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Bibliography on: Mesothelioma and Asbestos

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ESP: PubMed Auto Bibliography 26 Jan 2020 at 01:44 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: 2020-01-24

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 "sufficient evidence" 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) ( 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 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. 2. Directive EU. (EU) 2019/130 of the European parliament and of the council of 16 January 2019. Available from: 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. 4. SCOEL. SCOEL's involvement in setting Occupational Exposure Limits: Webpage accessed 2019-10-23. Available from: 5. SCOEL. Recommendation from the Scientific Committee on Occupational Exposure Limits for Silica, Crystalline (respirable dust). SCOEL/SUM/94. November 2003. Available from: 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: 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: 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: 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: 10. Health Council of the Netherlands. Guidelines for the calculation of occupational cancer risk values. Health Council of the Netherlands, 2012. Available from: 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. 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. 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.

RevDate: 2019-10-15

Kwak K, Paek D, KE Zoh (2019)

Exposure to asbestos and the risk of colorectal cancer mortality: a systematic review and meta-analysis.

Occupational and environmental medicine, 76(11):861-871.

Asbestos exposure is associated with mesothelioma and cancer of the lung, larynx and ovary. However, the association between asbestos exposure and colorectal cancer is controversial despite several systematic reviews of the literature, including a number of meta-analyses. We performed a systematic review and meta-analysis to evaluate quantitatively the association between exposure to asbestos and colorectal cancer. We searched for articles on occupational asbestos exposure and colorectal cancer in PubMed, EMBASE and Web of Science published before April 2018. In total, 44 articles were selected and 46 cohort studies were analysed. The overall pooled risk estimates and corresponding 95% CIs of the association between occupational asbestos exposure and colorectal cancer were calculated using a random-effects model. Subgroup analyses and sensitivity tests were also performed. There was a significantly increased risk of colorectal cancer mortality among workers exposed to asbestos occupationally, with an overall pooled SMR of 1.16 (95% CI: 1.05 to 1.29). The pooled SMR for colorectal cancer was elevated in studies in which the asbestos-associated risk of lung cancer was also elevated (1.43; 95% CI: 1.30 to 1.56). This implies that the risk of colorectal cancer mortality increases as the level of asbestos exposure rises. A sensitivity analysis showed robust results and there was no publication bias. Although the effect size was small and the heterogeneity among studies was large, our findings indicate that occupational exposure to asbestos is a risk factor for colorectal cancer.

RevDate: 2019-10-23

Vimercati L, Cavone D, Caputi A, et al (2019)

Malignant mesothelioma in construction workers: the Apulia regional mesothelioma register, Southern Italy.

BMC research notes, 12(1):636.

OBJECTIVE: Asbestos was widely used in construction in both a friable and a compact form until the 1990s, before its use was banned. Today, many of these materials are still in situ and represent a source of risk for construction workers. The objective of the study was to analyse the cases of mesothelioma arising among construction workers registered in the Apulia regional register of mesothelioma.

RESULTS: For the period 1993-2018, there were 178 male cases, and 10.2% of the cases were present in the regional register. The average age at diagnosis was 64.7 years. The site was pleural in 96.06% of cases, with a diagnosis of certainty in 86.5% of the total cases and 61.8% of cases with epithelial histology. The average latency is 43.9 years. In 75.2% of cases, the exposure began between 1941 and 1970, with an average duration of 24.3 years. The age at the start of exposure in 68.5% of cases is between 8 and 20 years. The ORs were 2.5 (C.I. 95% 1.01-6.17) for the epithelioid histotype and the high duration of exposure. The data underline the need for prevention and information on all activities involving construction workers in which asbestos-containing materials are still used.

RevDate: 2019-10-31

Takeda M, Ohe Y, Horinouchi H, et al (2019)

Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma.

Lung cancer (Amsterdam, Netherlands), 137:64-70.

OBJECTIVES: CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies.

MATERIAL AND METHODS: The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs).

RESULTS: Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response.

CONCLUSIONS: YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.

RevDate: 2019-09-27

Hinz TK, LE Heasley (2019)

Translating mesothelioma molecular genomics and dependencies into precision oncology-based therapies.

Seminars in cancer biology pii:S1044-579X(19)30288-3 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a rare, yet lethal asbestos-induced cancer and despite marked efforts to reduce occupational exposure, the incidence has not yet significantly declined. Since 2003, combined treatment with a platinum-based agent and pemetrexed has been the first-line therapy and no effective or approved second-line treatments have emerged. The seemingly slow advance in developing new MPM treatments does not appear to be related to a low level of clinical and pre-clinical research activity. Rather, we suggest that a key hurdle in successfully translating basic discovery into novel MPM therapeutics is the underlying assumption that as a rare cancer, it will also be molecularly and genetically homogeneous. In fact, lung adenocarcinoma and melanoma only benefitted from precision oncology upon full appreciation of the high degree of molecular heterogeneity inherent in these cancers, especially regarding the diversity of oncogenic drivers. Herein, we consider the recent explosion of molecular and genetic information that has become available regarding MPM and suggest ways in which the unfolding landscape may guide identification of novel therapeutic vulnerabilities within subsets of MPM that can be targeted in a manner consistent with the tenets of precision oncology.

RevDate: 2019-11-25

Geyer SJ (2019)

Malignant Mesothelioma and Its Nonasbestos Causes: Talcum Powder Does Not Create Occult Asbestos Exposure.

Archives of pathology & laboratory medicine, 143(12):1439.

RevDate: 2019-11-01

Hamaidia M, Gazon H, Hoyos C, et al (2019)

Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism.

JCI insight, 4(18):.

The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activity in the absence of adaptive immunity. We investigated direct macrophage cytotoxicity in malignant pleural mesothelioma, a lethal cancer that develops from mesothelial cells of the pleural cavity after occupational asbestos exposure. In particular, we analyzed the cytotoxic activity of mouse RAW264.7 macrophages upon cell-cell contact with autologous AB1/AB12 mesothelioma cells. We show that macrophages killed mesothelioma cells by oxeiptosis via a mechanism involving enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27-specific (H3K27-specific) methyltransferase of the polycomb repressive complex 2 (PRC2). A selective inhibitor of EZH2 indeed impaired RAW264.7-directed cytotoxicity and concomitantly stimulated the PD-1 immune checkpoint. In the immunocompetent BALB/c model, RAW264.7 macrophages pretreated with the EZH2 inhibitor failed to control tumor growth of AB1 and AB12 mesothelioma cells. Blockade of PD-1 engagement restored macrophage-dependent antitumor activity. We conclude that macrophages can be directly cytotoxic for mesothelioma cells independent of phagocytosis. Inhibition of the PRC2 EZH2 methyltransferase reduces this activity because of PD-1 overexpression. Combination of PD-1 blockade and EZH2 inhibition restores macrophage cytotoxicity.

RevDate: 2019-11-12

Kim RY, Sterman DH, AR Haas (2019)

Malignant Mesothelioma: Has Anything Changed?.

Seminars in respiratory and critical care medicine, 40(3):347-360.

Malignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma.

RevDate: 2019-09-12

Huang Q, YJ Lan (2019)

Colorectal cancer and asbestos exposure-an overview.

Industrial health [Epub ahead of print].

The relationship between colorectal cancer and asbestos exposure has not been fully clarified. This study aimed to determine the associations between asbestos exposure and colorectal cancer. We performed a meta-analysis to quantitatively evaluate this association. A fixed effects model was used to summarize the relative risks across studies. Sources of heterogeneity were explored through subgroup analyses and meta-regression. We analyzed the dose-effect relationship using lung cancer Standardized mortality ratio (SMR) and the risk of mesothelioma as a percent (%) as exposure surrogates. A total of 47 cohort studies were included. We identified 28 incidence cohort studies from 17 separate papers and extracted colorectal cancer Standardized incidence ratio (SIR). Cancer mortality data were extracted from 19 separate cohorts among 13 papers. The overall colorectal cancer SMR for synthesis cohort was 1.07 (95% CI 1.02-1.12). Statistically significant excesses were observed in exposure to mixed asbestos (SMR/SIR=1.07), exposure to production (SMR/SIR=1.11), among asbestos cement workers (SMR/SIR=1.18) and asbestos textile workers (SMR/SIR=1.11). Additionally, we determined that the SMR for lung cancer increased with increased exposure to asbestos, as did the risk for colorectal cancer. This study confirms that colorectal cancer has a positive weak associations with asbestos exposure.

