malignant Mesothelioma - Report of Two Cases with Different Presentations.

Indian journal of occupational and environmental medicine, 23(2):93-96.

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm that stems from the mesothelial cells lining the visceral cavities, namely, the pleura, peritoneum, pericardium, and tunica vaginalis of the testes. MPM is the most common variant of these and constitutes up to 80% of all malignant mesotheliomas. It is usually associated with asbestos exposure and is a locally invasive neoplasm that spreads along pleura and can involve lungs with locoregional metastasis. Diagnosis remains challenging due to the latency between asbestos exposure and clinical presentation and the variable clinicoradiological manifestations. Meticulous history taking, high index of, suspicion and multimodality approach toward diagnosis are the keys to better prognosis. We hereby present two interesting cases of MPM with different presentations.

RevDate: 2019-10-15

Levý M, Boublíková L, Büchler T, et al (2019)

Treatment of Malignant Peritoneal Mesothelioma.

Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti, 32(5):333-337.

Malignant mesothelioma is a highly malignant disease that most often occurs in the pleura of the thoracic cavity, followed by the peritoneum, pericardium, or tinea vaginalis testis. Malignant peritoneal mesothelioma (MPM) accounts for 10-15% of all mesotheliomas. The most significant risk factor for MPM is exposure to asbestos. There is no specific symptomatology, and imaging (computed tomography) and histopathology are crucial for diagnosis. There are no generally accepted guidelines for radical treatment of MPM. Previously, the prognosis of MPM patients was poor, with survival of up to 1 year. However, median survival of patients who are suitable candidates for radical therapy is currently 3-5 years. A combination of cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) is recommended in selected patients, while chemotherapy alone has insufficient efficacy. Systemic chemotherapy remains the only treatment option for patients who are unsuitable for CRS and HIPEC. In selected patients scheduled for or currently undergoing CRS and HIPEC, surgery may be performed in combination with systemic chemotherapy in the neoadjuvant or adjuvant setting; however, the benefit is unclear. There are no recommendations for follow-up of MPM patients after radical surgery. Existing guidelines for the pleural form (e.g., those issued by the European Society for Medical Oncology) do not specify the frequency or method of investigation. In the absence of specific serum markers, only CA 125 and mesothelin are generally available. Imaging methods include ultrasonography, computed tomography, and magnetic resonance imaging.

RevDate: 2019-10-14

Moline J, Bevilacqua K, Alexandri M, et al (2019)

Mesothelioma Associated with the Use of Cosmetic Talc.

Journal of occupational and environmental medicine [Epub ahead of print].

OBJECTIVE: To describe exposures to talcum powder leading to mesothelioma among 33 individuals as a non-occupational asbestos exposure.

METHODS: Cases were referred for medico-legal evaluation, and tissue digestions were performed in some cases. Tissue digestion for the six cases described was done according to standard methodology RESULTS:: Asbestos of the type found in talcum powder was found in all six cases evaluated.. Talcum powder usage was the only source of asbestos for all 33 cases.

CONCLUSIONS: Exposure to asbestos-contaminated talcum powders can cause mesothelioma. Clinicians should elicit a history of talcum powder usage in all patients presenting with mesothelioma.

RevDate: 2019-11-13

Ceresoli GL, A Rossi (2019)

Approved and emerging treatments of malignant pleural mesothelioma in elderly patients.

Expert review of respiratory medicine, 13(12):1179-1188.

Introduction: Malignant pleural mesothelioma (MPM) is a rare neoplasm with asbestos exposure as the dominant etiologic agent. Owing to the long latent period following exposure, MPM is often diagnosed late in life. Despite this, elderly patients are under-represented in clinical trials. To date, data regarding the tolerability and efficacy of anticancer treatments for elderly patients affected by MPM are still lacking.Areas covered: The current state-of-the-art of approved treatments employed in the treatment of MPM elderly patients is reviewed and discussed, with a look to emerging therapies. A structured search of bibliographic databases for peer-reviewed research literature and of main meeting abstracts using a focused review question was undertaken.Expert opinion: Even though the median age of MPM patients enrolled in the most recent experimental trials is increasing, no specific analysis has been reported so far in the elderly. Moreover, no data are available for the 'oldest of the elderly' (>75 years). Treatment of elderly patients with MPM is one of the major challenges to the clinician. There is a clear need of large, well-conducted retrospective studies and above all of prospective investigations in this patient population, both in the first-and in the second-line setting.


RJR Experience and Expertise


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


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


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


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


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


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


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


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

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

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

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Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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