RevDate: 2019-10-07

Abdelgied M, El-Gazzar AM, Alexander WT, et al (2019)

Carcinogenic effect of potassium octatitanate (POT) fibers in the lung and pleura of male Fischer 344 rats after intrapulmonary administration.

Particle and fibre toxicology, 16(1):34 pii:10.1186/s12989-019-0316-2.

BACKGROUND: Potassium octatitanate fibers (K2O•8TiO2, POT fibers) are used as an asbestos substitute. Their physical characteristics suggest that respirable POT fibers are likely to be carcinogenic in the lung and pleura. However, previous 2-year inhalation studies reported that respired POT fibers had little or no carcinogenic potential. In the present study ten-week old male F344 rats were left untreated or were administered vehicle, 0.25 or 0.5 mg rutile-type nano TiO2 (r-nTiO2), 0.25 or 0.5 mg POT fibers, or 0.5 mg MWCNT-7 by intra-tracheal intra-pulmonary spraying (TIPS), and then observed for 2 years.

RESULTS: There were no differences between the r-nTiO2 and control groups. The incidence of bronchiolo-alveolar cell hyperplasia was significantly increased in the groups treated with 0.50 mg POT and 0.50 mg MWCNT-7. The overall incidence of lung tumors, however, was not increased in either the POT or MWCNT-7 treated groups. Notably, the carcinomas that developed in the POT and MWCNT-7 treated rats were accompanied by proliferative fibrous connective tissue while the carcinomas that developed in the untreated rats and the r-nTiO2 treated rats were not (carcinomas did not develop in the vehicle control rats). In addition, the carcinoma that developed in the rat treated with 0.25 mg POT was a squamous cell carcinoma, a tumor that develops spontaneously in about 1 per 1700 rats. The incidence of mesothelial cell hyperplasia was 4/17, 7/16, and 10/14 and the incidence of malignant mesothelioma was 3/17, 1/16, and 2/14 in the 0.25 mg POT, 0.5 mg POT, and MWCNT-7 treated groups, respectively. Neither mesothelial cell hyperplasia nor mesothelioma developed in control rats or the rats treated with r-nTiO2. Since the incidence of spontaneously occurring malignant mesothelioma in rats is extremely low, approximately 1 per 1000 animals (Japan Bioassay Research Center [JBRC] historical control data), the development of multiple malignant mesotheliomas in the POT and MWCNT-7 treated groups was biologically significant.

CONCLUSION: The incidence of pleural mesotheliomas in male F344 rats administered POT fibers and MWCNT-7 was significantly higher than the JBRC historical control data, indicating that the incidence of pleural mesothelioma in the groups administered POT fibers and MWCNT-7 fibers via the airway using TIPS was biologically significant. The incidence of type II epithelial cell hyperplasia and the histology of the carcinomas that developed in the POT treated rats also indicates that respirable POT fibers are highly likely to be carcinogenic in the lungs of male F344 rats.

RevDate: 2019-09-05

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

Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives.

Frontiers in oncology, 9:740.

Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to asbestos exposure. Although the risk factors for MPM are well-known, the majority of MPM patients are diagnosed at an advanced stage and have a very poor prognosis. Circulating biomarkers for early diagnosis remain to be identified, and the current standard for MPM diagnosis relies on pleural biopsies. Robust non-invasive tests for the screening of asbestos-exposed subjects are therefore an important unmet clinical need. This review provides a critical summary of recent liquid biopsy-based studies aimed at discovering novel blood-based circulating biomarkers for the early diagnosis and prognostic stratification of MPM patients.

RevDate: 2019-11-28

Vimercati L, Cavone D, Delfino MC, 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):78 pii:10.1186/s12940-019-0512-4.

BACKGROUND: Malignant mesothelioma of the tunica vaginalis testis (MMTVT) is a rare disease with a poor prognosis. The diagnosis and management of these lesions are often difficult for pathologists, surgeons, oncologists and occupational physicians. A preoperative diagnosis of malignancy is rarely made, and there is no established effective therapy except orchidectomy.

METHODS: A systematic literature review was conducted among the articles published in the English literature on primary MMTVT. Moreover four cases from the Apulia mesothelioma register are reported here.

RESULTS: Two hundred eighty-nine cases of MMTVT have been reported from 1943 to 2018. Overall asbestos exposure has been investigated only for 58% of all cases reported in this review, while in 41.8% this data are not available. Noteworthy is the fact that in many reports there is not an anamnestic reconstruction of any asbestos exposure. A history of direct occupational, environmental or familial asbestos exposure is found in 27.6% of the cases. The four cases from the Apulia mesothelioma register are all with ascertained occupational exposure to asbestos.

CONCLUSIONS: The true incidence of asbestos exposure in MMTVT is underestimated because of insufficient information reported in older literature. To establish a broad consensus on the causal relationship between asbestos and MMTVT in the scientific community its necessary to analyze the same variables in the epidemiological studies. In general it should be recommended that a positive history of exposure to asbestos or to asbestos-containing materials are at risk for the development of a MMTVT and should be monitored.

RevDate: 2019-09-01

Hassan D, S Ligato (2019)

Localized Biphasic Malignant Peritoneal Mesothelioma with Rhabdoid Features Involving the Liver: Case Report and Review of the Literature.

Case reports in pathology, 2019:2732674.

Introduction: Localized malignant mesotheliomas, defined as sharply circumscribed tumors of the serosal membrane with the microscopic appearance of diffuse malignant mesothelioma, are rare tumors; their behavior and prognosis are uncertain. Intrahepatic mesotheliomas are postulated to arise from mesothelial cells of Glisson's capsule.

Case Presentation: A 69-year-old female with no history of asbestos exposure presented with a one-month history of increasing abdominal pain associated with constitutional symptoms. Computerized Tomography (CT) scan of the abdomen and pelvis revealed a sizable soft tissue mass within the right paracolic gutter, abutting the inferior hepatic margin, the lateral abdominal wall, and descending colon. Ultrasound-guided biopsy of the mass suggested a poorly differentiated hepatocellular carcinoma. There was no disease elsewhere on PET scan. Surgical resection of the mass was performed. Pathological assessment suggested the tumor to be arising from the liver with invasion of the liver, abdominal wall musculature, and the adventitial surface of the ascending colon. A final diagnosis of localized biphasic malignant peritoneal mesothelioma with rhabdoid features was rendered based on morphology and the result of immunohistochemical studies. The abdominal wall margin was positive. The patient progressed over the course of 6 months despite receiving adjuvant chemotherapy and immunotherapy with metastases and a decline in performance status and was transitioned to hospice.

Conclusion: Localized malignant peritoneal mesotheliomas are rare tumors that may present clinically as a liver mass and simulate primary hepatic or secondary tumors. Definitive diagnosis is obtained by surgical resection in most cases. The clinical outcome is variable with most cases having a poor outcome.

RevDate: 2019-11-10

Li Z, Jiang L, Chew SH, et al (2019)

Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia.

Redox biology, 26:101297.

Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2- and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells.

RevDate: 2019-11-03

Keshava HB, Tang A, Siddiqui HU, et al (2019)

Largely Unchanged Annual Incidence and Overall Survival of Pleural Mesothelioma in the USA.

World journal of surgery, 43(12):3239-3247.

BACKGROUND: Projections based on regulations curtailing asbestos use in the USA suggest that peak incidence of pleural mesothelioma would occur between 2000 and 2005 and then decline. We analyzed the National Cancer Database (NCDB) to assess current trends in disease incidence, patient demographics, cancer treatment, and survival.

METHODS: The NCDB was queried to identify patients diagnosed with pleural mesothelioma from 2004 through 2014. Clinical and pathologic characteristics, treatments, and survival were analyzed. Risk factors for death were identified by multivariable Cox regression.

RESULTS: A total of 20,988 patients with pleural mesothelioma were reported to the NCDB. The number of cases per year increased from 1783 to 1961, accounting for roughly 0.3% of all reported cancers each year. The proportion of elderly patients increased from 75 to 80%, but distribution by sex remained constant (20% female). The proportion of patients undergoing treatment increased from 34 to 54%. One-year survival increased from 37 to 47% and 3-year survival from 9 to 15% (p < 0.001). Factors associated with improved survival included younger age, female sex, epithelioid histology, treatment in an academic center, health insurance, higher income, and multimodality therapy.

CONCLUSIONS: The annual incidence of mesothelioma has not declined this century and remains stable. Reporting of histologic and clinical staging has improved. National trends suggest that survival is slowly increasing despite an aging cohort. Multimodal therapy and treatment at academic centers are modifiable risk factors associated with improved survival.

RevDate: 2019-08-28

Hoffmann PR, Hoffmann FW, Premeaux TA, et al (2019)

Multi-antigen Vaccination With Simultaneous Engagement of the OX40 Receptor Delays Malignant Mesothelioma Growth and Increases Survival in Animal Models.

Frontiers in oncology, 9:720.

Malignant Mesothelioma (MM) is a rare and highly aggressive cancer that develops from mesothelial cells lining the pleura and other internal cavities, and is often associated with asbestos exposure. To date, no effective treatments have been made available for this pathology. Herein, we propose a novel immunotherapeutic approach based on a unique vaccine targeting a series of antigens that we found expressed in different MM tumors, but largely undetectable in normal tissues. This vaccine, that we term p-Tvax, is comprised of a series of immunogenic peptides presented by both MHC-I and -II to generate robust immune responses. The peptides were designed using in silico algorithms that discriminate between highly immunogenic T cell epitopes and other harmful epitopes, such as suppressive regulatory T cell epitopes and autoimmune epitopes. Vaccination of mice with p-Tvax led to antigen-specific immune responses that involved both CD8+ and CD4+ T cells, which exhibited cytolytic activity against MM cells in vitro. In mice carrying MM tumors, p-Tvax increased tumor infiltration of CD4+ T cells. Moreover, combining p-Tvax with an OX40 agonist led to decreased tumor growth and increased survival. Mice treated with this combination immunotherapy displayed higher numbers of tumor-infiltrating CD8+ and CD4+ T cells and reduced T regulatory cells in tumors. Collectively, these data suggest that the combination of p-Tvax with an OX40 agonist could be an effective strategy for MM treatment.

RevDate: 2019-08-17

Bousema JE, van de Luijtgaarden KM, Wilhelmus S, et al (2019)

Acute severe abdominal pain in a young woman caused by a well-differentiated papillary mesothelioma of the peritoneum.

BMJ case reports, 12(8): pii:12/8/e229769.

Acute abdominal pain is a common symptom in young women. We describe a patient with acute illness and severe lower abdominal pain. Laboratory tests were normal except for mildly deranged inflammatory markers. No abnormalities were reported on abdominal ultrasonography and MRI, whereas diagnostic laparoscopy revealed a tumour located dorsally from the uterus. We resected the tumour and pathology results showed a well-differentiated papillary mesothelioma of the peritoneum (WDPMP). Microscopy showed evidence of acute ischaemia in the resected lesion, which was likely the cause of the acute abdominal pain. WDPMP is a rare disease that arises from the serous membranes which does not seem to have a relation to asbestos exposure. Generally, WDPMP has a mild clinical course and good long-term prognosis.

RevDate: 2019-08-31

Consonni D, Migliore E, Barone-Adesi F, et al (2019)

Gender differences in pleural mesothelioma occurrence in Lombardy and Piedmont, Italy.

Environmental research, 177:108636.

BACKGROUND: Higher mesothelioma rates in men (vs women) reflect more frequent and more intense asbestos exposure. We assessed the impact of exposure difference between genders on age-specific rates of pleural mesothelioma (PM) occurrence using data from two Italian regions.

METHODS: We used data from the Lombardy and Piedmont mesothelioma registries (period 2000-2016, age 45-74 years) to compare rates of PM in men and women and to estimate the rate advancement period (RAP).

RESULTS: Based on 3384 cases (2405 men, 979 women) in Lombardy and 2042 (1389 men, 653 women) in Piedmont, the rate ratio was 2.81 (90% confidence interval: 2.61-3.03) in Lombardy and 2.39 (2.17-2.62) in Piedmont. In both regions RAP ranged from 7 to 10 years (at age 45 and 63 in men, respectively).

CONCLUSION: Men showed more than twofold increased PM rates and reached the same incidence as women 7-10 years earlier. RAP can be a useful measure of exposure impact on premature disease occurrence.

RevDate: 2019-08-16

Betti M, Aspesi A, Sculco M, et al (2019)

Genetic predisposition for malignant mesothelioma: A concise review.

Mutation research, 781:1-10.

Malignant mesothelioma (MM) is an aggressive cancer associated with asbestos exposure. Studies of familial malignant pleural mesothelioma (MPM) have suggested the existence of a genetic predisposition. Information on the role of genetic risk factors in the development of MM has been growing in the last years, and both low- and high-risk genetic factors have been identified, but genetic factors alone (without any exposure to asbestos or other mineral fibers) have never been shown to induce MM. Low-risk genetic factors have been identified in studies that systematically analyzed the whole genome. When considered alone these low-risk genetic factors carry a relative risk of MPM that is 10- to 15-fold lower than that carried by asbestos exposure; however, a large number of these factors in combination may increase the impact of asbestos exposure. High-risk genetic factors include truncating variants in the tumor suppressor BAP1 and in other tumor suppressor genes belonging to DNA repair pathways. Heterozygous germline variants in these genes may favor carcinogenesis if a second somatic variant occurs that impairs the wild-type allele. This impairment can cause genetic instability due to the suppression of a specific DNA repair pathway, and transformation. This genetic predisposition may have translational consequences, as it may predict patient response to drugs that induce tumor-specific synthetic lethality.

RevDate: 2019-08-15

Barone-Adesi F, Ferrante D, Chellini E, et al (2019)

Role of asbestos clearance in explaining long-term risk of pleural and peritoneal cancer: a pooled analysis of cohort studies.

Occupational and environmental medicine, 76(9):611-616.

OBJECTIVES: Models based on the multistage theory of cancer predict that rates of malignant mesothelioma continuously increase with time since first exposure (TSFE) to asbestos, even after the end of external exposure. However, recent epidemiological studies suggest that mesothelioma rates level off many years after first exposure to asbestos. A gradual clearance of asbestos from the lungs has been suggested as a possible explanation for this phenomenon. We analysed long-term trends of pleural and peritoneal cancer mortality in subjects exposed to asbestos to evaluate whether such trends were consistent with the clearance hypothesis.

METHODS: We used data from a pool of 43 Italian asbestos cohorts (51 801 subjects). The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalised to include a term representing elimination of fibres over time.

RESULTS: Rates of pleural cancer increased until 40 years of TSFE, but remained stable thereafter. On the other hand, we observed a monotonic increase of peritoneal cancer with TSFE. The model taking into account asbestos clearance fitted the data better than the traditional one for pleural (p=0.004) but not for peritoneal (p=0.09) cancer.

CONCLUSIONS: Rates of pleural cancer do not increase indefinitely after the exposure to asbestos, but eventually reach a plateau. This trend is well described by a model accounting for a gradual elimination of the asbestos fibres. These results are relevant for the prediction of future rates of mesothelioma and in asbestos litigations.

RevDate: 2019-08-14

Gudmundsson G, K Tomasson (2019)

[Asbestos and its effects on health of Icelanders - review].

Laeknabladid, 105(7):327-334.

Asbestos are crystallized silicate minerals that form fibers with different structures and characteristics. Asbestos fibers are very durable and can tolerate very high temperatures. Therefore it was common to use asbestos as a fire retardants, heat insulation and where high temperature is used. Asbestos has been banned in Iceland from 1983 but can still be found in large amounts in buildings, ships and hot water pipes. Large amounts of asbestos were imported in the years before the ban but diminished soon to almost nothing today. Needle or filamentous shaped dust is released when working with asbestos. It is this dust that is dangerous for health. The latent time from exposure to disease can be up to forty years. Asbestos reaches the lungs via inhalation and can cause asbestosis that is a form of lung fibrosis with slow progression. Asbestos can also cause benign pleural effusions, pleural plaques and diffuse pleural thickening. Asbestos is a carcinogen. Lung cancer is most common but asbestos is also a risk factor for cancers of other organs. Mesothelioma is most common in the pleura but can be seen in other membranes. The incidence of these tumors is high in Iceland and is still increasing among males. Of all the European countries mortality is highest in Iceland. It is important for physicians to include asbestos exposure in the differential diagnosis of lung diseases and when lung cancer is diagnosed.

RevDate: 2019-11-01

Jiang Y, Mei Z, Cao H, et al (2019)

Meningeal metastasis of a malignant peritoneal mesothelioma: A case report and literature review.

Cancer biology & therapy, 20(12):1409-1415.

Malignant peritoneal mesothelioma is a very rare tumor originating from the peritoneal serous mesothelium. Meningeal metastasis of malignant peritoneal is even more rare. Here, we reported a case of a 60-year-old female patient with a history of exposure to asbestos for 10 years who presented with massive peritoneal effusion followed by disorder of consciousness and symptoms of cranial nerve injury. The patient was diagnosed as peritoneal mesothelioma with meningeal metastasis through neurological symptoms, cytological finding of cerebrospinal fluid combined with cranial magnetic resonance imaging (MRI). The patient received systemic chemotherapy and total craniospinal irradiation. The follow up visits showed that the survival time of patient after diagnosis of meningeal metastasis from peritoneal mesothelioma was 5 months. To our knowledge, this is the first case of menigeal metastasis of peritoneal mesothelioma. We hope this particular case may be helpful in providing some experience to the treatment of peritoneal mesothelioma with meningeal metastasis.

RevDate: 2019-08-13

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 pii:5548996 [Epub ahead of print].

RevDate: 2019-08-17

Munson PB, Hall EM, Farina NH, et al (2019)

Exosomal miR-16-5p as a target for malignant mesothelioma.

Scientific reports, 9(1):11688 pii:10.1038/s41598-019-48133-0.

Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. MM is essentially incurable without a means of early diagnosis and no successful standard of care. These facts indicate a deep chasm of knowledge that needs to be filled. Our group recently delved into MM tumor biology from the perspective of exosome-contained microRNAs (miRNAs). We discovered that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly miR-16-5p. This observation lead us to hypothesize that MM cells preferentially secreted tumor-suppressor miRNAs via exosomes. Through separate avenues of potential therapeutic advance, we embarked on an innovative strategy to kill MM tumor cells. We employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p leading to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, we force-fed MM tumor exosomes back to MM tumor cells, which led to cell death, and a reduction in the same oncoproteins. We recapitulated these results with direct transfection of miR-16-5p, confirmed that this is a cancer-cell specific effect, and elucidated a part of the miR-16-5p mechanism of exosome loading.

RevDate: 2019-11-28

Luberto F, Ferrante D, Silvestri S, et al (2019)

Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy.

Environmental health : a global access science source, 18(1):71 pii:10.1186/s12940-019-0510-6.

BACKGROUND: Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos.

METHODS: The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution.

RESULTS: Mortality was significantly increased for 'All Causes' and 'All Malignant Neoplasm (MN)', in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%.

CONCLUSIONS: Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

RevDate: 2019-08-07

Corti A, Bonetti J, Dominici S, et al (2019)

Induction of gamma-glutamyltransferase activity and consequent prooxidant reactions in human macrophages exposed to crocidolite asbestos.

Toxicological sciences : an official journal of the Society of Toxicology pii:5544276 [Epub ahead of print].

Asbestos is the main causative agent of malignant pleural mesothelioma. The variety known as crocidolite (blue asbestos) owns the highest pathogenic potential, due to the dimensions of its fibers as well as to its content of iron. The latter can in fact react with macrophage-derived hydrogen peroxide in the so called Fenton reaction, giving rise to highly reactive and mutagenic hydroxyl radical. On the other hand, hydroxyl radical can as well originate after thiol-dependent reduction of iron, a process capable of starting its redox cycling. Previous studies showed that glutathione (GSH) is one such thiols, and that cellular gamma-glutamyltransferase (GGT) can efficiently potentiate GSH-dependent iron redox cycling and consequent oxidative stress. As GGT is expressed in macrophages and is released upon their activation, the present study was aimed at verifying the hypothesis that GSH/GGT-dependent redox reactions may participate in the oxidative stress following the activation of macrophages induced by crocidolite asbestos. Experiments in acellular systems confirmed that GGT-mediated metabolism of GSH can potentiate crocidolite-dependent production of superoxide anion, through the production of highly reactive dipeptide thiol cysteinyl-glycine. Cultured THP-1 macrophagic cells, as well as isolated monocytes obtained from healthy donors and differentiated to macrophages in vitro, were investigated as to their expression of GGT and the effects of exposure to crocidolite. The results show that crocidolite asbestos at sub-toxic concentrations (50-250 ng/1,000 cells) can upregulate GGT expression, which raises the possibility that macrophage-initiated, GSH/GGT-dependent prooxidant reactions may participate in the pathogenesis of tissue damage and inflammation consequent to crocidolite intoxication.

RevDate: 2019-08-06

Wronkiewicz SK, Roggli VL, Hinrichs BH, et al (2019)

Chrysotile fibers in tissue adjacent to laryngeal squamous cell carcinoma in cases with a history of occupational asbestos exposure.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc pii:10.1038/s41379-019-0332-7 [Epub ahead of print].

Asbestos describes a group of naturally occurring fibrous silicate mineral compounds that have been associated with a number of respiratory maladies, including mesothelioma and lung cancer. In addition, based primarily on epidemiologic studies, asbestos has been implicated as a risk factor for laryngeal and pharyngeal squamous cell carcinoma (SCC). The main objective of this work was to strengthen existing evidence via empirical demonstration of persistent asbestos fibers embedded in the tissue surrounding laryngeal and pharyngeal SCC, thus providing a more definitive biological link between exposure and disease. Six human papillomavirus (HPV)-negative laryngeal (n = 4) and pharyngeal (n = 2) SCC cases with a history working in an asbestos-exposed occupation were selected from a large population-based case-control study of head and neck cancer. A laryngeal SCC case with no history of occupational asbestos exposure was included as a control. Tissue cores were obtained from adjacent nonneoplastic tissue in tumor blocks from the initial primary tumor resection, and mineral fiber analysis was performed using a scanning electron microscope equipped with an energy dispersive X-ray analyzer (EDXA). Chrysotile asbestos fiber bundles were identified in 3/6 of evaluated cases with a history of occupational asbestos exposure. All three cases had tumors originating in the larynx. In addition, a wollastonite fiber of unclear significance was identified one of the HPV-negative pharyngeal SCC cases. No mineral fibers were identified in adjacent tissue of the case without occupational exposure. The presence of asbestos fibers in the epithelial tissue surrounding laryngeal SCC in cases with a history of occupational asbestos exposure adds a key line of physical evidence implicating asbestos as an etiologic factor.

RevDate: 2019-10-31

Jacobs NFB, Towle KM, Finley BL, et al (2019)

An updated evaluation of potential health hazards associated with exposures to asbestos-containing drywall accessory products.

Critical reviews in toxicology, 49(5):430-444.

Following a previously published (2012) evaluation of the potential health hazards related to the use of asbestos-containing drywall accessory products, additional information regarding asbestos exposures during the use of accessory products, as well as studies of chrysotile asbestos risk as a function of exposure, have been published in the peer-reviewed literature. The purpose of this analysis is to update the original evaluation with this new information. It was previously estimated that a professional drywaller performing joint compound-associated tasks could have a lifetime cumulative chrysotile exposure of 12-26 f/cc-year. Using conservative assumptions regarding airborne asbestos levels during different drywalling tasks, task duration, and job tenure, we found that a range of 4.3-36.3 f/cc-year is a plausible estimate of a career drywaller's cumulative asbestos exposure from historical joint compound use. The estimated range for bystander exposures would be below (sometimes significantly below) this range depending on the frequency and duration of work near drywallers. Further, the estimated drywaller and bystander total fiber exposures were well below a recently published "no-observed adverse effect level, best estimate" for predominately chrysotile exposures of 89-168 f/cc-year for lung cancer and 208-415 f/cc-year for mesothelioma. We also determined that, even if the chrysotile or possibly talc ingredients in the drywall products had contained asbestiform tremolite, the cumulative tremolite exposures would have been well below a recently published tremolite no-effect level of 0.5-2.6 f/cc-year. Based on our calculations, typical drywall work using asbestos-containing drywall accessory products is not expected to increase the risk of asbestos-related lung cancer or mesothelioma. These conclusions are consistent with the lack of epidemiological evidence that drywall work resulted in an increased incidence of asbestos-related disease in the drywall trades.

RevDate: 2019-11-15

Marsh GM, Ierardi AM, Benson SM, et al (2019)

Occupational exposures to cosmetic talc and risk of mesothelioma: an updated pooled cohort and statistical power analysis with consideration of latency period.

Inhalation toxicology, 31(6):213-223.

Objectives: We previously published a pooled statistical power analysis of mesothelioma incidence in the Italian, Norwegian, Austrian, and French cosmetic talc miner and miller cohorts. Soon thereafter, updates to the Italian and Norwegian cohorts were published, providing an additional 14,322 person-years of observation. In this study, we provide an updated power analysis using the newly available information. Methods: We pooled the current results regarding pleural cancer/mesothelioma mortality or incidence in four cosmetic talc miner and miller cohorts in Italy, Norway, Austria, and France. We used the expected numbers of cases as reported by the authors and the power analysis was based on an a priori one-sided significance level of 0.05 and Poisson distribution probabilities. Results: There was a pooled total of 113,344 person-years in the cohorts. Although 3.0 pleural cancers/mesotheliomas were expected, there were no reported pleural cancer or mesothelioma cases in any cohort. Our pooled analysis was associated with 79 and 62% power to detect a 3.0-fold and 2.5-fold or greater increase in pleural cancer/mesothelioma, respectively. These favorable power characteristics were effectively maintained when restricting the pooled cohort to workers with a latency period of 30 or more years (observation time from first employment). Conclusions: The epidemiological evidence from the cosmetic talc miner/miller cohort studies does not support the hypothesis that exposure to cosmetic talc is associated with the development of pleural cancer/mesothelioma.

RevDate: 2019-11-19

Butnor KJ, Pavlisko EN, Sporn TA, et al (2019)

Mesothelioma of the tunica vaginalis testis.

Human pathology, 92:48-58.

Malignant mesothelioma (MM) arising from the serosal membranes of the tunica vaginalis testis (TVT) is rare. Most examples in the published medical literature are individual case reports. This study presents the clinicopathological findings of mesothelioma of the TVT in one of the largest series to date. Individuals with mesothelioma of the TVT were identified from a database of more than 4000 mesothelioma cases, and their clinicopathological features were recorded. Eighteen men with MM and 2 with well-differentiated papillary mesothelioma of the TVT were identified, which represented 0.6% of males with mesothelioma in study population. The median age at diagnosis was 72 years (range, 32-85 years). A neoplasm was not suspected preoperatively in 12 of the 17 (71%) men whose clinical presentation was known, 7 of whom presented with hydrocele and 5 with inguinal hernia. The other 5 had a clinically recognized mass. Seven of the men underwent herniorrhaphy; 7, radical orchiectomy; 3, hydrocelectomy; and 3, paratesticular mass biopsy or excision as the initial diagnostic procedure. Twelve of the MM cases were epithelioid and 6 were biphasic. Among the 6 men with MM who had ≥6 months of follow-up, 1 was alive with no evidence of disease at 6 months, and 5 were known to have died of disease 8-74 months (median = 31.5 months) following diagnosis. Three men with MM had received either chemotherapy or radiation therapy. Of the 2 men initially diagnosed with well-differentiated papillary mesothelioma, 1 was alive without evidence of disease 5 years after diagnosis, while the other had findings more compatible with MM with peritoneal involvement 2 years following initial diagnosis. In 15 of the 18 cases of MM (83%), there was documented occupational or paraoccupational exposure to asbestos, the average duration of which was 33 years (range, 2-46 years). Information regarding the presence or absence of pleural plaques was available in 5 of the MM cases, and pleural plaques had been found in 4. Lung tissue was not available for fiber analysis in any of the cases. One additional case originally diagnosed at another institution as MM of the TVT was reclassified as adenocarcinoma following performance of additional immunohistochemical testing. TVT is a rare site of MM, the diagnosis of which is often unsuspected preoperatively. Like its counterparts at other serosal sites, MM of the TVT is an aggressive tumor with a poor prognosis that evidence would suggest is etiologically associated with asbestos in at least some cases.

RevDate: 2019-12-05

Sorahan TM (2019)

Cancer incidence in UK electricity generation and transmission workers, 1973-2015.

Occupational medicine (Oxford, England), 69(5):342-351.

BACKGROUND: Long-term health outcomes in cohorts of workers from the electricity supply industry have been studied.

AIMS: The aim of the study was to examine updated cancer incidence findings among a cohort of UK electricity generation and transmission workers.

METHODS: Cancer morbidity experienced by 81 616 employees of the former Central Electricity Generating Board of England and Wales was investigated for the period 1973-2015. All employees had worked for at least 6 months with some employment between 1973 and 1982. Standardized registration ratios (SRRs) were calculated based on national rates.

RESULTS: Overall cancer morbidity was slightly below expectation in males. Significant excesses were found in male workers for mesothelioma (observed [Obs] 763, SRR 326), skin cancer (non-melanoma) (Obs 5616, SRR 106), and prostate cancer (Obs 4298, SRR 106), and in female workers for cancer of the small intestine (Obs 13, SRR 220), nasal cancer (Obs 11, SRR 407), and breast cancer (Obs 758, SRR 110). More detailed analyses showed important contrasts, particularly for mesothelioma, lung cancer, skin cancer, prostate cancer and breast cancer.

CONCLUSIONS: A clear occupational excess of mesothelioma was not matched by a corresponding excess of asbestos-induced lung cancer. Confident interpretation of the excesses of cancers of the nasal cavities and small intestine is not possible, although occupational exposures received in this industry may well not be involved. An excess of skin cancer in transmission workers may be associated with outdoor working.

RevDate: 2019-08-03

Churg A, Galateau-Salle F, Roden AC, et al (2019)

Malignant mesothelioma in situ: morphologic features and clinical outcome.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc pii:10.1038/s41379-019-0347-0 [Epub ahead of print].

The existence of an in situ phase of malignant mesothelioma has long been postulated but until recently has been impossible to prove. Here we describe ten patients with mesothelioma in situ, defined by a single layer of surface mesothelial cells showing loss of BAP1 nuclear immunostaining, no evidence of tumor by imaging and/or by direct examination of the pleura/peritoneum, and no invasive mesothelioma developing for at least 1 year. Nine cases were pleural and one peritoneal. Most patients were biopsied for repeated effusions of unknown etiology; in two patients mesothelioma in situ was found incidentally in lung cancer resections. In addition to surface mesothelium with BAP1 loss, one case had a surface papillary proliferation with BAP1 loss, and two cases had a small (few millimeter) nodule with BAP1 loss. CDKN2A was deleted by FISH in one of eight cases. Methylthioadenosine phosphorylase showed partial loss in the surface mesothelium by immunohistochemistry in three cases. Invasive malignant mesothelioma developed in seven patients with time between biopsy and invasive disease from 12 to 92 (median 60) months. Invasive mesothelioma has not developed in the other three patients at 12, 57, and 120 months, but the latter patient, who has pleural plaques, still has repeated pleural effusions, probably representing a so-called "benign asbestos effusion." We conclude that mesothelioma in situ, as diagnosed using the criteria outlined above, is associated with a high risk of developing invasive mesothelioma, but typically over a relatively protracted time, so that curable interventions maybe possible.

RevDate: 2019-08-02

Itano H, Takeda T, Yamada T, et al (2019)

Heterologous sarcomatoid pleural mesothelioma with osteosarcomatous differentiation: a report of autopsy case that accomplished trimodality therapy and review of the literature.

General thoracic and cardiovascular surgery pii:10.1007/s11748-019-01182-8 [Epub ahead of print].

Heterologous mesothelioma is a very rare subtype of sarcomatoid mesothelioma characterized by the presence of malignant heterologous elements. A 69-year-old man with a strong history of asbestos exposure presented with a 5-cm mass in his chest wall, destroying the right 5th rib and spreading along the parietal pleura, on a CT. Biopsy revealed heterologous mesothelioma with osteosarcomatous elements, following which left extrapleural pneumonectomy was performed with combined resection of pericardium, hemidiaphragm, and 4th, 5th, and 6th costal segments. A small cytokeratin-positive epithelioid component in the resected tumor definitively confirmed the diagnosis. Post-operative chemotherapy and intensity-modulated radiotherapy were undertaken. After 12-month disease-free period post treatment, rapid intraperitoneal recurrence resulted in death. Autopsy revealed no tumors in the left thorax. We present here a case of heterologous osteosarcomatous pleural mesothelioma that followed a unique clinical course after trimodality therapy. In addition, literature of 54 cases of the similar heterologous mesothelioma was reviewed.

RevDate: 2019-09-11

Gogou E, Hatzoglou C, Zarogiannis SG, et al (2019)

Mesothelioma Mortality Rates in Greece for the Period 2005-2015 Is Increased Compared to Previous Decades.

Medicina (Kaunas, Lithuania), 55(8): pii:medicina55080419.

Background and Objective: To present summary statistics regarding malignant mesothelioma (MM) mortality in Greece during the period 2005-2015 and compare it with previous decades, along with gender, age and geographical area analysis. Materials and Methods: The Hellenic Statistical Authority provided the data, which included all deaths for the period 1983 to 2015 that mentioned MM as the death cause in the corresponding death certificate. MM mortality rates have been calculated with respect to gender, age, and geographical location in Greece. Furthermore, a comparison analysis was made among three eleven consecutive year periods, in order to assess potential changes in the mortality rates. Results: The MM mortality rate has significantly increased during the period 2005-2015 both in males and females compared to earlier decades. The maximum number of MM deaths has shifted to an older age group of 70-80 years during the 2005-2015 period as compared to that of 1983-2004 in both genders. Additionally, MM mortality rates have significantly increased in all geographical areas except for the Epirus Prefecture. Conclusions: Our results demonstrate an increased MM mortality rate in Greece for the decade 2005-2015 as compared to the two previous decades. This increase is possibly due to the fact that the peak in asbestos production and use in Greece was in mid 1990s, while the asbestos ban came in effect in 2005. Based on these findings the MM epidemic in Greece has not yet peaked, therefore it is important to implement screening strategies for early MM detection.

RevDate: 2019-08-02

Borrelli E, Babcock Z, S Kogut (2019)

Costs of medical care for mesothelioma.

Rare tumors, 11:2036361319863498 pii:10.1177_2036361319863498.

Malignant mesothelioma is a rare and devastating form of cancer with an increasing economic burden. We sought to describe the direct cost burden of mesothelioma to the US health system. A systematic literature review was performed to locate published estimates of the medical cost of mesothelioma. In addition, we performed an analysis of hospital discharge data from the National Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. We also reviewed publicly available legal settlements. We found that published estimates of the cost of medical care for mesothelioma are sparse, and differ with respect to nation, timeframe, and types of cost included. For the year 2014 in the United States, we estimated a mean cost per mesothelioma hospitalization of US$24,124 (95% confidence interval: US$20,819-US$28,983) and a total cost for hospital care of US$44,214,835. In conclusion, we found that reports describing the direct medical cost of care for mesothelioma in the United States are lacking, yet the per-patient cost of care is substantial, as evidenced by analyses of inpatient care and legal settlements.

RevDate: 2019-10-15

Lee MJ, Kuehne N, Hueniken K, et al (2019)

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.

Molecular carcinogenesis, 58(11):1960-1973.

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.

RevDate: 2019-08-02

Di Somma S, Iannuzzi CA, Passaro C, et al (2019)

The Oncolytic Virus dl922-947 Triggers Immunogenic Cell Death in Mesothelioma and Reduces Xenograft Growth.

Frontiers in oncology, 9:564.

Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure that urgently requires effective therapeutic strategies. Current treatments are unable to increase significantly patient survival, which is often limited to <1 year from diagnosis. Virotherapy, based on the use of oncolytic viruses that exert anti-cancer effects by direct cell lysis and through the induction of anti-tumor immune response, represents an alternative therapeutic option for rare tumors with limited life expectancy. In this study, we propose the use of the adenovirus dl922-947, engineered to allow selective replication in cancer cells, to counteract MPM. Methods: We performed a thorough preclinical assessment of dl922-947 effects in a set of MPM cell lines and xenografts. Cytotoxicity of dl922-947 alone and in combination assays was evaluated by sulforhodamine B assay. Cell cycle, calreticulin expression, and high mobility group box protein 1 (HMGB1) secretion were determined by flow cytometry, whereas ATP content was determined by a luminescence-based bioassay. The modulation of angiogenic factors in MPM-infected cells was evaluated through ELISA. Results: We found that dl922-947 infection exhibits cytotoxic effects in MPM cell lines, affecting cell viability, cell cycle progression, and regulating main hallmarks of immunogenic cell death inducing calreticulin surface exposure, HMGB1 and ATP release. Our results also suggest that dl922-947 may affect angiogenic signals by regulation of VEGF-A and IL-8 secretion. Furthermore, dl922-947 shows anti-tumor efficacy in murine xenograft models reducing tumor growth and enhancing survival. Finally, the combination with cisplatin potentiated the cytotoxic effect of dl922-947. Conclusions: Overall our data identify virotherapy, based on the use of dl922-947, as a new possible therapeutic strategy against MPM, which could be used alone, in combination with standard chemotherapy drugs, as shown here, or other approaches also aimed at enhancing the antitumoral immune response elicited by the virus.

RevDate: 2019-09-18

Krówczyńska M, E Wilk (2019)

Environmental and Occupational Exposure to Asbestos as a Result of Consumption and Use in Poland.

International journal of environmental research and public health, 16(14): pii:ijerph16142611.

Asbestos is harmful to human health; exposure to asbestos causes a wide range of asbestos-related diseases.

AIM: Malignant mesothelioma (MM) is unique to occupational and environmental asbestos exposure.

METHODS: Environmental asbestos exposure was examined in relation to asbestos use and manufacturing, the quantity of the asbestos-containing products still in use, the concentrations of asbestos fibres in the air and the number of MM cases diagnosed each year per county.

RESULTS: The correlation coefficient of the measurements of the asbestos fibre concentrations in the air and the quantity of asbestos-cement products in use is high and amounts to 0.68. Meanwhile, the correlation coefficient of the measurements of asbestos fibre concentrations in air and MM morbidity rate resulting from environmental exposure calculated for particular counties in provinces is low and amounts to 0.37. The highest MM morbidity rate was observed for Małopolskie and Śląskie, a typical industrial area of Poland.

CONCLUSIONS: There are MM cases which are still attributable to occupational asbestos exposure, although MM cases resulting from environmental exposure to asbestos have an increased MM risk. Poland is among those countries with a low MM incidence rate, which seems to be an underestimation of environmental asbestos exposure. As long as asbestos-cement products are used in the environment, actions should be undertaken to protect public health.

RevDate: 2019-10-31

Korchevskiy A, Rasmuson JO, EJ Rasmuson (2019)

Empirical model of mesothelioma potency factors for different mineral fibers based on their chemical composition and dimensionality.

Inhalation toxicology, 31(5):180-191.

Context: The potency of various mineral fiber types to produce mesothelioma was previously evaluated for numerous cohorts, but the differences in potencies for distinct fiber types have yet to be explained. Objective: To develop an empirical model that would reconstruct mesothelioma potency factors for various types of fiber based on their chemical composition and dimensionality. Methods: Typical chemical composition and dimensionality metrics (aspect ratios) were obtained and combined with mesothelioma potency factors estimated by Hodgson and Darnton method for Quebec chrysotile, South Africa amosite, South Africa and Australian crocidolite, Russian anthophyllite, Libby amphiboles, and Turkey erionite. The forward stepwise log-log regression method was utilized to determine the best combination of input parameters. Results: Mesothelioma potency factors (RM) for selected cohorts were effectively reconstructed utilizing the median aspect ratio of fibers and equivalent fractions of SiO2, total Fe oxides or total equivalent Fe3+ as Fe2O3, and MgO. Modeled potency factors increase as the aspect ratio, SiO2, and total Fe oxide (or Fe2O3) content grow, and as the MgO content diminishes. Correlation coefficients up to 0.999, p < 0.01, were achieved. The models also yield reasonable estimates of mesothelioma potencies for other fiber types, including Bolivian crocidolite, Russian chrysotile, fluoro-edenite, and others. Conclusion: In spite of the empirical approach, the proposed models provide a starting point for targeted studies of mesothelioma mechanisms by elucidating significant contributing physicochemical factors. The models have an exploratory and preliminary character but can potentially be useful to introduce quantitative structure-activity relationship approaches for the toxicology of fibrous minerals.

RevDate: 2019-07-17

Henley SJ, Peipins LA, Rim SH, et al (2019)

Geographic Co-Occurrence of Mesothelioma and Ovarian Cancer Incidence.

Journal of women's health (2002) [Epub ahead of print].

Background: Asbestos is an established cause of several cancers, including mesothelioma and ovarian cancer. Incidence of mesothelioma, the sentinel asbestos-associated cancer, varies by state, likely reflecting different levels of asbestos exposure. We hypothesized that states with high mesothelioma incidence may also have high ovarian cancer incidence. Materials and Methods: Using data from the Centers for Disease Control and Prevention National Program for Cancer Registries and the National Cancer Institute Surveillance, Epidemiology, and End Results Program, we examined the geographic co-occurrence of mesothelioma and ovarian cancer incidence rates by U.S. state for 2003-2015. Results: By state, mesothelioma incidence ranged from 0.5 to 1.3 cases per 100,000 persons and ovarian cancer incidence ranged from 9 to 12 cases per 100,000 females. When states were grouped by quartile of mesothelioma incidence, the average ovarian cancer incidence rate was 10% higher in states with the highest mesothelioma incidence than in states with the lowest mesothelioma incidence. Ovarian cancer incidence tended to be higher in states with high mesothelioma incidence (Pearson correlation r = 0.54; p < 0.0001). Conclusions: Data from state cancer registries show ovarian cancer incidence was positively correlated with mesothelioma incidence, suggesting asbestos may be a common exposure. The potential for asbestos exposure has declined since the 1970s because fewer products contain asbestos; however, some products, materials, and buildings may still release asbestos and thousands of workers may be exposed. Ensuring that people are protected from exposure to asbestos in their workplaces, homes, schools, and communities may reduce the risk of several cancers.

RevDate: 2019-07-19

Zona A, Iavarone I, Buzzoni C, et al (2019)

[SENTIERI: Epidemiological Study of Residents in National Priority Contaminated Sites. Fifth Report].

Epidemiologia e prevenzione, 43(2-3 Suppl 1):1-208.

INTRODUCTION AND OBJECTIVES: This volume provides an update of the health status of the populations living in the National Priority Contaminated Sites (NPCSs) included in the SENTIERI Project. This update is part of an epidemiological surveillance programme carried out in NPCSs, promoted by the Italian Ministry of Health as a further step of a project started in 2006, when the health status of residents in contaminated sites was first addressed within the National Strategic Program "Environment and Health". The Report focuses on five health outcomes: mortality, cancer incidence, hospital discharges, congenital anomalies, and children, adolescents and young adults' health. A key element of SENTIERI project is the a priori evaluation of the epidemiological evidence of a causal association between the considered cause of disease and the exposure. When an a priori evidence is identified, it is given a greater importance in the comment of the study findings.

METHODS: The present update of the SENTIERI Project concerns 45 NPCSs including in all 319 Italian Municipalities (out of over 8,000 Municipalities), with an overall population of 5,900,000 inhabitants at the 2011 Italian Census. Standardized Mortality Ratios (SMRs) and Standardized Hospitalization Ratios (SHRs), referring to a time window of 2006-2013, were computed for all the 45 NPCSs, using as a reference the corresponding mortality and hospitalization rates of the Regions where each NCPS is located. Standardized Incidence Ratios (SIRs) were computed by the Italian Association of Cancer Registries (AIRTUM) for the 22 NPCSs served by a Cancer Registry. AIRTUM covers about 56% of Italy, with partly different time-windows. SIRs have been estimated using as reference population the 4 macroareas in which Italy is divided (North-West, North-East, Centre, South). Prevalence of congenital anomalies was computed for 15 NPCSs.

RESULTS: An all-cause excess of 5,267 and 6,725 deaths was observed, respectively, in men and women; the cancer death excess was of 3,375 in men and 1,910 in women. It was estimated an excess of cancer incidence of 1,220 case in men and 1,425 in women over a five-year time window. With regard to the diseases with an a priori environmental aetiological validity, an excess for malignant mesothelioma, lung, colon, and gastric cancer, and for non-malignant respiratory diseases was observed. Cancer excess mainly affected NPCSs with presence of chemical and petrochemical plants, oil refineries, and dumping hazardous wastes. An excess of non-malignant respiratory disease was also detected in NPCSs in which steel industries and thermoelectric plants were present. An excess of mesothelioma was observed in NPCSs characterized by presence of asbestos and fluoro-edenite; it was also observed where the presence of asbestos was not reported in the legislative national decrees which define the NPCS areas. It is worth noting that, even if the presence of asbestos is not reported in many NPCSs legislative decrees, petrochemical plants and steel industries, for instance, are often characterized by the presence of a large amount of this mineral that, in the past, was extensively used as an insulating material. For the first time, the present Report includes a focus on the health status of children and adolescents (1,160,000 subjects, aged 0-19 years), and young adults (660,000 subjects, aged 20-29 years). Among infants (0-1 year), an excess of 7,000 hospitalizations was observed, 2,000 of which due to conditions of perinatal origin. In the age class 0-14, an excess of 22,000 hospitalizations for all causes was observed; 4,000 of them were due to acute respiratory diseases, and 2,000 to asthma. Data on cancer incidence for subjects aged 0-24 years were derived from general population cancer registries for twenty NPCSs, and from children cancer registries (age group: 0-19 years) for six NPCSs; 666 cases where diagnosed in the age group 0-24 years, corresponding to an excess of 9%. The main contributions to this excess are from soft tissue sarcomas in children (aged 0-14 years), acute myeloid leukaemia in children (aged 0-14 years) and in the age group 0-29 years, non-Hodgkin lymphoma and testicular cancer in young adults (aged 20-29 years). In seven out of 15 NPCSs, an excess prevalence rate of overall congenital anomalies at birth was observed. Congenital anomalies excesses included the following sites: genital organs, heart, limbs, nervous system, digestive system, and urinary system.

CONCLUSIONS: The main findings of SENTIERI Project have been the detection of excesses for the diseases which showed an a priori epidemiological evidence of a causal association with the environmental exposures specific for each considered NPCS. These observations are valuable within public health, because they contribute to priority health promotion activities. Looking ahead, the health benefits of an improved environmental quality might be appreciated in terms of reduction of the occurrence of adverse health effects attributable to each Site major pollutant agents. Due to the methodological approach of the present study, it was not possible to adjust for several confounding factors reported to be risk factors for the studied diseases (e.g., smoking, alcohol consumption, obesity). Even if excesses of mortality, hospitalization, cancer incidence, and prevalence of congenital anomalies were found in several NPCSs, the study design and the multifactorial aetiology of the considered diseases do not permit, for all of them, to draw conclusions in terms of causal links with environmental contamination. Moreover, it must be taken into consideration that economic factors and the availability of health services may also play a relevant role in a diseases outcome. A few observations regarding some methodological limitations of SENTIERI Project should be made. There is not a uniform environmental characterisation of the studied NPCSs in term of quality and detection of the pollutants, because this information is present in different databases which at present are not adequately connected. Moreover, the recognition of a contaminated site as a National Priority Site is based on soil and groundwater pollution, and the available information on air quality is currently sparse and not homogenous. Another limitation, in term of statistical power, is the small population size of many NPCSs and the low frequency of several health outcomes. A special caution must be paid in data interpretation when considering the correspondence between the contaminated areas and the municipality boundaries, as they do not always coincide perfectly: in some cases, a small municipality with a large industrial site, while in other settings only a part of the municipality is exposed to the sources of pollution. Furthermore, all available health information systems are currently accessible at municipality level. The real breakthrough is essentially comprised of the development and fostering of a networking system involving all local health authorities and regional environmental protection agencies operating in the areas under study. The possibility to integrate the geographic approach of SENTIERI Project with a set of ad hoc analytic epidemiological investigations, such as residential cohort studies, case control studies, children health surveys, biomonitoring surveys, and with socioepidemiological studies, might greatly contribute to the identification of health priorities for environmental remediation activities. Finally, as discussed in the last section of the report, there is a need to adopt, in each NPCS, a two-way oriented communication plan involving public health authorities, scientific community, and resident population, taking into account that the history, the cultural frame and the network of relationships specific of each local context play a major role in the risk perception perspective.

RevDate: 2019-07-22

Mumma MT, Sirko JL, Boice JD, et al (2019)

Mesothelioma mortality within two radiation monitored occupational cohorts.

International journal of radiation biology [Epub ahead of print].

Purpose: The risk of mesothelioma, including cancers of the pleura and peritoneum, was examined within two large cohorts of workers monitored for exposure to ionizing radiation. Methods and materials: Mortality was assessed among 253,632 workers routinely monitored for external radiation, including 30,724 industrial radiographers (IR) at shipyards, 142,583 workers at nuclear power plants (NPP), and 83,441 IR who had not worked at an NPP or shipyard. Follow-up was from 1969 through 2011. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were computed; observed numbers of deaths from mesothelioma (including cancers of the pleura and peritoneum) and asbestosis were compared with numbers expected based on age-, sex-, and calendar year-specific national mortality rates. Job history and quantitative asbestos exposure data were unavailable, but work at a shipyard was taken as a surrogate for the likelihood of exposure. Cox proportional hazards models were used to estimate hazard ratios (HRs) for mesothelioma in relation to estimated cumulative radiation exposure to the lung. Results: The mean duration of follow-up was 25.3 years (max 42 years). The mean cumulative lung dose was 28.6 mGy (7.3% > 250 mGy). Nearly 20% of the workers had died by 2011. A total of 421 mesothelioma deaths were found (75% occurring after 1999) with increased SMRs among workers monitored in shipyards (SMR 9.97; 95% CI 8.50-11.63) and for NPP workers (SMR 5.55; 95% CI 4.88-6.29), but not for IR who had not worked in shipyards (SMR 1.15; 95% CI 0.53-2.19). Likewise, deaths from asbestosis (n = 189) were also increased for shipyard and NPP workers (SMR = 18.1 and 9.2, respectively), but not among workers who never worked at a shipyard or NPP (SMR = 0.70; n = 1). Radiation dose to the lung was not associated with a statistically meaningful dose-response trend for mesothelioma in the combined cohorts (HR at 100 mGy = 1.10; 95% CI 0.96-1.27; p = .18), nor was mesothelioma risk associated with radiation exposure among IR who had not worked in a shipyard and assumed minimally exposed to asbestos. Conclusions: An elevated rate of death from mesothelioma was observed in two radiation-exposed occupational groups with potential for asbestos exposure. The increased risk of death from asbestosis, combined with little evidence of a rising trend in mesothelioma mortality with increasing radiation exposure, suggests that the mesothelioma (and asbestosis) excess in these workers was due to asbestos exposure in shipyards and power plants and not to occupational low-dose radiation.

RevDate: 2019-07-12

Williams M, Cheng YY, Kirschner MB, et al (2019)

Transcriptional suppression of the miR-15/16 family by c-Myc in malignant pleural mesothelioma.

Oncotarget, 10(41):4125-4138 pii:27010.

MicroRNA downregulation is frequent in malignant pleural mesothelioma (MPM), but the mechanisms responsible for loss of miR-15/16 and miR-193a are yet to be elucidated and were investigated in this study. Copy Number Variation (CNV) of microRNA-coding genes was analyzed in MPM cells by digital droplet PCR (ddPCR) and revealed heterozygous loss of miR-193a and miR-15a/16-1, but no change in miR-15b/16-2. Epigenetic control of microRNA expression was inferred following decitabine and Trichostatin A (TSA) treatment which did not substantially affect microRNA expression. Knockdown of c-Myc expression led to upregulation of SMC4, miR-15b and 16, and to a lesser extent DLEU2 and miR-15a, whereas c-Myc overexpression repressed microRNA expression. Chromatin immunoprecipitation (ChIP) assays confirmed the interaction of c-Myc with the DLEU2 and SMC4 promoters. Tumor microRNA expression was determined in samples from MPM patients, with samples of pleura from cardiac surgery patients used as controls. In tumor samples, a strong correlation was observed between the expression of miR-15b and 16 (R2=0.793), but not miR-15a and 16. Our data suggest that in MPM, the downregulation of miR-15/16 is due to transcriptional repression by c-Myc, primarily via control of the miR-15b/16-2 locus, while miR-193a-3p loss is due to genomic deletion.

RevDate: 2019-07-10

Taylor L, Cooper D, A Aujayeb (2019)

Malignant deciduoid mesothelioma: a rare variant of epithelioid mesothelioma.

BMJ case reports, 12(7): pii:12/7/e229945.

We describe a case of a deciduoid mesothelioma, a rare variant of epithelioid mesothelioma, which is associated with a very poor prognosis. A review of the relevant literature is also included. The patient was a man with probable asbestos exposure and presented with classic features of pleural malignancy. Diagnosis was reached with close correlation between clinical, radiological and pathological findings.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

Electronic Scholarly Publishing
961 Red Tail Lane
Bellingham, WA 98226

E-mail: RJR8222 @

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )