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Bibliography on: Mesothelioma and Asbestos

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ESP: PubMed Auto Bibliography 13 Nov 2018 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: 2018-11-12

Røe OD (2018)

[Asbestos and mesothelioma in Denmark 2017: status of a man-made cancer epidemic].

Ugeskrift for laeger, 180(46):.

Asbestos-induced cancer is an increasing problem in Denmark, and 32 years after the closure of the Danish Eternit Factory in Aalborg there are > 140 new mesothelioma cases diagnosed yearly, numbers rapidly increasing. Asbestos-induced lung cancer may be six times this number. The non-occupational exposure and even neighborhood exposure as a risk factor suggests, that compensation for mesothelioma should be universal. At the Aalborg University Hospital a multidisciplinary research team has been formed to do epidemiological, translational and clinical studies through national and international collaborations. Transformative research on asbestos cancer should be stimulated.

RevDate: 2018-11-09

Berzenji L, P Van Schil (2018)

Multimodality treatment of malignant pleural mesothelioma.

F1000Research, 7:.

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

RevDate: 2018-11-08

Guarrera S, Viberti C, Cugliari G, et al (2018)

Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(18)33412-9 [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive tumour strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for non-invasive early diagnosis tests to monitor asbestos-exposed people.

METHODS: We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82/68 Training Set; replication in 81/69, Test Set) sampled from the same areas.

RESULTS: Evidence of differential methylation between MPM cases and controls was found (>800 CpG sites, Pfdr<0.05), mainly in immune system related genes. Considering the "top" differentially methylated signals, 7 single-CpGs and 5 genomic regions of coordinated methylation replicated with similar effect size in the Test Set (pfdr<0.05). The top hypomethylated single-CpG (cases vs controls effect size<-0.15, pfdr <0.05 in both Training and Test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the Test set, comparison of receiver operating characteristic (ROC) curves and the area under the curve (AUC) of two models, including/excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC=0.81 vs AUC=0.89, DeLong's test p=0.0013).

CONCLUSIONS: We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to MPM carcinogenic process.

RevDate: 2018-11-07

Matsushita A, Sato T, Mukai S, et al (2018)

TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation.

Oncogene pii:10.1038/s41388-018-0417-7 [Epub ahead of print].

Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40-50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified. Here, we show that TAZ is expressed and underphosphorylated (activated) in the majority of MM cells compared to immortalized mesothelial cells. ShRNA-mediated TAZ knockdown highly suppressed cell proliferation, anchorage-independent growth, cell motility, and invasion in MM cells harboring activated TAZ. Conversely, transduction of an activated form of TAZ in immortalized mesothelial cells enhanced these in vitro phenotypes and conferred tumorigenicity in vivo. Microarray analysis determined that activated TAZ most significantly enhanced the transcription of genes related to "cytokine-cytokine receptor interaction." Among selected cytokines, we found that IL-1 signaling activation plays a major role in proliferation in TAZ-activated MM cells. Both IL1B knockdown and an IL-1 receptor antagonist significantly suppressed malignant phenotypes of immortalized mesothelial cells and MM cells with activated TAZ. Overall, these results indicate an oncogenic role for TAZ in MMs via transcriptional induction of distinct pro-oncogenic genes including cytokines. Among these, IL-1 signaling appears as one of the most important cascades, thus potentially serving as a target pathway in MM cells harboring Hippo pathway inactivation.

RevDate: 2018-11-01

Langer AM, RP Nolan (2018)

The role of fiber type and cumulative exposure in controlling mesothelioma risk.

Toxicology and applied pharmacology pii:S0041-008X(18)30484-8 [Epub ahead of print].

The acceptance of primary tumors arising on the serosal surface of body cavities and its association with asbestos exposure was established in 1960. Epidemiological studies followed in an effort to determine if all asbestos fiber types produced the same malignancy and with the same mortality incidence. Three asbestos mortality studies were published in 1979 authored by the same research team from the Mount Sinai School of Medicine. The studies followed the same design making their datasets internally consistent and uniquely comparable. Insulation workers who were exposed to three commercial fiber types (amosite, chrysotile, crocidolite), factory workers who manufactured amosite-containing insulation for U.S. warships, and chrysotile miners and millers from Thetford Mines, Quebec, comprised the three cohorts. Lifetime cumulative exposures for these three cohorts (expressed in fiber/mL-years) were available from different source materials. Mortality data were obtained on these workforces and ascertainment of their cause(s) of death was based on medical-pathology evidence rather than information available on death certificates. Depending on the exposure estimates for the three cohorts the calculated mesothelioma risk for mid range mixed fiber exposure (insulators) is about 269 times (range 157 to 490) that of chrysotile exposure alone and for amosite at mid range exposure about 139 times (range 30 to 213) that of chrysotile exposure alone. Risk comparisons are the result of range in cumulative exposure estimates. Based on the available data from three Mt. Sinai studies, these differences in mesothelioma risk regarding fiber type were apparently knowable to the asbestos community as early as 1979. The amphibole asbestos exposures carry far greater mesothelioma risk than chrysotile exposure alone. Mixed fiber exposure (chrysotile and amphibole asbestos) is associated with the highest mesothelioma mortality among the workforces studied.

RevDate: 2018-10-30

Pastorino S, Yoshikawa Y, Pass HI, et al (2018)

A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.

PATIENTS AND METHODS: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing.

RESULTS: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study (P < .0001).

CONCLUSION: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

RevDate: 2018-10-30

Laaksonen S, Ilonen I, Kuosma E, et al (2018)

Malignant pleural mesothelioma in Finland: regional and gender variation.

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

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare occupational cancer with a poor prognosis. Even with a multimodality treatment approach, the treatment outcomes remain unsatisfactory. The use of asbestos has been banned in most developed countries, but MPM continues to be a significant occupational disease also in these countries. Aim of this study is to identify modern epidemiology and assess equality in care.

METHODS: Our study cohort consists of 1010 patients diagnosed with MPM in Finland during 2000-2012. The data were collected from the Finnish Cancer Registry, the National Workers' Compensation Center Registry and the National Registry of Causes of Death, Statistics Finland.

RESULTS: Women were diagnosed a mean of 4.5 years later than males (p = .001), but survival did not differ (overall median survival 9.7 months). A workers' compensation claim was more common in males (OR 11.0 [95% CI 7.5-16.2]) and in regions with a major asbestos industry (OR 1.7 [95% CI 1.3-2.2]). One-year and three-year survivals did not differ regionally. Patients without chemotherapy treatment had an inferior survival (RR 1.8 [95% CI 1.5-2.0]). The initial survival benefit gained with pemetrexed was diluted at 51 months.

CONCLUSIONS: MPM is a disease with a poor prognosis, although chemotherapy appears to improve survival time. Significant gender and regional variation exists among patients, with notable differences in diagnostic and treatment practices. Long-term outcomes with pemetrexed remain indeterminate.

IMPACT: Emphasize centralized consult services for the diagnosis, treatment and support that patients receive for MPM, facilitating equal outcomes and compensation.

RevDate: 2018-10-29

Plato N, Martinsen JI, Kjaerheim K, et al (2018)

Mesothelioma in Sweden: Dose-Response Analysis for Exposure to 29 Potential Occupational Carcinogenic Agents.

Safety and health at work, 9(3):290-295.

Background: There is little information on the dose-response relationship between exposure to occupational carcinogenic agents and mesothelioma. This study aimed to investigate this association as well as the existence of agents other than asbestos that might cause mesothelioma.

Methods: The Swedish component of the Nordic Occupational Cancer (NOCCA) study consists of 6.78 million individuals with detailed information on occupation. Mesothelioma diagnoses recorded in 1961-2009 were identified through linkage to the Swedish Cancer Registry. We determined cumulative exposure, time of first exposure, and maximum exposure intensity by linking data on occupation to the Swedish NOCCA job-exposure matrix, which includes 29 carcinogenic agents and corresponding exposure for 283 occupations. To assess the risk of mesothelioma, we used conditional logistic regression models to estimate hazard ratios and 95% confidence intervals.

Results: 2,757 mesothelioma cases were identified in males, including 1,416 who were exposed to asbestos. Univariate analyses showed not only a significant excess risk for maximum exposure intensity, with a hazard ratio of 4.81 at exposure levels 1.25-2.0 fb/ml but also a clear dose-response effect for cumulative exposure with a 30-, 40-, and 50-year latency time. No convincing excess risk was revealed for any of the other carcinogenic agents included in the Swedish NOCCA job-exposure matrix.

Conclusion: When considering asbestos exposure, past exposure, even for short periods, might be enough to cause mesothelioma of the pleura later in life.

RevDate: 2018-10-28

Tsao AS, Lindwasser OW, Adjei AA, et al (2018)

Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 13(11):1655-1667.

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.

RevDate: 2018-10-26

Harris EJ, Kao S, McCaughan B, et al (2018)

Prediction modelling using routine clinical parameters to stratify survival in Malignant Pleural Mesothelioma patients undergoing cytoreductive surgery.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(18)33186-1 [Epub ahead of print].

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an uncommon cancer with a poor prognosis and heterogeneous survival. Surgery for MPM is offered in some specialist centres to highly selected patients. A previously described classification and regression tree (CART) model stratified survival in unselected MPM patients using routinely collected clinical data. This study aimed to examine the performance of this CART model on a highly selected surgical population.

METHODS: Data were collected from subjects undergoing cytoreductive surgery for MPM from specialist centres in Hyõgo, Japan and Sydney, Australia between 1991 and 2016. The CART model was applied using the combination of clinical variables to stratify subjects into risk groups (1-4); survival characteristics were then compared.

RESULTS: 289 cases were included (205 from Australia, 84 from Japan). Overall median survival was 34.6 (IQR 17.5-56.1) months; median age 63.0 (IQR 57.0-67.8) years, 240/289 (83.0%) were male. There were no clinically meaningful differences between the two cohorts. Survival across the four risk groups was significantly different (p<0.0001); the model stratified survival well with a Harrell's c-statistic of 0.62 (96% CI 0.57-0.66) at 36 months. The group with the longest survival (median 82.5 months) had: no weight loss, Hb >153g/L and serum albumin >43g/L at time of referral to the surgical centre.

CONCLUSION: Using routinely available clinical variables the CART model was able to stratify surgical patients into risk groups with statistically different survival characteristics with fair to good performance. Presence of weight loss, anaemia and low albumin should confer caution when considering surgical therapy for MPM.

RevDate: 2018-10-26

Trenti E, Palermo SM, D'Elia C, et al (2018)

Malignant mesothelioma of tunica vaginalis testis: Report of a very rare case with review of the literature.

Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica, 90(3):212-214.

INTRODUCTION: Mesothelioma of the tunica vaginalis testis is a extremely rare tumor and represents 0.3 to 0.5% of all malignant mesotheliomas. Exposure to asbestos often precedes illness. Because of its low incidence and nonspecific clinical presentation, it is mostly diagnosed accidentally during surgery for other reasons and the prognosis is usually poor. We present a case of a patient with a mesothelioma of tunica vaginalis testis, diagnosed secondarily during hydrocele surgery, with long-term survival after radical surgery.

MATERIALS AND METHODS: a 40 years old patient was admitted to our department for routine surgery of a left hydrocele. During the operation a frozen section analysis was requested because of the unusual nodular thickening of the tunica vaginalis: the examination revealed a diffuse malignant mesothelioma with epithelioid structure and tubular-papillary proliferation. Therefore a left hemi-scrotectomy with left inguinal lymph node dissection was performed.

RESULTS: The definitive histology confirmed the previous report of diffuse malignant mesothelioma with angio-invasion but normal testicle findings and negative lymph nodes. No metastases were found on the CT-scan. For the first 2 years a CT was repeated every 4 months, for other 3 years every 6 months and then yearly. Six years after surgery the patient is classified as no evidence of disease.

CONCLUSIONS: malignant mesothelioma of the tunica vaginalis testis is a rare entity, often initially thought to be a hydrocele or an epididymal cyst. An aggressive approach with hemiscrotectomy with or without inguinal and retroperitoneal lymphadenectomy can reduce the risk of recurrence.

RevDate: 2018-10-26

Matboli M, Shafei AE, Ali MA, et al (2018)

Clinical significance of serum DRAM1 mRNA, ARSA mRNA, hsa-miR-2053 and lncRNA-RP1-86D1.3 axis expression in malignant pleural mesothelioma.

Journal of cellular biochemistry [Epub ahead of print].

AIM AND BACKGROUND: Malignant pleural mesothelioma (MPM) is a lethal cancer mainly caused by chronic exposure of asbestos. In this pilot study, we aimed to assess the expression of serum RNA-based biomarker panel exploring their clinical utility as diagnostic and prognostic biomarkers for MPM.

METHODS: We have selected an MPM-specific RNA-based biomarker panel through bioinformatics analysis based on the integration of DNA damage regulated autophagy modulator 1 (DRAM1) and arylsulfatase A (ARSA) gene expression with their epigenetic regulators microRNA (miR-2053) and long noncoding RNA (lncRNA-RP1-86D1.3). Then, quantitative real-time polymerase chain reaction (qPCR) validation in sera of 60 MPM patients, 20 chronic asbestos exposure patients, and 20 healthy volunteers was done. Lastly, the prognostic power of the selected panel was assessed.

RESULTS: The expression of serum DRAM1 messenger RNA (mRNA), ARSA mRNA, hsa-miR-2053 and lncRNA-RP1-86D1.3 were positive in 78.3%, 90%, 85%, and 83.3% of MPM patients, respectively. The RNA-based biomarker panel was able to discriminate between MPM patients and controls with high accuracy and their combined sensitivity reached 100% for the diagnosis of MPM. Kaplan-Meier analysis showed that hsa-miR-2053 is an independent prognostic factor of MPM.

CONCLUSION: Our preliminary data revealed that the chosen RNAs play an important role in driving MPM development and progression.

RevDate: 2018-10-25

Pascotto E, Gianoncelli A, Calligaro C, et al (2018)

Ferruginous bodies resolved by synchrotron XRF in a dog with peritoneal malignant mesothelioma.

Environmental science and pollution research international pii:10.1007/s11356-018-3521-x [Epub ahead of print].

Mesothelioma is a malignant tumor mainly correlated to occupational asbestos exposure. Rare reports describe its occurrence also in animals, mainly linked to asbestos in the environment. Asbestos exposure is demonstrated by the appearance of characteristic histological hallmarks: asbestos containing ferruginous bodies that are iron-based structures forming around fibers and also other dust particles. Here we present a clinical case of a suspect of mesothelioma in the peritoneum of a dog with parallel histological observation of ferruginous bodies. To possibly correlate the dog tumor to environmental exposure, we performed X-ray fluorescence (XRF) analyses at two different synchrotrons to resolve the ferruginous bodies' composition. While the histological examination diagnoses a tubulo-papillary mesothelioma, the XRF analyses show that ferruginous bodies contain Si particles, resembling formations of exogenous origin; however, the morphology is unlikely that of asbestos fibers. We speculate that the peritoneal mesothelioma of this dog could be related to environmental exposure to non-asbestos material.

RevDate: 2018-10-23

Ibrahim AM, Al-Akchar M, Obaidi Z, et al (2018)

Malignant Peritoneal Mesothelioma: A Rare Cause of Ascites.

Journal of investigative medicine high impact case reports, 6:2324709618807506 pii:10.1177_2324709618807506.

Malignant peritoneal mesothelioma (MPM) is a rare diagnosis that presents with difficulties in diagnosis and management. This article reports a case of an 88-year-old male who presented with a 2-week history of abdominal distention and bloating. He worked at an insulation production factory between the ages of 23 and 25 years with presumed asbestos exposure. On the computed tomography scan of the abdomen/pelvis, the patient was found to have diffuse omental, peritoneal, and mesenteric nodularity with moderate to large ascites. Omental biopsy revealed MPM. The overall prognosis of MPM remains poor, with a median survival time of 12 months at the time of diagnosis. Treatment modalities offered in the United States include chemotherapy alone, cytoreductive surgery alone, or cytoreductive surgery/chemotherapy combination.

RevDate: 2018-10-23

Grosso F, Roveta A, Gallizzi G, et al (2018)

Management of recurrent pleural mesothelioma: Successful rechallenge with nintedanib in combination with chemotherapy.

Clinical case reports, 6(10):2000-2004 pii:CCR31775.

Malignant pleural mesothelioma (MPM) is a rare neoplasm, generally caused by asbestos exposure. This case details how a patient treated with nintedanib during the LUME-Meso study was rechallenged with nintedanib. The findings highlight the benefit of nintedanib rechallenge and the potential use of continuous anti-angiogenic therapy in MPM treatment.

RevDate: 2018-10-23

Adhikary G, Grun D, Alexander HR, et al (2018)

Transglutaminase is a mesothelioma cancer stem cell survival protein that is required for tumor formation.

Oncotarget, 9(77):34495-34505 pii:26130.

Mesothelioma is a rare cancer of the mesothelial cell layer of the pleura, peritoneum, pericardium and tunica vaginalis. It is typically caused by asbestos, notoriously resistant to chemotherapy and generally considered incurable with a poor life expectancy. Transglutaminase 2 (TG2), a GTP binding regulatory protein, is an important cancer stem cell survival and therapy resistance factor. We show that TG2 is highly expressed in human mesothelioma tumors and in mesothelioma cancer stem cells (MCS cells). TG2 knockdown or TG2 inhibitor treatment reduces MCS cell spheroid formation, matrigel invasion, migration and tumor formation. Time to tumor first appearance is doubled in TG2 knockout cells as compared to wild-type. In addition, TG2 loss is associated with reduced expression of stemness, and epithelial mesenchymal transition markers, and enhanced apoptosis. These studies indicate that TG2 is an important MCS cell survival protein and suggest that TG2 may serve as a mesothelioma cancer stem cell therapy target.

RevDate: 2018-10-23
CmpDate: 2018-10-23

Behrens MA (2018)

Asbestos Trust Transparency.

Fordham law review, 87(1):107-124.

RevDate: 2018-10-19

Betti M, Aspesi A, Ferrante D, et al (2018)

Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes.

Genes, chromosomes & cancer, 57(11):573-583.

Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.

RevDate: 2018-10-15

Brentisci C, Gangemi M, Migliore E, et al (2018)

Comment on "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:5132702 [Epub ahead of print].

RevDate: 2018-10-15

Jargin SV (2018)

Asbestos and Mesothelioma: A Comment.

Indian journal of occupational and environmental medicine, 22(2):113-114.

RevDate: 2018-10-15

Duke KS, Thompson EA, Ihrie MD, et al (2018)

Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes.

Nanotoxicology [Epub ahead of print].

The fiber-like shape of multi-walled carbon nanotubes (MWCNTs) is reminiscent of asbestos, suggesting they pose similar health hazards when inhaled, including pulmonary fibrosis and mesothelioma. Mice deficient in the tumor suppressor p53 are susceptible to carcinogenesis. However, the chronic pathologic effect of MWCNTs delivered to the lungs of p53 heterozygous (p53+/-) mice has not been investigated. We hypothesized that p53+/- mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs. Wild-type (p53+/+) or p53+/- mice were exposed to MWCNTs (1 mg/kg) via oropharyngeal aspiration weekly over four consecutive weeks and evaluated for cellular and pathologic outcomes 11-months post-initial exposure. No lung or pleural tumors were observed in p53+/+ or p53+/- mice exposed to either t- or rMWCNTs. In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53+/- and p53+/+ mice. A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in p53+/- mice compared to p53+/+ mice. Importantly, p53+/- mice had larger granulomas induced by rMWCNTs as compared to p53+/+ mice. These findings indicate that a combination of p53 deficiency and physicochemical characteristics including nanotube geometry are factors in susceptibility to MWCNT-induced lymphoid infiltration and granuloma formation.

RevDate: 2018-10-14

Fournel L, Janet-Vendroux A, Canny-Hamelin E, et al (2018)

[Malignant pleural mesothelioma: The role of surgery].

Revue de pneumologie clinique pii:S0761-8417(18)30212-8 [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease, whose incidence is increasing. Asbestos is the primary causal agent.

STATE OF KNOWLEDGE: Knowledge about MPM has evolved. Thoracoscopy is essential for diagnosis of MPM. It allows performing pleural biopsies, to study the extent of the disease and to relieve dyspnea. The pathological diagnosis is also better codified with immunohistochemistry and with analysis by expert of Mesopath group. Curative surgical treatments are pleurectomy decortication and extended pneumonectomy in combination with chemotherapy and/or radiotherapy. Those heavy treatments improve survival in highly selected patients. For the other patients, supportive measures will be considered to reduce pain and dyspnea.

PROSPECT: Radical surgical treatment is only offered in therapeutic trials or multimodal treatment. Its place is not formally established. New therapies associated to surgical treatment are being studied.

CONCLUSIONS: Surgical management of MPM has to be operated in specialized teams where the survival benefit and quality of life is discussed case by case.

RevDate: 2018-10-13

Mansfield AS, Peikert T, Smadbeck JB, et al (2018)

Neoantigenic potential of complex chromosomal rearrangements in mesothelioma.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(18)33179-4 [Epub ahead of print].

INTRODUCTION: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy.

MATERIAL AND METHODS: We used mate-pair (n=22), RNA (n=28) and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome.

RESULTS: We observed that inter- or intra-chromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific MHC molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival.

DISCUSSION: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

RevDate: 2018-10-12

Toyokuni S (2018)

Iron Addiction with Ferroptosis-resistance in Asbestos-induced Mesothelial Carcinogenesis: Toward the Era of Mesothelioma Prevention.

Free radical biology & medicine pii:S0891-5849(18)31753-2 [Epub ahead of print].

Cancer is the primary cause of human mortality in most countries. This tendency has increased as various medical therapeutics have advanced, which suggests that we cannot escape carcinogenesis, although the final outcome may be modified by exposomes and statistics. Cancer is classified by its cellular differentiation. Mesothelial cells are distinct in that they line somatic cavities, facilitating the smooth movement of organs, but are not exposed to the external environment. Malignant mesothelioma, or simply mesothelioma, develops either in the pleural, peritoneal or pericardial cavities, or in the tunica vaginalis testes. Mesothelioma has been a relatively rare cancer but is socially important due to its association with asbestos exposure, caused by modern industrial development. The major pathogenic mechanisms include oxidative stress either via catalytic reactions against the asbestos surface or frustrated phagocytosis of macrophages, and specific adsorption of hemoglobin and histones by asbestos fibers in the presence of phagocytic activity of mesothelial cells. Multiwall carbon nanotubes of ~50 nm-diameter, additionally adsorbing transferrin, are similarly carcinogenic to mesothelial cells in rodents and were thus classified as Group 2B carcinogens. Genetic alterations found in human and rat mesothelioma notably contain changes found in other excess iron-induced carcinogenesis models. Phlebotomy and iron chelation therapies have been successful in the prevention of mesothelioma in rats. Alternatively, loading of oxidative stress by non-thermal plasma to mesothelioma cells causes ferroptosis. Therefore, carcinogenesis by foreign fibrous inorganic materials may overlap the uncovered molecular mechanisms of birth of life and its evolution.

RevDate: 2018-10-12

Smeele P, d'Almeida SM, Meiller C, et al (2018)

Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis.

Molecular cancer, 17(1):148 pii:10.1186/s12943-018-0891-0.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis.

RevDate: 2018-10-12

Funahashi S, Okazaki Y, Nishiyama T, et al (2018)

Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice.

Free radical research [Epub ahead of print].

Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.

RevDate: 2018-10-10

Sarun KH, Lee K, Williams M, et al (2018)

Genomic Deletion of BAP1 and CDKN2A Are Useful Markers for Quality Control of Malignant Pleural Mesothelioma (MPM) Primary Cultures.

International journal of molecular sciences, 19(10): pii:ijms19103056.

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis.

RevDate: 2018-10-09

White R, Pulford E, Elliot DJ, et al (2018)

Quantitative mass spectrometry to identify protein markers for diagnosis of malignant pleural mesothelioma.

Journal of proteomics pii:S1874-3919(18)30359-2 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a devastating malignancy with a prognosis of <12 months. Even with bans on the use of asbestos in most Western countries, the incidence is still increasing due to the long latency periods between exposure and development of the disease. Diagnosis is often delayed due to invasive biopsies and lack of distinguishable markers. Patients frequently present with pleural effusions months to years before a radiologically detectable mass appears. This study aimed to investigate the proteome of pleural effusions taken from patients with MPM, adenocarcinoma and benign conditions in an attempt to identify a biomarker for early diagnosis. We identified several proteins that may be possible targets and warrant further investigation. Due to the predominance of up regulated proteins involved in VEGF signalling in MPM, we analysed VEGFA levels in effusions and found a strong correlation between VEGFA levels and survival in MPM.

RevDate: 2018-10-08

Mlika M, Lamzirbi O, Limam M, et al (2018)

[Clinical and pathological profile of the pleural malignant mesothelioma: A retrospective study about 30 cases].

Revue de pneumologie clinique pii:S0761-8417(18)30096-8 [Epub ahead of print].

BACKGROUND: The malignant pleural mesothelioma (MPM) is a rare tumour usually associated to asbestos exposure. The delay between the exposure and the occurrence of the cancer can reach 40 years. This caused the pick of incidence described in many countries including Tunisia. The diagnosis is suspected based on clinical features but positive diagnosis is microscopic. Our aim was to describe the clinical and microscopic features of MPM through a single institution experience.

PATIENTS AND METHODS: We conducted a retrospective study about 30 MPM diagnosed over a 20-year-period (1995-2015). We included only patients with complete records including clinical, radiologic and microscopic features. All the microscopic diagnoses were reviewed by 2 pathologists. A mean of 12 slides per case was reviewed. The diagnosis was based on the 2015 WHO classification.

RESULTS: The mean age of the patients was 61 years, average 22 to 80 years. The sex ratio was 6,5. An asbetose exposition was reported in 21 cases. The most frequent symptoms was chest pain reported in 25 cases. Physical exam was normal in 9 cases. It revealed pleural syndorm in most patients (60 %). Imaging findings consisted mainly in diffuse pleural thickening in 17 cases. Twelve tumours were classified as stage I, 3 stage II, 14 stage III et 1 stage IV. Pleural biopsy was performed using needle in 18 cases, through thoracoscopy in 16 cases, thoracotomy in 3 cases and allowed the diagnosis in respectively 7 cases/18, 16 cases/16 and 3 cases/3. A lymph node biopsy was performed through mediastinoscopy in one case and yelded the diagnosis. The diagnosis was performed on surgical specimen in 2 patients: one bullectomy and one right upper lobectomy. The microscopic exam concluded to an EM in 17 cases, sarcomatoid mesothelioma (SM) in 4 cases and biphasic mesothelioma (BM) in 9 cases. Pan-cytokeratin antibody was used in all cases in association with 2 antibodies with positive diagnostic value and 2 antibodies with negative diagnostic value. It was repeated in 15 cases and the most used antibodies were the anti-calretinin and the TTF1. This was due to the lack of fixation in one case and in order to reach a quality criteria in the other cases. Surgical resection was possible in 2 patients. 15 patients were lost of view after a mean follow-up period of 3 months. Thirteen patients died before or during the follow-up.

CONCLUSION: This work was about a Tunisian experience in the diagnosis and management of MPM. The major limits faced were the incomplete databases, the small number of patients included. Microsocpic positive diagnosis necessitates a degree of expertise and every laboratory has to determine the most valuable antibodies through its experience in order to optimize the diagnosis and to reduce the delay of diagnosis.

RevDate: 2018-10-07

van Gerwen M, Wolf A, Liu B, et al (2018)

Short-term outcomes of pleurectomy decortication and extrapleural pneumonectomy in mesothelioma.

Journal of surgical oncology [Epub ahead of print].

BACKGROUND/OBJECTIVES: We evaluated postoperative mortality and complications after extrapleural pneumonectomy (EPP) and pleurectomy decortication (P/D) to better understand their effectiveness in malignant pleural mesothelioma (MPM).

METHODS: A meta-analysis was done to evaluate 30-day mortality and postoperative complications. In addition, in-patients data of 500 eligible patients with MPM who underwent EPP or P/D was extracted from the New York Statewide Planning and Research Cooperative System (SPARCS). Multivariate analyses and propensity matching were used to compare in-hospital mortality and postoperative complications in EPP vs P/D.

RESULTS: The meta-analysis showed a statistically significant difference in 30-day mortality (5% [95% CI: 4-6] vs P/D 2% [95% CI: 1-3]), proportion of complications (46% [95% CI: 36-56] vs 24% [95% CI: 15-34]) and postoperative arrhythmias (20% [95% CI: 12-31] vs 5% [95% CI: 2-8]) for EPP vs P/D. In-hospital mortality (OR adj : 2.6; 95% CI: 0.86-7.75) and postoperative complications (OR adj : 1.1; 95% CI: 0.68-1.86) were not different in EPP compared with P/D while supraventricular arrhythmia was significantly more frequent after EPP vs P/D (OR adj : 5.2; 95% CI: 2.34-11.33).

CONCLUSIONS: Postoperative mortality, postoperative complications, and particularly supraventricular arrhythmia are less frequent after P/D vs EPP. P/D, a less invasive surgery, may provide a better option when technically feasible for patients with MPM.

RevDate: 2018-10-05

Fear VS, Tilsed C, Chee J, et al (2018)

Combination immune checkpoint blockade as an effective therapy for mesothelioma.

Oncoimmunology, 7(10):e1494111 pii:1494111.

Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated. Here, we used our well characterised mesothelioma tumour model to investigate the efficacy of different ICBP treatments to generate effective therapy for mesothelioma. We show that tumour resident regulatory T cell co-express high levels of CTLA-4, OX40 and GITR relative to T effector subsets and that these receptors are co-expressed on a large proportion of cells. Targeting any of CTLA-4, OX40 or GITR individually generated effective responses against mesothelioma. Furthermore, the combination of αCTLA-4 and αOX40 was synergistic, with an increase in complete tumour regressions from 20% to 80%. Other combinations did not synergise to enhance treatment outcomes. Finally, an early pattern in T cell response was predictive of response, with activation status and ICP receptor expression profile of T effector cells harvested from tumour and dLN correlating with response to immunotherapy. Taken together, these data demonstrate that combination ICPB can work synergistically to induce strong, durable immunity against mesothelioma in an animal model.

RevDate: 2018-10-03

Kalinke LP, Kalinke MA, Sarquis LMM, et al (2018)

[A proposal for the creation of a system to monitor cases of malignant mesothelioma in Curitiba, Paraná, Brazil].

Cadernos de saude publica, 34(9):e00171917 pii:S0102-311X2018000905016.

The study proposes the creation of a system to monitor cases of malignant mesothelioma in the municipality of Curitiba, Paraná State, Brazil, based on the Italian model. This diagnosis-type action-research project featured exploratory and planning phases conducted from July 2015 to May 2017. The following search tools were used: Hospital-Based Cancer Registries Integrator with specific morphologies for mesothelioma; Hospital-Based Cancer Registry with codes C38.4 and C45 of the International Classification of Diseases, 10th revision, and/or records coded by the ICD-O with topographies C38 and C48; Population-Based Cancer Registry of the Curitiba Municipal Health Department, with the same codes. The study also identified, analyzed, and adapted to the Brazilian reality the model, questionnaires, and registry software for mesothelioma from Lombardy, Italy. Fifteen cases of mesothelioma were recorded in the Hospital-Based Cancer Registries Integrator. Two cases were recorded in the University Hospital-Based Cancer Registry and 16 in the Cancer Hospital. There were 317 cases recorded in the Population-Based Cancer Registry during the same period. Although some information was complete, data were lacking on patients' occupational history, thereby preventing the determination of a causal nexus. Given a predicted increase in cases of mesothelioma in the coming decades and the response to court cases, the implementation of registries has become essential to facilitate knowledge and follow-up on the determination of the causal link and specific sources of asbestos exposure in the country.

RevDate: 2018-10-01

Zhang C, Hao Y, Wu L, et al (2018)

Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma.

International journal of oncology [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a rare form of cancer that is associated with asbestos exposure. Unfortunately, current therapies have limited efficacy. Previous studies have indicated that curcumin exerts antiproliferative and antitumor effects, and has low toxicity. The present study aimed to evaluate the anticancer effects of curcumin on the RN5 MPM cell line. The inhibitory effects of curcumin on cell viability were determined using the sulforhodamine B assay. In addition, cell cycle progression was analyzed by propidium iodide (PI) staining and flow cytometry, and curcumin‑induced apoptosis was measured by Annexin V/PI double staining. The translocation of apoptosis-inducing factor (AIF) was assessed by western blotting and immunofluorescence, and the expression levels of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (Akt)‑mammalian target of rapamycin (mTOR) signaling pathway proteins and mitochondria-associated proteins were evaluated by western blotting. In vivo antitumor effects were evaluated in a subcutaneous murine model. Briefly, tumors were harvested from the mice, and immunohistochemistry was conducted to evaluate cell proliferation, apoptosis and angiogenesis. The results indicated that curcumin inhibited RN5 cell viability and induced apoptotic cell death. In addition the findings suggested that curcumin-induced cell apoptosis occurred via the mitochondrial pathway, and caspase‑independent and AIF-dependent pathways. Further analysis revealed that curcumin may act as a PI3K-Akt-mTOR signaling pathway inhibitor by downregulating PI3K, p-Akt, p-mTOR and p-p70 ribosomal protein S6 kinase. Furthermore, curcumin inhibited tumor angiogenesis in vivo. In conclusion, curcumin may be potent enough to be developed as a novel therapeutic agent for the treatment of MPM.

RevDate: 2018-09-28

Arnold DT, De Fonseka D, Perry S, et al (2018)

Investigating Unilateral Pleural Effusions: The role of cytology.

The European respiratory journal pii:13993003.01254-2018 [Epub ahead of print].

The vast majority of undiagnosed unilateral pleural effusions have fluid sent for cytological analysis. Despite widespread use, there is uncertainty about its sensitivity to diagnose malignant pleural effusions (MPEs). Our aim was to ascertain the utility of cytology using a large prospective cohort.Consecutive patients presenting with an undiagnosed unilateral pleural effusion were recruited to this UK-based study. All had pleural fluid sent for cytological analysis. Cytological sensitivity was based on the final diagnosis at 12 months, confirmed by two consultants.Over 8-years, 921 patients were recruited, of which 515 had a MPE. Overall sensitivity of fluid cytology to diagnose malignancy was 46% (95%CI 42-58). There was variation in sensitivity depending on cancer primary, with mesothelioma (6%) and haematological malignancies (40%), being significantly lower than adenocarcinomas (79%). MPEs secondary to ovarian cancer had high pick-up rates (95%). In asbestos-exposed males with exudative effusions, the risk of MPE was 60%, but cytological sensitivity was 11%.This is the largest prospective study of pleural fluid cytology and informs discussions with patients about the likely requirement for investigations following thoracentesis. In patients presenting with a clinical suspicion of mesothelioma, cytological sensitivity is low, so more definitive investigations could be performed sooner.

RevDate: 2018-09-27

Ascoli V, Murer B, Nottegar A, et al (2018)

What's new in mesothelioma.

Pathologica, 110(1):12-28.

Malignant pleural mesothelioma is a neoplasm characterized by a very poor prognosis and medico-legal implications. Diagnosis, prognosis and therapy are often challenging and include several issues. Cytological diagnosis is frequently the first step of the diagnostic process, and although its sensitivity may be somewhat lower, diagnostic criteria should be taken into account. When effusion cytology is inconclusive for the diagnosis, tissue biopsies should be taken. Even if the morphologic criteria for deciding whether a mesothelial proliferation is a benign or a malignant process have been defined, the separation of benign from malignant mesothelial proliferation is often a difficult problem for the pathologist, particularly on small biopsies. Thirdly, when the diagnosis is made, despite many efforts have been made to identify possible new biomarkers for early diagnosis, prognostic stratification and also predictive tools should be defined. Nowadays, the main prognostic parameter is still represented by the histological subtype, having the epithelioid MPM a better outcome than the sarcomatoid or biphasic MPM. A nuclear grading system have been also proposed to stratify patient outcome. Reliable predictive biomarkers are still lacking in MPM and a personalized therapeutic concept is eagerly needed. Mesothelioma occurs mostly as sporadic cancer and the main risk factor is asbestos exposure, but it also occurs among blood relatives suggesting possible increased genetic susceptibility besides shared exposures. Recently the study of genetic predisposition syndrome raised new aspect in the occurrence of mesothelioma cases.

This review summarize these most important issues.

RevDate: 2018-09-27

Santarelli L, Gaetani S, Monaco F, et al (2018)

Four-miRNA signature to identify asbestos-related lung malignancies.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-18-0453 [Epub ahead of print].

BACKGROUND: Altered miRNA expression is an early event upon exposure to occupational/environmental carcinogens; thus, identification of a novel asbestos-related profile of miRNAs able to distinguish asbestos-induced cancer from cancer with different ethiology can be useful for diagnosis. We therefore performed a study to identify miRNAs associated with asbestos-induced malignancies.

METHODS: Four groups of patients were included in the study, including patients with asbestos-related (NSCLCAsb) and asbestos-unrelated non-small cell lung cancer (NSCLC) or with malignant pleural mesothelioma (MPM), and disease-free subjects (CTRL). The selected miRNAs were evaluated in asbestos-exposed population.

RESULTS: Four serum miRNAs, i.e. miR-126, miR-205, miR-222 and miR-520g, were found to be implicated in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in asbestos-exposed subjects, and both miRNAs are involved in major pathways linked to cancer development. Epigenetic changes and cancer-stroma cross-talk could induce repression of miR-126 to facilitate tumor formation, angiogenesis and invasion.

CONCLUSIONS: This study indicates that miRNAs are potentially involved in asbestos-related malignancies, and their expression outlines mechanism(s) whereby miRNAs may be involved in an asbestos-induced pathogenesis.

IMPACT: The discovery of a miRNA panel for asbestos-related malignancies would impact on occupational compensation and may be utilized for screening asbestos-exposed populations.

RevDate: 2018-09-26

Johnen G, Burek K, Raiko I, et al (2018)

Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers.

Scientific reports, 8(1):14321 pii:10.1038/s41598-018-32315-3.

Malignant mesothelioma (MM) is strongly associated with a previous asbestos exposure. To improve timely detection of MM in asbestos workers, better screening tools - like minimally-invasive biomarkers - are desirable. Between 2008 and 2018 2,769 patients with benign asbestos-related diseases were recruited to participate in annual screens. Using a nested case-control design the protein markers calretinin and mesothelin were determined by enzyme-linked immunosorbent assays in prediagnostic plasma samples of 34 MM cases as well as 136 matched controls from the cohort. Conditional on a pre-defined specificity of 98% for calretinin and 99% for mesothelin the markers reached individual sensitivities of 31% and 23%, respectively, when including the incident cases with samples taken between one and 15 months before diagnosis. The combination of both markers increased the sensitivity to 46% at 98% specificity. Marker complementation increased with earlier sampling. The marker combination improves the sensitivity of the individual markers, indicating a useful complementation and suggesting that additional markers may further improve the performance. This is the first prospective cohort study to evaluate a detection of MM by calretinin and its combination with mesothelin up to about a year before clinical diagnosis. Whether an earlier diagnosis will result in reduced mortality has yet to be demonstrated.

RevDate: 2018-09-22

Boffetta P, Malvezzi M, Pira E, et al (2018)

International Analysis of Age-Specific Mortality Rates From Mesothelioma on the Basis of the International Classification of Diseases, 10th Revision.

Journal of global oncology.

Past analyses of mortality data from mesothelioma relied on unspecific codes, such as pleural neoplasms. We calculated temporal trends in age-specific mortality rates in Canada, the United States, Japan, France, Germany, Italy, the Netherlands, Poland, the United Kingdom, and Australia on the basis of the 10th version of the International Classification of Diseases, which includes a specific code for mesothelioma. Older age groups showed an increase (in the United States, a weaker decrease) during the study period, whereas in young age groups, there was a decrease (in Poland, a weaker increase, starting, however, from low rates). Results were consistent between men and women and between pleural and peritoneal mesothelioma, although a smaller number of events in women and for peritoneal mesothelioma resulted in less precise results. The results show the heterogeneous effect of the reduction of asbestos exposure on different age groups; decreasing mortality in young people reflects reduced exposure opportunity, and increasing mortality in the elderly shows the long-term effect of early exposures.

RevDate: 2018-09-21
CmpDate: 2018-09-21

Barbiero F, Zanin T, Pisa FE, et al (2018)

Mortality in a cohort of asbestos-exposed workers undergoing health surveillance.

La Medicina del lavoro, 109(2):83-86.

BACKGROUND: The coastal area of Friuli Venezia Giulia (FVG) region, north-eastern Italy, was characterized by work activities in which asbestos was used until the early 1990s, particularly in shipbuilding. A public health surveillance program (PHSP) for asbestos-exposed workers was established, although limited evidence exists about the efficacy of such programs in reducing disease occurrence and mortality.

OBJECTIVES: To compare mortality in a cohort of 2,488 men occupationally exposed to asbestos, enrolled in a PHSP in FVG between the early 1990s and 2008, with that of the general population of FVG and Italy.

METHODS: Standardized Mortality Ratios (SMR), with 95% Confidence Interval (95% CI), for all causes, all cancers, lung (LC) and pleural cancer (PC) were estimated in the cohort and in subgroups of workers with the first hire in shipbuilding that caused asbestos exposure (<1974, 1974-1984, 1985-1994).

RESULTS: A strong excess in mortality for PC with reference to FVG (SMR=6.87, 95% CI 4.45-10.17) and Italian population (SMR=13.95, 95% CI 9.02-20.64) was observed. For LC, the FVG-based SMR was 1.49 (95% CI 1.17-1.89) and the Italy-based 1.43 (95% CI 1.12-1.81). Mortality among workers with the first hire in shipbuilding before 1974 was high for PC (FVG-based SMR=8.98, 95% CI 5.56-13.75; Italy-based SMR=18.41, 95% CI 11.40-28.17) and for LC (FVG-based SMR =1.60, 95% CI 1.18-2.11; Italy-based SMR=1.54, 95% CI 1.14-2.03). Further, for LC between 1974 and 1984, the FVG-based SMR was 2.45 (95% CI 1.06-4.82), and the Italy-based SMR was 2.33 (95% CI 1.01-4.60).

CONCLUSIONS: This cohort experienced an excess mortality for pleural and lung cancer, compared with regional and national populations. For lung cancer, the excess was stronger in workers with the first hire in shipbuilding before 1985, suggesting a key role of asbestos exposure.

RevDate: 2018-09-13

Finkelstein MM (2018)

Response to: 'The epidemiology of malignant mesothelioma in women: gender differences and modalities of asbestos exposure' by Marinaccio et al.

RevDate: 2018-09-13

Marinaccio A, Corfiati M, Binazzi A, et al (2018)

Letter concerning: 'Response to: 'The epidemiology of malignant mesothelioma in women: gender differences and modalities of asbestos exposure' by Marinaccio et al'.

RevDate: 2018-09-09

Kharazmi E, Chen T, Fallah M, et al (2018)

Familial risk of pleural mesothelioma increased drastically in certain occupations: A nationwide prospective cohort study.

European journal of cancer (Oxford, England : 1990), 103:1-6 pii:S0959-8049(18)31125-0 [Epub ahead of print].

OBJECTIVE: We aimed to explore the effect of occupation on familial risk of pleural mesothelioma in a nationwide cohort study design.

METHOD: The nationwide Swedish Family-Cancer Database includes all Swedes born after 1931 and their biological parents, totalling 16.1 million individuals with about 2.3 million cancer patients. Hazards ratios (HRs) were calculated adjusting for age, sex and region of residence.

RESULTS: Having asbestos-related occupation in the absence of family history of mesothelioma increased risk of mesothelioma more than threefold (adjusted HR = 3.2, 95% confidence interval [CI]: 3.0-3.5). In those who had a history of mesothelioma in their first-degree relatives and an asbestos-related occupation, risk of mesothelioma dramatically increased compared with individuals without such occupations and family history (without chronic obstructive pulmonary disease [COPD] HR = 24, 95% CI: 15-39; with COPD 45, 95% CI: 15-141). In those who had a family history of mesothelioma and no history of an asbestos-related occupation, risk of mesothelioma did not show significant increase compared with those who had no family history of mesothelioma and no asbestos-related occupation (HR = 1.6; 95% CI: 0.7-3.8).

CONCLUSION: First-degree relatives of patients with pleural mesothelioma had a drastic risk of developing this malignancy in case of certain occupations, which shows a gene-environment interaction is probable in risk of mesothelioma.

RevDate: 2018-09-03

Marant Micallef C, Shield KD, Vignat J, et al (2018)

Cancers in France in 2015 attributable to occupational exposures.

International journal of hygiene and environmental health pii:S1438-4639(18)30326-2 [Epub ahead of print].

BACKGROUND: Recent and comprehensive estimates for the number of new cancer cases in France attributable to occupational exposures are lacking.

OBJECTIVES: To estimate the number of new cancer cases attributable to occupational exposures, using a newly developed methodology and the most recent data, for a comprehensive set of occupational carcinogens in France in 2015.

METHODS: Surveys among employees, the national labor force data, a cohort of agricultural workers, national monitoring of workers exposed to ionizing radiation and job-exposure matrix in France were used. The number and proportion of new cancer cases attributable to established occupational carcinogens (Group 1) was estimated using estimation of lifetime exposure and risk estimates from cohort studies. Cancer data were obtained from the French Cancer Registries Network.

RESULTS: In France in 2015, an estimated 7905 new cancer cases, 7336 among men and 569 among women, were attributable to occupational exposures, representing 2.3% of all new cancer cases (3.9% and 0.4% among men and women respectively). Among men and women, lung cancer was impacted the most, followed by mesothelioma and bladder cancer in men, and by mesothelioma and ovary in women. These cancers contributed to 89% of the total cancers attributable to occupational carcinogens in men, and to 80% in women. The main contributing occupational agent was asbestos among men (45%) and women (60%).

CONCLUSIONS: Currently, occupational exposures contribute to a substantial burden of cancer in France. Enhanced monitoring and implementation of protective labor policies could potentially prevent a large proportion of these cancers.

RevDate: 2018-08-31

Terracini B (2018)

Commentary: Past and current asbestos exposure and future mesothelioma risks in Britain. The Inhaled Particles Study (TIPS).

International journal of epidemiology pii:5086068 [Epub ahead of print].

RevDate: 2018-08-30

Reid A, Franklin P, Berry G, et al (2018)

Are children more vulnerable to mesothelioma than adults? A comparison of mesothelioma risk among children and adults exposed non-occupationally to blue asbestos at Wittenoom.

Occupational and environmental medicine pii:oemed-2018-105108 [Epub ahead of print].

OBJECTIVES: The presence of asbestos in public buildings is a legacy of past asbestos use in many developed countries. Of particular concern is the amount and current condition in schools and the vulnerability of children to mesothelioma. Our aim was to compare the risk of mesothelioma between those exposed to blue asbestos as children and as adults at Wittenoom.

METHODS: Public sources were used to establish the Wittenoom residents' cohort. Mesothelioma incidence rates per 100 000 person-years at risk were derived for those first exposed to asbestos at Wittenoom as children (<15 years) or adults separately. Proportional hazards survival models examined the slope of the exposure-response relationship between asbestos exposure and incidence of mesothelioma in different sex and age groups.

RESULTS: The mesothelioma rate was lower among those first exposed as children (76.8 per 100 000) than those first exposed as adults (121.3 per 100 000). Adjusting for cumulative exposure to asbestos and sex, those exposed as adults had a greater risk of mesothelioma (adjusted HR 2.5, 95% CI 1.7 to 3.7). The slope of the exposure-response relationship did not differ between those exposed as children and those exposed as adults.

CONCLUSION: We found no greater susceptibility to mesothelioma among those first exposed to asbestos as children than those first exposed as adults. However, given the long latency of mesothelioma, and the greater years of life yet to be lived by the Wittenoom children, it is likely that there will be more cases of mesothelioma in the future among those first exposed as children.

RevDate: 2018-08-29

Rath EM, Cheng YY, Pinese M, et al (2018)

BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state.

PloS one, 13(8):e0203003 pii:PONE-D-18-15089.

Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

RevDate: 2018-08-28
CmpDate: 2018-08-28

Dodson RF (2016)

Preface: Respirable elongated mineral particles and human health-Revisited.

Journal of toxicology and environmental health. Part B, Critical reviews, 19(5-6):149-150.

RevDate: 2018-08-25

Muscella A, Cossa LG, Vetrugno C, et al (2018)

ADP sensitizes ZL55 cells to the activity of cisplatin.

Journal of cellular physiology [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor in which cisplatin therapy is commonly used, although its effectiveness is limited. It follows that research efforts dedicated to identify promising combinations that can synergistically kill cancer cells are needed. Because we recently demonstrated that ADP inhibits the proliferation of ZL55 cells, an MPM-derived cell line obtained from bioptic samples of asbestos-exposed patients. Our objective in this study was to investigate the hypothesis that ADP also potentiates the cytotoxic activity of cisplatin. Results show that in ZL55 cells ADP enhanced (a) the cytotoxicity of cisplatin by 12-fold, (b) the restraint of cell clonogenic potential cisplatin-mediated, and (c) the number of apoptotic cells. Cisplatin, but not ADP, caused caspases activation; nevertheless, poly(ADP-ribose) polymerase-1 was not only cleaved in cisplatin-treated cells but also in cells treated with ADP alone. Furthermore, ADP, but not cisplatin, decreased mTOR and 6SK phosphorylations. Both ADP and cisplatin increased p53 protein, but ADP was also able to enhance p53 messenger RNA. P53 silencing resulted in a very large decrement of cell death induced by ADP or by cisplatin and reverted ADP effects on mTOR/S6K phosphorylation, suggesting that activated p53 may act as a negative regulator of mTOR. Consistently, the inhibition of mTOR by rapamycin also sensitized cells to cisplatin, and the effects of cisplatin plus rapamycin were identical to those obtained with cisplatin plus ADP. These findings suggest that the combination of ADP and cisplatin may be a promising strategy for the clinical treatment of cisplatin-resistant MPM.

RevDate: 2018-08-24

Kang DM, Kim JE, Kim YK, et al (2018)

Occupational Burden of Asbestos-Related Diseases in Korea, 1998-2013: Asbestosis, Mesothelioma, Lung Cancer, Laryngeal Cancer, and Ovarian Cancer.

Journal of Korean medical science, 33(35):e226.

Background: Asbestos exposure causes asbestos-related diseases (ARDs) including asbestosis, malignant mesothelioma, lung cancer, laryngeal cancer, and ovarian cancer. Although Korea used substantial amounts of asbestos in the past, no study has focused on its occupational burden of disease (OBD). Therefore, this study aimed to determine the OBDs of ARDs in Korea.

Methods: The CARcinogen Exposure (CAREX) database was used to determine the proportion of exposed population. Relative risks for lung cancer, laryngeal cancer, and ovarian cancer were used to determine the population-attributable fraction. Data for deaths caused by ARDs during 1998-2013 were obtained from the World Health Organization mortality database. The potential years of life lost (PYLL) and annual average PYLL (APYLL) indicated OBDs.

Results: In Korea, the number of ARD-attributable deaths and PYLL due to all ARDs during 1998-2013 were 4,492 and 71,763.7, respectively. The number of attributable deaths and PYLL due to asbestosis, malignant mesothelioma, lung cancer, laryngeal cancer, and ovarian cancer were 37 and 554.2, 808 and 15,877.0, 3,256 and 47,375.9, 120 and 1,605.5, and 271 and 6,331.1, respectively; additionally, the APYLL were 15.0, 19.7, 14.6, 13.4, and 23.4, respectively, and the average age at death was 70.4, 62.6, 69.1, 69.9, and 61.8, respectively. Our study showed that although the use of asbestos has ceased in Korea, the incidence of ARDs tends to increase.

Conclusion: Therefore, efforts to reduce future OBDs of ARDs, including early detection and proper management of ARDs, are needed in Korea.

RevDate: 2018-08-23

Krupoves A (2018)

Asbestos exposure and mesothelioma risk.

International journal of epidemiology pii:5075854 [Epub ahead of print].

RevDate: 2018-08-23

Farioli A, Mattioli S, Curti S, et al (2018)

Letter to the editor re: Dragani et al. (2018), "Malignant mesothelioma diagnosed at a younger age is associated with heavier asbestos exposure".

Carcinogenesis pii:5078160 [Epub ahead of print].

RevDate: 2018-08-22

Chatfield EJ (2018)

Measurement of elongate mineral particles: What we should measure and how do we do it?.

Toxicology and applied pharmacology pii:S0041-008X(18)30376-4 [Epub ahead of print].

The length distributions of single fibrils of Coalinga, UICC-B and wet dispersed chrysotile were measured by transmission electron microscopy (TEM). It was found that the distributions significantly diverged above approximately 10 μm (μm) in length, corresponding to differences in published results of animal experiments. This result is in contrast to published data in which counting of an insufficient number of fibers resulted in an erroneous conclusion that the length distribution of Coalinga chrysotile fibrils was indistinguishable from those of other sources of chrysotile. The size distributions of the respirable particle size fractions from acknowledged tremolite asbestos samples were found to be dominated by elongate particles longer than 5 μm that are within the dimensional range of non-asbestiform amphiboles. Prior studies have shown that these elongate particles obscure a correlation between a specific size range of particles and results of animal implantation studies that used tremolite of various morphologies. In the prior studies, a reference protocol was developed from four crushed non-asbestiform amphiboles to differentiate the size range of amphibole particles that correlates with the mesothelioma frequencies observed in the animal studies. In the work reported here, this correlation was tested with TEM analyses of amphiboles from Libby, MT, Sparta, NJ and Homestake mine, Lead, SD, which represent known environmental/occupational situations. Further TEM analyses of the tremolite samples used in the original animal implantation studies have also shown that the numbers of elongate tremolite particles with lengths ≤5 μm implanted into the animals are not correlated with the observed mesothelioma frequencies.

RevDate: 2018-08-22

Finkelstein MM (2018)

Letter Concerning: Glynn ME, Keeton KA, Gaffney SH, Sahmel J. Ambient Asbestos Fiber Concentrations and Long-Term Trends in Pleural Mesothelioma Incidence Between Urban and Rural Areas in the United States (1973-2012). Risk Analysis 2018;38(3):454-471.

Risk analysis : an official publication of the Society for Risk Analysis, 38(8):1521-1523.

RevDate: 2018-08-22

Keeton KA, Glynn ME, Gaffney SH, et al (2018)

Response to Letter to the Editor Regarding "Ambient Asbestos Fiber Concentrations and Long-Term Trends in Pleural Mesothelioma Incidence Between Urban and Rural Areas in the United States (1973-2012)" by Finkelstein.

Risk analysis : an official publication of the Society for Risk Analysis, 38(8):1524-1528.

RevDate: 2018-08-20

Bosio M, Salvaterra E, Datturi F, et al (2018)

5-hydroxymethylcytosine but not MTAP methylation status can stratify malignant pleural mesothelioma based on the lineage of origin.

Multidisciplinary respiratory medicine, 13:27 pii:137.

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, mainly associated with work or environmental exposure to asbestos. MPM's molecular profile is largerly unexplored and effective therapies are still lacking. MPM rarely harbours those somatic genetic lesions that usually characterize solid epithelial-derived tumors. On this basis, our study aims at investigating MPM epigenetic profile.

Methods: We here assessed through immunohistochemistry, FISH and methylation specific PCR, the expression of 5-hydroxymethylcytosine (5- hmC) - an epigenetic marker and an important regulator of embryonic development and carcinogenesis - and the methylation status of the promoter of the MTAP gene - encoding for an enzyme involved in the rescue process of methionine and adenine - in two relevant series of FF-PE MPM samples derived from MPM thoracoscopic biopsies. Tissue sampling was performed at diagnosis.

Results: Within the limitations of the study cohort, the 5-hmC immunophenotype was different among the histological MPM types analysed. In fact, 18% of the epithelial MPMs were negative, 47% weakly positive, and 35% of the cases showed an intense expression of 5-hmC. Sarcomatoid and biphasic MPMs showed intense 5-hmC expression pattern (positive and weakly positive in more than 80% of cases). Among MPM featuring epithelial lineage, none showed methylation of MTAP promoter.

Conclusions: Mesothelial sarcomatoid tumors featured a methylation profile characterized by a permanent gene silencing. Epithelial MPM methylation profile was in-between that of sarcomatoid MPM and the one of epithelial-derived tumors. MTAP promoter methylation level cannot be considered a suitable biomarker of epithelial MPM arousal.

RevDate: 2018-08-17

Smith-Hannah A, R Naous (2018)

Primary peritoneal Epithelioid mesothelioma of clear cell type with a novel VHL gene mutation: a case report.

Human pathology pii:S0046-8177(18)30303-4 [Epub ahead of print].

Clear cell variant of epithelioid mesothelioma is an extremely rare tumor with only isolated cases reported so far in the peritoneum. Here, we report a case of peritoneal epithelioid mesothelioma, clear cell variant, in a 63-year-old female patient with a novel VHL gene mutation and an unusual indolent clinical course. The patient, who has no clinical history of asbestos exposure, presented with a 27.2 cm upper abdominal mass and a 5.5 cm liver lesion. Retrospective review of the patient's abdominal CT scan 4 years ago showed two small abdominal lesions that were felt clinically to represent hemangiomas. These were retrospectively considered to have grown in size and represented the current abdominal mass. Both masses were subsequently biopsied and showed a proliferation of monomorphic epithelioid cells with distinct cell membranes, fine chromatin and clear to finely vacuolated pale eosinophilic cytoplasm arranged in nests and solid sheets. Immunohistochemical staining confirmed it to be malignant mesothelioma. Clear cell variant of peritoneal epithelioid mesothelioma should always be considered in patients with an abdominal or pelvic mass with clear cell features. Given the rarity of such entity, its clinical course and prognosis remains unclear.

RevDate: 2018-08-16

Panou V, Gadiraju M, Wolin A, et al (2018)

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

Purpose The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). Methods We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. Results Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). Conclusion A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

RevDate: 2018-08-16

Löffler MW, Steinhilber J, Hilke FJ, et al (2018)

First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications.

BMC medical genetics, 19(1):144 pii:10.1186/s12881-018-0651-4.

BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported.

CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing.

DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.

RevDate: 2018-08-15

Salazar C, Kanter Md N, A Abboud (2018)

Malignant Pleural Mesothelioma, Biphasic Type: An Unusual and Insidious Case of Rapidly Progressive Small Blue Cell Tumor.

Cureus, 10(6):e2749.

Malignant pleural mesothelioma (MPM) is a rare neoplasm. It predominantly affects elderly individuals aged over 70 years presenting with a unilateral pleural tumor usually associated with previous asbestos exposure. The respiratory symptoms are associated with ipsilateral pleural involvement with concomitant pleural effusions. The diagnosis of MPM is established by the morphologic and immunohistochemical features of a cytologic specimen. MPM can present as three histologic subtypes: epithelioid, sarcomatoid, or biphasic. We present a case of an 85-year-old Caucasian female with a history of occupational asbestos exposure. She complained of 1-week history of progressive sharp right flank and scapular pain with mild shortness of breath, dry cough and pleuritic chest pain. CT of the chest showed a large loculated right pleural effusion with adjacent pleural thickening. CT abdomen and pelvis was negative for other neoplastic findings. CT-guided core biopsy of the right pleural-based mass was positive for a spindle to plasmacytoid small blue cell tumor. An extensive immunohistochemical panel was non-specific. A focal OSCAR keratin and WT-1 expression in the absence of carcinoma markers, a malignant mesothelioma, biphasic type was diagnosed. Further workup with PET-CT and cytotoxic chemotherapy combined with immunotherapy or tyrosine kinase inhibitors was recommended by oncology. The patient refused further imaging and treatment, and palliative care was consulted.

RevDate: 2018-08-14

Krówczyńska M, E Wilk (2018)

Asbestos Exposure and the Mesothelioma Incidence in Poland.

International journal of environmental research and public health, 15(8): pii:ijerph15081741.

Asbestos is carcinogenic to humans; the exposure to asbestos causes a wide range of diseases.

AIM: Malignant mesothelioma (MM) is unique for asbestos exposure.

METHODS: Based on the physical inventory of asbestos-cement roofing, the social-economic situation of communes, the proximity of asbestos manufacturing plants, the land use data referring to the surface of the built-up area, and the historical data on the annexations, the amount of asbestos-containing products in use was estimated by computing best Random Forest models. Per capita asbestos use is an indicator to compare the state of asbestos use among countries. MM cases in the local administrative units (provinces) were tested by the application of Moran's I and Getis and Ord statistic.

RESULTS: The total amount of asbestos roofing in Poland was estimated at 738,068,000 m² (8.2 million tons). In total there were 28 plants in Poland located in 11 provinces throughout the country. The amount of asbestos-cement roofing in use is correlated primarily with the measurements of asbestos concentration fibers (rs = 0.597). MM raw morbidity rate was calculated, stratified by province, and classified into five groups with respect to incidence. Hotspots of MM cases are in the southern part of Poland.

CONCLUSIONS: MM cases are concentrated in the same geographical areas, which may indicate an increasing impact of environmental exposure. The results of the local and global autocorrelation clearly indicate a statistically significant relationship between incidences of MM in provinces. Poland and other Eastern European countries are among countries with low MM incidence rate. Detailed investigation is desirable since the current MM morbidity rate in Poland seems to be underestimated.

RevDate: 2018-08-13

Negi Y, Kuribayashi K, Doi H, et al (2018)

Double cancer comprising malignant pleural mesothelioma and squamous cell carcinoma of the lung treated with radiotherapy: A case report.

Molecular and clinical oncology, 9(2):181-186.

Pleurectomy/decortication (P/D) is the surgical treatment of choice for early malignant mesothelioma, but it remains unclear whether radiotherapy along with P/D should be used as multimodal treatment for this disease. We herein present the case of a 76-year-old man with a history of asbestos exposure who was diagnosed with left-sided malignant pleural mesothelioma in February 2010. The patient underwent chemotherapy with a combination of cisplatin and pemetrexed and achieved stable disease, after which time he was kept under observation. A positron emission tomography/computed tomography scan performed in February 2011 revealed nodular shadows with fluorodeoxyglucose uptake in S3 of the left lung; using bronchoscopy, the patient was diagnosed with stage IIB (cT3N0M0) primary squamous cell carcinoma. Chemoradiotherapy with vinorelbine and 60 Gy/20 fr radiotherapy was performed, and a partial response was obtained, suggesting that the radiotherapy used to treat the carcinoma of the lung may have also helped control the disease activity of the pre-existing mesothelioma. The present case indicates the value of radiotherapy in the treatment of malignant mesothelioma. The aim of the present study was to examine the possibility of new multimodal treatments for mesothelioma, along with a discussion of the relevant literature.

RevDate: 2018-08-11

Aida S, Aida J, Naoi M, et al (2018)

Measurement of telomere length in cells from pleural effusion: Asbestos exposure causes telomere shortening in pleural mesothelial cells.

Pathology international [Epub ahead of print].

We estimated the telomere lengths of neoplastic and non-neoplastic mesothelial cells and examined their correlation with asbestos exposure and the expression of markers of mesothelial malignancy. Cell blocks of pleural effusion obtained from 35 cases of non-neoplastic disease (NN), 12 cases of malignant mesothelioma (MM) and 12 cases of carcinomatous effusion due to lung adenocarcinoma (LA) were examined. Fifteen of the 35 NN cases had pleural plaques (NNpp+) suggestive of asbestos exposure, and the other 20 cases had no pleural plaques (NNpp-). Telomere length was measured using the tissue quantitative fluorescence in situ hybridization method, and expressed as normalized telomere-to-centromere ratio. NN cases had significantly longer telomeres than MM (P < 0.001) and LA (P < 0.001) cases. Telomeres in NNpp+ cases were slightly shorter than those of NNpp- cases (P = 0.047). MM and LA showed almost the same telomere length. NN cases with shorter telomeres tended to show aberrant expression of epithelial membrane antigen (EMA), CD146, glucose transporter 1 (GLUT1) and IGF-II messenger RNA-binding protein 3 (IMP3). These results suggest that telomere shortening and subsequent genetic instability play an important role in the development of MM. Measurement of telomere length of cells in pleural effusion might be helpful for earlier detection of MM.

RevDate: 2018-08-07

Lucas C (2018)

Miracle mineral or mesothelioma: cancer and asbestos in the USA.

The Lancet. Oncology, 19(7):868.

RevDate: 2018-08-05

Garabrant DH, ST Pastula (2018)

A comparison of asbestos fiber potency and elongate mineral particle (EMP) potency for mesothelioma in humans.

Toxicology and applied pharmacology pii:S0041-008X(18)30314-4 [Epub ahead of print].

We analyzed the mesothelioma mortality in cohorts of workers exposed to crocidolite, amosite, and chrysotile to estimate asbestos fiber potency for mesothelioma, using the method of Hodgson and Darnton (2000). We relied on the original 17 cohort studies in their analysis, along with 3 updates of those studies and 3 new asbestos cohort studies published since 2000. We extended the analyses to examine the mesothelioma potency of tremolite in vermiculite from Libby, Montana, and for non-asbestiform elongate mineral particles (EMPs) in taconite iron ore, talc, and South Dakota gold mining. Mesothelioma potency (RMeso) was calculated as the percent of all expected deaths that were due to mesothelioma per fiber/cc-year of exposure. The RMeso was 0.0012 for chrysotile, 0.099 for amosite, and 0.451 for crocidolite: thus, the relative potency of chrysotile:amosite:crocidolite was 1:83:376, which was not appreciably different from the estimates by Hodgson and Darnton in 2000. The RMeso for taconite mining fibers was 0.069 which was slightly greater than that for amosite. The RMeso for Libby fibers was 0.028 which was greater than that for chrysotile and less than that for amosite. Talc and gold mining EMPs were non-potent for mesothelioma. Although there are a number of methods for estimating fiber potency of asbestos and non-asbestiform EMPs, the method of Hodgson and Darnton provides a uniform method by which fiber potency can be compared across many fiber types. Our estimates of RMeso provide a useful addition to our knowledge of mesothelioma potency for different asbestos and non-asbestiform EMP fibers.

RevDate: 2018-08-03

Lin RT, Chang YY, Wang JD, et al (2018)

Upcoming epidemic of asbestos-related malignant pleural mesothelioma in Taiwan: A prediction of incidence in the next 30 years.

Journal of the Formosan Medical Association = Taiwan yi zhi pii:S0929-6646(18)30250-X [Epub ahead of print].

BACKGROUND/PURPOSE: Globally, asbestos-related diseases (ARDs) keep rising over the coming decades. The epidemic of ARDs will be a burden on public health. We aimed to predict the malignant pleural mesothelioma (MPM) incidence in the next 30 years for Taiwan based on historical asbestos consumption.

METHODS: We collected annual data on local asbestos consumption during 1939-2015 and sex-specific incidence of pleural cancer as a proxy for MPM during 1979-2013. We applied Poisson log-linear models to predict future MPM numbers under the assumption that latency periods between asbestos exposure and MPM incidence were between 25 and 45 years.

RESULTS: Asbestos consumption reached a peak in the 1980s, with a total of 668 thousand metric tons during 1939-2015. The observed number of MPM incidence increased by 9- and 6-fold in males and females during 1979-2013, with a cumulative number of 907. Given a latency period of 31 years, MPM incidences were expected to peak around 2012-2016 for males and 2016-2020 for females. In 2017-2046, the predicted total number of new MPM might reach 659 cases (95% confidence interval = 579-749); and the male to female ratios ranged from 1.8 to 2.8.

CONCLUSION: The MPM epidemic in Taiwan will likely peak in 2012-2020 as a result of local asbestos consumption. Approximately 659 new MPM cases in the next 30 years warrant an urgent need to implement a total asbestos ban and put more resources on a comprehensive surveillance, diagnosis, and follow-up health care system for ARDs.

RevDate: 2018-07-31

Sage AP, Martinez VD, Minatel BC, et al (2018)

Genomics and Epigenetics of Malignant Mesothelioma.

High-throughput, 7(3): pii:ht7030020.

Malignant mesothelioma is an aggressive and lethal asbestos-related disease. Diagnosis of malignant mesothelioma is particularly challenging and is further complicated by the lack of disease subtype-specific markers. As a result, it is especially difficult to distinguish malignant mesothelioma from benign reactive mesothelial proliferations or reactive fibrosis. Additionally, mesothelioma diagnoses can be confounded by other anatomically related tumors that can invade the pleural or peritoneal cavities, collectively resulting in delayed diagnoses and greatly affecting patient management. High-throughput analyses have uncovered key genomic and epigenomic alterations driving malignant mesothelioma. These molecular features have the potential to better our understanding of malignant mesothelioma biology as well as to improve disease diagnosis and patient prognosis. Genomic approaches have been instrumental in identifying molecular events frequently occurring in mesothelioma. As such, we review the discoveries made using high-throughput technologies, including novel insights obtained from the analysis of the non-coding transcriptome, and the clinical potential of these genetic and epigenetic findings in mesothelioma. Furthermore, we aim to highlight the potential of these technologies in the future clinical applications of the novel molecular features in malignant mesothelioma.

RevDate: 2018-07-31

Jean D, MC Jaurand (2018)

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis.

International journal of molecular sciences, 19(8): pii:ijms19082191.

Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by Cdkn2a and Trp53 seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation.

RevDate: 2018-07-23

Rosskamp M, De Schutter H, Henau K, et al (2018)

Assessing the completeness and correctness of the registration of malignant mesothelioma in Belgium.

Lung cancer (Amsterdam, Netherlands), 122:38-43.

OBJECTIVES: Malignant mesothelioma (MM) is a rare and aggressive cancer mostly caused by asbestos exposure, and for which the diagnosis is difficult. This study aimed to assess the completeness and correctness of MM registration using 3 independent national databases: the Belgian Cancer Registry (BCR), the population-based mortality statistics (certificates of death, COD), and the Belgian Mesothelioma Registry (BMR).

METHODS: The study cohort included all MM reported to the BCR and diagnosed between 2004 and 2012 (n = 2292), all patients reviewed by the pathology commission of the BMR (2004-2012; n = 2019), and COD data for all Belgian citizens (2004-2013). Available data were compared in terms of registered cases, histological diagnosis, performed immunohistochemical (IHC) tests, and IHC test results.

RESULTS: Comparison of BCR with BMR registrations showed 94.8% concordant cases. The proportion of MM diagnoses originally reported to BCR with unspecified MM morphology was reduced from 25.8% to less than 1%.

RESULTS: from IHC tests were available for 95.3% of concordant MM cases. Different IHC patterns could be distinguished by MM histology. MM cases registered at BCR for which COD mentioned an MM as underlying cause of death represented 76.4% of deceased cases. MM long-term survivors (survival >3 years; 10.9%) were characterised by distinct clinical and biological characteristics.

CONCLUSIONS: A comparison of independent Belgian MM registration databases elucidated under-registration and misclassification and revealed possible reasons for observed discordances. Combining all the available information resulted in enhanced completeness and correctness of MM registration in Belgium and allowed for the identification and characterisation of MM long-term survivors.

RevDate: 2018-07-21

Sonvico F, Barbieri S, Colombo P, et al (2018)

Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences pii:S0928-0987(18)30333-6 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by a long latency period of 20-50 years after exposure to the main aetiology agent that is asbestos. MPM treatments include surgery, chemotherapy, and radiation therapy, with the combination pemetrexed and cisplatin being the standard chemotherapy approach. Despite this multimodality therapy one of the major issues after surgery is the high rate of local recurrence of the tumor. One possible approach would be the intrapleural application of implants loaded with anticancer drug to be applied during surgery to prevent local tumor recurrence. The implant proposed in the present work is a polymeric film of hyaluronic acid loaded with pemetrexed. The film developed is a hydrophilic, thin and flexible film sufficiently resistant to be applied intrapleurally adhering to the mesothelial surface. The release of pemetrexed from the film was found to be complete within2 h in phosphate buffered saline. In an orthotopic model of mesothelioma recurrence in rats, pemetrexed loaded films showed the same antitumor efficacy of pemetrexed disodium solutions administered intravenously or intrapleurally, while when administered in combination with cisplatin-loaded hyaluronate film, the implants almost completely prevented tumor recurrence. The local administration of drug-loaded polymer implants appears an ideal chemotherapy strategy especially for patients in which surgery is already selected as a viable therapeutic option.

RevDate: 2018-07-21

Mossman BT (2018)

Mechanistic in vitro studies: What they have told us about carcinogenic properties of elongated mineral particles (EMPs).

Toxicology and applied pharmacology pii:S0041-008X(18)30331-4 [Epub ahead of print].

In vitro studies using target and effecter cells of mineral-induced cancers have been critical in determining the mechanisms of pathogenesis as well as the properties of elongated mineral particles (EMPs) important in eliciting these responses. Historically, in vitro models of 'mutagenesis' and immortalized cell lines were first used to test the theory that EMPs were mutagenic to cells, and 'genotoxicity', as defined as damage to DNA often culminating in cell death, was observed in a dose-dependent fashion as responses of many cell types to a number of EMPs. As two-stage and multi-step models of cancer development emerged in the 1970s and 1980s, differentiated 3D organ cultures and monolayers of lung epithelial and mesothelial cells were used to probe the mechanisms of cancer development. These studies demonstrated a spectrum of pre-neoplastic changes, including hyperplasia and squamous metaplasia, in response to long (>5 μm in length) needlelike EMPs whereas long, curly chrysotile fibers caused acute cytotoxicity. Shorter fibers of many types were taken up by cells and encompassed in phagolysosomes. Comparative studies using chemical carcinogens showed that chemical agents interacted directly with DNA whereas long EMPs appeared to be promoters of cancers via a number of mechanisms such as inflammation, generation of oxidants, and instigation of cell division. The multitude of these signaling cascades and epigenetic mechanisms of both lung cancers and mesotheliomas have been most recently studied in normal or telomerase immortalized human cells. Importantly, many of these pathways are elicited by long, straight amphibole asbestos fibers or carbon nanotubes in rodents and not by short (<5 μm) EMPs, fragments, or nonfibrous particles. However, the chemistry and surface properties of long fibers are also critical in cell responses to minerals.

RevDate: 2018-07-21

Abello A, Steinkeler J, AK Das (2018)

A BILATERAL METACHRONOUS MESOTHELIOMA OF THE TUNICA VAGINALIS.

Urology pii:S0090-4295(18)30721-0 [Epub ahead of print].

This is a unique case of bilateral metachronous testicular mesothelioma of the tunica vaginalis. Testicular mesothelioma is a rare entity found in patients with or without asbestos occupational exposure. The tumor most commonly presents as a unilateral testicular mass. More rare presentations include bilateral synchronous or metachronous tumors. Treatment is with surgical resection and prognosis is not generally favorable. The benefits of adjuvant therapy with radiation or chemotherapy remain unknown and further studies are needed.

RevDate: 2018-07-19

Panou V, Vyberg M, Meristoudis C, et al (2018)

Non-occupational exposure to asbestos is the main cause of malignant mesothelioma in women in North Jutland, Denmark.

Scandinavian journal of work, environment & health pii:3756 [Epub ahead of print].

Objectives Diffuse malignant mesothelioma (MM) is mainly caused by asbestos inhalation. The malignancy is rare among women and studies of the prevalence and causative role of non-occupational asbestos exposure among women with MM are scarce. This observational study aimed to elucidate the asbestos exposure patterns among women with MM. Methods All histological and cytological specimens from women diagnosed with MM between 1974-2015 at the Institute of Pathology, Aalborg University Hospital in Denmark, were re-evaluated. Occupational and habitation information were obtained from Danish registries and medical journals based on record linkage via the unique person ID. The number of MM cases in each parish in the region of North Jutland was determined and the incidence density in parishes was used to calculate the spatial relative risk (RR) of MM among women. Results Diagnosis of MM was confirmed in 91 women. Exposure types were classified as occupational (9%), domestic (10%), environmental (22%), combination of domestic and environmental (34%) and unknown (25%). Twenty continuous parishes formed a MM "hotspot" around the asbestos-consuming industries in the city of Aalborg. Of these, the maximum RR was found in a parish housing an asbestos factory [RR 10.5, 95% confidence interval (CI) 5.5-19.4, environmental exposure in particular RR 2.9, 95% CI 0.7-6.1]. Conclusion Non-occupational asbestos exposure is the main cause of MM and may account for up to 66% of MM cases among women in North Jutland, Denmark.

RevDate: 2018-07-19

Nabavi N, Wei J, Lin D, et al (2018)

Pre-clinical Models for Malignant Mesothelioma Research: From Chemical-Induced to Patient-Derived Cancer Xenografts.

Frontiers in genetics, 9:232.

Malignant mesothelioma (MM) is a rare disease often associated with environmental exposure to asbestos and other erionite fibers. MM has a long latency period prior to manifestation and a poor prognosis. The survival post-diagnosis is often less than a year. Although use of asbestos has been banned in the United States and many European countries, asbestos is still being used and extracted in many developing countries. Occupational exposure to asbestos, mining, and migration are reasons that we expect to continue to see growing incidence of mesothelioma in the coming decades. Despite improvements in survival achieved with multimodal therapies and cytoreductive surgeries, less morbid, more effective interventions are needed. Thus, identifying prognostic and predictive biomarkers for MM, and developing novel agents for targeted therapy, are key unmet needs in mesothelioma research and treatment. In this review, we discuss the evolution of pre-clinical model systems developed to study MM and emphasize the remarkable capability of patient-derived xenograft (PDX) MM models in expediting the pre-clinical development of novel therapeutic approaches. PDX disease model systems retain major characteristics of original malignancies with high fidelity, including molecular, histopathological and functional heterogeneities, and as such play major roles in translational research, drug development, and precision medicine.

RevDate: 2018-07-20

Strbac D, Goricar K, Dolzan V, et al (2018)

Matrix Metalloproteinases Polymorphisms as Baseline Risk Predictors in Malignant Pleural Mesothelioma.

Radiology and oncology, 52(2):160-166 pii:raon-2018-0005.

Background: Malignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases. Matrix metalloproteinases (MMPs) have been identified as modulators of the tumour microenvironment and carcinogenesis. Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM. The aim of our study was to investigate selected MMP polymorphisms as baseline risk predictors in MM development in combination with other well known risk factors, such as asbestos exposure.

Patients and methods: The study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%-75%), while frequencies were used to describe categorical variables. Deviation from the Hardy-Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs).

Results: Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44-1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35-0.86; P = 0.009). None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma.

Conclusions: The MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction.

RevDate: 2018-07-18

An YS, Kim HD, Kim HC, et al (2018)

The characteristics of asbestos-related disease claims made to the Korea Workers' Compensation and Welfare Service (KCOMWEL) from 2011 to 2015.

Annals of occupational and environmental medicine, 30:45 pii:256.

Background: This study aimed to enhance understanding of the epidemiologic characteristics of asbestos-related diseases, and to provide information that could inform policy-making aimed at prevention and compensation for occupational asbestos exposure, through analyzing asbestos-related occupational disease claims to Korea Workers' Compensation and Welfare Service from 2011 to 2015.

Methods: We analyzed 113 workers who filed medical care claims or survivor benefits for asbestos exposure and occupational-related disease from 2011 to 2015. Among these claims, we selected approved workers' compensation claims relating to malignant mesothelioma and lung cancer, and analyzed the general characteristics, exposure characteristics, pathological characteristics, and occupation and industry distribution.

Results: Malignant mesothelioma and lung cancer occurred predominantly in males at 89.7 and 94%, respectively. The mean age at the time of diagnosis for malignant mesothelioma and lung cancer was 59.5 and 59.7 years, respectively, while the latency period for malignant mesothelioma and lung cancer was 34.1 and 33.1 years, respectively. The companies involving exposed workers were most commonly situated within the Busan-Ulsan-Gyeongnam region. Histology results for lung cancer indicated adenocarcinoma as the most common form, accounting for approximately one half of all claims, followed by squamous cell carcinoma, and small cell lung cancer. The most common occupation type was construction in respect of malignant mesothelioma, and shipbuilding in respect of lung cancer.

Conclusions: Considering the long latency period of asbestos and that the peak period of asbestos use in Korea was throughout the mid-1990s, damage due to asbestos-related diseases is expected to show a continued long-term increase. Few studies providing an epidemiologic analysis of asbestos-related diseases are available; therefore, this study may provide baseline data to assist in predicting and preparing for future harm due to asbestos exposure.

Trial registration: DUIH 2018-02-004-001. Registered 28 Februrary 2018.

RevDate: 2018-07-18

Aguilar-Madrid G, Pesch B, Calderón-Aranda ES, et al (2018)

Biomarkers for Predicting Malignant Pleural Mesothelioma in a Mexican Population.

International journal of medical sciences, 15(9):883-891 pii:ijmsv15p0883.

Background: Diagnosis of malignant pleural mesothelioma (MPM) remains a challenge, especially when resources in pathology are limited. The study aimed to evaluate cost-effective tumor markers to predict the probability of MPM in plasma samples in order to accelerate the diagnostic workup of the tissue of potential cases. Methods: We conducted a case-control study stratified by gender, which included 75 incident cases with MPM from three Mexican hospitals and 240 controls frequency-matched by age and year of blood drawing. Plasma samples were obtained to determine mesothelin, calretinin, and thrombomodulin using enzyme-linked immunosorbent assays (ELISAs). We estimated the performance of the markers based on the area under the curve (AUC) and predicted the probability of an MPM diagnosis of a potential case based on the marker concentrations. Results: Mesothelin and calretinin, but not thrombomodulin were significant predictors of a diagnosis of MPM with AUCs of 0.90 (95% CI: 0.85-0.95), 0.88 (95% CI: 0.82-0.94), and 0.51 (95% CI: 0.41-0.61) in males, respectively. For MPM diagnosis in men we estimated a true positive rate of 0.79 and a false positive rate of 0.11 for mesothelin. The corresponding figures for calretinin were 0.81 and 0.18, and for both markers combined 0.84 and 0.11, respectively. Conclusions: We developed prediction models based on plasma concentrations of mesothelin and calretinin to estimate the probability of an MPM diagnosis. Both markers showed a good performance and could be used to accelerate the diagnostic workup of tissue samples in Mexico.

RevDate: 2018-07-17

Kittaneh M, C Berkelhammer (2018)

Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members.

Journal of translational medicine, 16(1):194 pii:10.1186/s12967-018-1559-7.

Germline mutations in the BRCA-1 associated tumor protein 1 (BAP1) increase susceptibility to mesothelioma and other cancers. We describe a patient with a family history of peritoneal mesothelioma, who developed malignant peritoneal mesothelioma at age 45 in the absence of known asbestos exposure. These findings lead us to hypothesize that the mesothelioma occurred in the setting of germline a BAP1 mutation. This was confirmed by genetic testing. The subsequent therapeutic choices for the patient and testing of at-risk family members highlight the importance of recognizing this genetic syndrome and screening for individuals at high risk.

RevDate: 2018-07-12

Fazzo L, Minelli G, De Santis M, et al (2018)

Epidemiological surveillance of mesothelioma mortality in Italy.

Cancer epidemiology, 55:184-191 pii:S1877-7821(18)30108-5 [Epub ahead of print].

BACKGROUND: Malignant mesothelioma (MM) is causally linked to asbestos exposure with an estimated etiological fraction of 80% or more.

METHODS: Standardized rates of all mesothelioma (C45, ICD-10) and malignant pleural mesothelioma (C45.0, ICD-10) mortality in Italy were computed at national and regional levels, for the period 2003-2014. Standardized Mortality Ratios (SMRs, with 95% Confidence Intervals) were calculated for each of the 8047 Italian municipalities, for both diseases, with respect to Regional figures. A geographical clustering analysis at municipal level was performed, applying SatScan methods.

RESULTS: In Italy, 16,086 persons (about 1,340/year) died for MM, in analysed period. National Standardized rates of MM mortality are 3.65/100,000 in men and 1.09/100,000 in women, with an increasing annual trend, among male population. The highest rates were found in men from Northern Regions. Significant clusters (p < 0.10) were found corresponding to areas that hosted major asbestos-cement plants, naval shipyards, petrochemical plants and refineries. Furthermore, excesses were found corresponding to chemical and textile industries; the latter involving, particularly, female population. Excesses were found also in areas near the chrysotile mine of Balangero, and in Biancavilla, a town with a stone quarry contaminated by fluoro-edenitic fibres; an excess of MM mortality was observed among male population living in a minor island where a Navy shipyard is located.

CONCLUSIONS: Mortality for mesothelioma in Italy is still increasing, twenty-six years after the asbestos ban. Epidemiological surveillance of mesothelioma mortality allows to detect the temporal trend of the disease and highlights previously unknown or underestimated sources of asbestos exposure.

RevDate: 2018-07-08

Dragani TA, Colombo F, Pavlisko EN, et al (2018)

Malignant mesothelioma diagnosed at a younger age is associated with heavier asbestos exposure.

Carcinogenesis pii:5047164 [Epub ahead of print].

Asbestos exposure is the main etiology of malignant mesothelioma, but there are conflicting data on whether the intensity of exposure modulates the development of this disease. This study considered 594 patients with malignant mesothelioma for whom count data on asbestos bodies and fibers (per gram of wet lung tissue) were available. The relationships between age at diagnosis (a time-to-event outcome variable) and these two measures of internal asbestos exposure, along with other possible modulating factors (sex, tumor location, histological subtype, and childhood exposure), were assessed on multivariable Cox proportional hazard models, stratifying by decade of birth year. For both measures of asbestos in lung tissue, younger age at diagnosis was associated with higher internal measures of exposure to asbestos. Stratified Cox analyses showed that for each doubling in asbestos body count patients were 1.07-times more likely to be diagnosed at a younger age (HR = 1.07; 95% CI, 1.04 - 1.09; P = 2.4 x 10-7), and for each doubling in asbestos fiber count patients were 1.13-times more likely to be diagnosed at a younger age (HR = 1.13; 95% CI, 1.09 - 1.17; P = 5.6 x 10-11). None of the other variables considered was associated with age at diagnosis. Our finding that tumors become clinically apparent at a younger age in heavily exposed subjects suggests that asbestos is involved not only in the of malignant mesothelioma tumor initiation but, somehow, also in the progression of the disease.

RevDate: 2018-07-08

Pranay P, Serafimov V, Hall J, et al (2018)

Metastatic biphasic pleural mesothelioma presenting with cauda equina syndrome.

Radiology case reports, 13(3):736-739 pii:S1930-0433(18)30051-7.

Patient with previous asbestos exposure on a watchful wait and watch regime presents acutely with cauda equina syndrome. Radiological imaging confirmed a mass with direct invasion of the spinal cord. Histology confirmed metastatic pleural mesothelioma.

RevDate: 2018-07-04

Jones RG, Karthik F, Dugar A, et al (2018)

Nivolumab Immunotherapy in Malignant Mesothelioma: A Case Report Highlighting a New Opportunity for Exceptional Outcomes.

The American journal of case reports, 19:783-789 pii:909584.

BACKGROUND Malignant pleural mesothelioma (MPM) is a highly lethal cancer with a median survival of ~12 months even with aggressive intervention. Frontline therapy relies on systemic cisplatin and pemetrexed chemotherapy and has a response rate of ~35-41%; currently, there are no US Food and Drug Administration approved second-line therapies for MPM. Herein, we present a patient with MPM who experienced rapid disease progression after standard therapy but who had an exceptional and sustained response to immune checkpoint inhibition with single agent nivolumab. CASE REPORT A 68-year-old male with a history of work-related asbestos exposure was diagnosed with MPM. He was treated with primary resection followed by systemic chemotherapy with cisplatin and pemetrexed. When chemotherapy failed, he was switched to immunotherapy with nivolumab and achieved an exceptional response. CONCLUSIONS We report the first case of a patient with MPM who experienced rapid disease progression after standard therapy but had an exceptional and sustained response to immune checkpoint inhibition with single agent nivolumab. As outcomes with traditional chemotherapy regimens remain disappointing, there is a substantial need for new approaches to MPM; our case highlights a new therapeutic opportunity even in the face of aggressive disease. Indeed, a new era of investigation utilizing immunotherapy for mesothelioma is beginning, with much anticipation.

RevDate: 2018-07-03

Mutti L, Peikert T, Robinson BWS, et al (2018)

State of the Art: Concise Review Scientific Advances and New Frontiers in Mesothelioma Therapeutics.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(18)30720-2 [Epub ahead of print].

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that arises from the mesothelial surface of the pleural and peritoneal cavities, the pericardium, and rarely, the tunica vaginalis. The incidence of MPM is expected to increase worldwide in the next two decades. However, even with the use of multimodality treatment, MPM remains challenging to treat with a 5-year survival rate of less than 5%. The International Association for the Study of Lung Cancer has gathered experts in different areas of mesothelioma research and management to summarize the most significant scientific advances and new frontiers related to mesothelioma therapeutics.

RevDate: 2018-07-01

Hylebos M, Op de Beeck K, van den Ende J, et al (2018)

Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma.

Familial cancer pii:10.1007/s10689-018-0095-1 [Epub ahead of print].

Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somatic BAP1 variant. Also, no germline or somatic copy number changes in the BAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other 'Cancer census genes' (i.e. MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 and MYO5A). Of these, the one in RBM15 seems to be the most interesting given its low minor allele frequency and absence in the germline DNA of the index patient's mother. The importance of this 'Cancer census gene' in familial MM clustering needs to be evaluated further. Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.

RevDate: 2018-07-14

Kane AB, Hurt RH, H Gao (2018)

The asbestos-carbon nanotube analogy: An update.

Toxicology and applied pharmacology pii:S0041-008X(18)30294-1 [Epub ahead of print].

Nanotechnology is an emerging industry based on commercialization of materials with one or more dimensions of 100 nm or less. Engineered nanomaterials are currently incorporated into thin films, porous materials, liquid suspensions, or filler/matrix nanocomposites with future applications predicted in energy and catalysis, microelectronics, environmental sensing and remediation, and nanomedicine. Carbon nanotubes are one-dimensional fibrous nanomaterials that physically resemble asbestos fibers. Toxicologic studies in rodents demonstrated that some types of carbon nanotubes can induce mesothelioma, and the World Health Organization evaluated long, rigid multiwall carbon nanotubes as possibly carcinogenic for humans in 2014. This review summarizes key physicochemical similarities and differences between asbestos fibers and carbon nanotubes. The "fiber pathogenicity paradigm" has been extended to include carbon nanotubes as well as other high-aspect-ratio fibrous nanomaterials including metallic nanowires. This paradigm identifies width, length, and biopersistence of high-aspect-ratio fibrous nanomaterials as critical determinants of lung disease, including mesothelioma, following inhalation. Based on recent theoretical modeling studies, a fourth factor, mechanical bending stiffness, will be considered as predictive of potential carcinogenicity. Novel three-dimensional lung tissue platforms provide an opportunity for in vitro screening of a wide range of high aspect ratio fibrous nanomaterials for potential lung toxicity prior to commercialization.

RevDate: 2018-07-20

Roggli VL (2018)

Measuring EMPs in the lung what can be measured in the lung: Asbestiform minerals and cleavage fragments.

Toxicology and applied pharmacology pii:S0041-008X(18)30293-X [Epub ahead of print].

Asbestos mineral fibers have been associated with the development of a variety of diseases in humans and experimental animals, including asbestosis, lung cancer, and mesothelioma. Asbestos includes several mineral types divided into two mineral groups, serpentine and amphibole forms. Chrysotile is the serpentine mineral classified as asbestos, whereas the amphiboles include amosite, crocidolite, tremolite, actinolite and anthophyllite. There are a number of mineral fibers that occur with asbestiform morphology and that have been associated with various asbestos-induced diseases. These include the Libby amphiboles (associated with a vermiculite mine northwest of Libby, MT), erionite (in Turkey and North America), fluoro-edenite (in Sicily), and perhaps balangeroite (in Italy). In addition, each of the asbestos minerals occurs in a non-fibrous form, and these may occur as cleavage fragments that satisfy the definition for a fiber, i.e., particles with an aspect ratio of at least 3:1 and roughly parallel sides. Cleavage fragments of non-asbestiform minerals have not been associated with asbestos-induced diseases nor are these minerals regulated by the Occupational Safety and Health Administration. Finally, there are a number of other mineral species which can occur in human lung samples that satisfy the definition for a fiber as given above. These similarly have not been associated with asbestos-induced diseases. All of these various minerals satisfying the definition for a fiber can be referred to as elongated mineral particles (EMP). It is the purpose of this presentation to discuss the role of scanning electron microscopy (SEM) equipped with an energy dispersive x-ray analyzer (EDXA) in the detection and classification of EMP in human lung samples.

RevDate: 2018-06-28

Colin DJ, Cottet-Dumoulin D, Faivre A, et al (2018)

Experimental Model of Human Malignant Mesothelioma in Athymic Mice.

International journal of molecular sciences, 19(7): pii:ijms19071881.

Malignant pleural mesothelioma (MPM) is a thoracic aggressive cancer caused by asbestos exposure, which is difficult to diagnose and treat. Here, we characterized an in vivo orthotopic xenograft model consisting of human mesothelioma cells (designed as H2052/484) derived from a pleural NCI-H2052 tumor injected in partially immunodeficient athymic mice. We assessed tumor formation and tumor-dependent patterns of inflammation. H2052/484 cells conserved their mesothelioma phenotype and most characteristics from the parental NCI-H2052 cells. After intra-thoracic injection of H2052/484 cells, thoracic tumors developed in nearly all mice (86%) within 14 days, faster than from parental NCI-H2052 cells. When the mice were euthanized, the pleural lavage fluid was examined for immune cell profiles. The pleural immune cell population increased with tumor development. Interestingly, the proportion of myeloid-derived suppressor cell and macrophage (especially CD206⁺ M2 macrophages) populations increased in the pleural fluid of mice with large mesothelioma development, as previously observed in immunocompetent mice. This reliable orthotopic model recapitulates human mesothelioma and may be used for the study of new treatment strategies.

RevDate: 2018-06-29

Bensaid D, Blondy T, Deshayes S, et al (2018)

Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma.

Clinical epigenetics, 10:79 pii:517.

Background: Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really efficient treatments are available for this pathology. Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells. We previously showed that a hypomethylating agent (decitabine) and a histone deacetylase inhibitor (HDACi) (valproic acid (VPA)) combination was immunogenic and led to the induction of an anti-tumor immune response in a mice model of mesothelioma. However, VPA is not very specific, is active at millimolar concentrations and is responsible for side effects in clinic. To improve this approach, we studied four newly synthetized HDACi, two hydroxamates (ODH and NODH) and two benzamides (ODB and NODB), in comparison with VPA and SAHA. We evaluated their toxicity on immune cells and their immunogenicity on MPM cells in combination with decitabine.

Results: All the tested HDACi were toxic for immune cells at high concentrations. Combination with decitabine increased toxicity of HDACi only towards T-cell clone. A decrease in the proportion of regulatory T cells and natural killer cells was observed in particular with VPA and ODH. In MPM cells, all HDACi combinations induced NY-ESO-1 cancer testis antigen (CTA) expression and the recognition of the treated cells by a NY-ESO-1 specific T-CD8 clone. However, for MAGE-A1, MAGE-A3 and XAGE-1b mRNA expression, the results obtained depended on the HDACi used and on the CTA studied. Depending on the MPM cell line studied, molecules alone increased moderately PD-L1 expression. When combined, a higher stimulation of this immune check point inhibitor expression was observed. Decitabine-induced anti-viral response seemed to be inhibited in the presence of HDACi.

Conclusions: This work shows that the combination of decitabine and HDACi could be of interest for MPM immunotherapy. However, this combination induced PD-L1 expression which suggests that an association with anti-PD-L1 therapy should be performed to induce an efficient anti-tumor immune response.

RevDate: 2018-06-22

Cox LAT (Jr) (2018)

Biological mechanisms of non-linear dose-response for respirable mineral fibers.

Toxicology and applied pharmacology pii:S0041-008X(18)30282-5 [Epub ahead of print].

Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation. As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses? Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds.

RevDate: 2018-06-24

Blum W, Henzi T, Châtel-Soulet HE, et al (2018)

Absence of calretinin protein expression in malignant mesotheliomas from asbestos-exposed NF2+/- mice and mouse mesothelioma cell lines from various mouse strains.

Biomarker research, 6:19 pii:132.

Background: Calretinin is the most widespread positive marker for the immunohistochemical identification of malignant mesothelioma (MM) and was proposed to serve as a blood-based biomarker. Functionally, evidence has accumulated that calretinin might be implicated in MM tumorigenesis. We aimed to identify calretinin (CR; Calb2) in murine MM and reactive mesothelial cells in granuloma from asbestos-exposed NF2+/- mice, a line heterozygous for the tumor suppressor merlin (NF2), used as a mouse MM model. Additionally, we sought to ascertain the presence of calretinin in MM cell lines from other mouse strains. We also intended to investigate the role of calretinin in mesotheliomagenesis by comparing the survival of asbestos-exposed NF2+/- and NF2+/-CR-/- mice.

Methods: NF2+/- and NF2+/-CR-/- mice, both lines on a C57Bl/6J background, were exposed to asbestos following an established protocol. Tumor histology and asbestos-induced mortality were assessed. MM and granuloma from NF2+/- mice were analyzed with immunohistochemical methods for calretinin expression. Levels of Calb2 mRNA and calretinin expression in tumors and MM cell lines of various mouse strains were determined by RT-qPCR and Western blot analysis, respectively.

Results: No expression of calretinin at the protein level was detected, neither in MM from NF2+/- mice, NF2+/- MM-derived cell lines nor immortalized mesothelial cells of mouse origin. At the mRNA level we detected Calb2 expression in MM cell lines from different mouse strains. Survival of NF2+/- and NF2+/-CR-/- mice exposed to asbestos showed no significant difference in a log-rank (Kaplan-Meier) comparison.

Conclusions: The concomitant determination of calretinin and mesothelin blood levels has been proposed for early detection of human MM. Mouse MM models based on asbestos exposure are assumed to yield helpful information on the time course of appearance of mesothelin and calretinin in the blood of asbestos-treated mice determining the earliest time point for interventions. However, the observed absence of calretinin in MM from NF2+/- mice and derived cell lines, as well as from MM cells from Balb/c and C3H mice likely precludes the use of calretinin as a biomarker for mouse MM. The results also indicate possible species differences with respect to an involvement of calretinin in the formation of MM.

RevDate: 2018-06-19

Granieri A, Borgogno FV, Franzoi IG, et al (2018)

Development of a Brief Psychoanalytic Group therapy (BPG) and its application in an asbestos national priority contaminated site.

Annali dell'Istituto superiore di sanita, 54(2):160-166.

The aim of the present paper is to describe the development of a Brief Psychoanalytic Group therapy for contaminated sites and its application in the National Priority Contaminated Site of Casale Monferrato. Before presenting the core of the clinical intervention, a brief examination of some clinical features encountered working with malignant mesothelioma patients and their caregivers is offered. These aspects have been pivotal elements in the construction of a psychoanalytically oriented time-limited (i.e., 12 sessions) group therapy. This model of intervention was designed by one of the Authors (AG) and is aimed at reducing the impact of living in a threatening place where both physical well-being and health are put to the test. At a psychological level, in fact, living in contaminated sites arouses death anxieties, which can deeply compromise the quality of time remaining to live together with loved ones after a fatal cancer diagnosis.

RevDate: 2018-06-19

Comba P, D'Angelo M, Fazzo L, et al (2018)

Mesothelioma in Italy: the Casale Monferrato model to a national epidemiological surveillance system.

Annali dell'Istituto superiore di sanita, 54(2):139-148.

The purpose of the present paper is to review the origin and development of the epidemiology of mesothelioma in Italy, starting with the detection and investigation of the major outbreak of the disease observed in Casale Monferrato, Piedmont Region. Over the last four decades, mortality among the cohort of ex-Eternit workers has been measured at three points in time. More recently, population based case-control studies in the area of Casale Monferrato have provided new light on the dose-response curve of the relationship between asbestos exposure and mesotheliomas. The publication of the first Casale Monferrato study had a major impact in the country and contributed to the decision of the Italian Parliament to ban the use of asbestos. The experience of Casale Monferrato represents a lesson in several terms, from the epidemiological surveillance to the health care of the victims and the relationship between epidemiologists, victims, their relatives and residents in contaminated areas.

RevDate: 2018-06-21

Losi L, Botticelli L, Taccagni G, et al (2018)

Malignant peritoneal mesothelioma in a woman with bilateral ovarian serous borderline tumour: Potential interactions between the two diseases.

Gynecologic oncology reports, 24:39-42 pii:S2352-5789(18)30020-1.

We report a case of a 59-year-old woman with peritoneal malignant mesothelioma and no previous exposure to asbestos with a diagnosis of bilateral ovarian serous borderline tumour with peritoneal implants one year before. We discuss the histopathological and immunohistochemical findings to explain possible and potential interactions between the two diseases. To our knowledge, the association of both serous borderline ovarian tumour and malignant peritoneal mesothelioma has never been described before in the same woman and in such a tight temporal connection. This finding raises numerous issues about the origin of the two tumours and further biomolecular studies are needed to fully understand the carcinogenetic process. From a clinical point of view, this case report can be useful to gynaecologists because it leads to recommend a careful examination of the peritoneal cavity during a surgical resection of borderline serous tumour. Moreover, it may suggest performing a close follow-up associated with a careful surveillance of the patient, especially in the case of micropapillary pattern, to oncologists. A complete clinical approach could help to detect sooner possible relapses or other metachronous malignancies.

RevDate: 2018-07-10

Ledda C, Senia P, V Rapisarda (2018)

Biomarkers for Early Diagnosis and Prognosis of Malignant Pleural Mesothelioma: The Quest Goes on.

Cancers, 10(6): pii:cancers10060203.

Malignant pleural mesothelioma (MM) is a highly aggressive tumor characterized by a poor prognosis. Although its carcinogenesis mechanism has not been strictly understood, about 80% of MM can be attributed to occupational and/or environmental exposure to asbestos fibers. The identification of non-invasive molecular markers for an early diagnosis of MM has been the subject of several studies aimed at diagnosing the disease at an early stage. The most studied biomarker is mesothelin, characterized by a good specificity, but it has low sensitivity, especially for non-epithelioid MM. Other protein markers are Fibulin-3 and osteopontin which have not, however, showed a superior diagnostic performance. Recently, interesting results have been reported for the HMGB1 protein in a small but limited series. An increase in channel proteins involved in water transport, aquaporins, have been identified as positive prognostic factors in MM, high levels of expression of aquaporins in tumor cells predict an increase in survival. MicroRNAs and protein panels are among the new indicators of interest. None of the markers available today are sufficiently reliable to be used in the surveillance of subjects exposed to asbestos or in the early detection of MM. Our aim is to give a detailed account of biomarkers available for MM.

RevDate: 2018-07-01

Utell MJ, LD Maxim (2018)

Refractory ceramic fibers: Fiber characteristics, potential health effects and clinical observations.

Toxicology and applied pharmacology pii:S0041-008X(18)30269-2 [Epub ahead of print].

Refractory ceramic fibers (RCFs) are amorphous fibers that belong to a class of materials termed synthetic vitreous fibers (SVFs), also called man-made mineral fibers (MMMFs), which includes alkaline earth silicate wool, glass wool, rock (stone) wool, slag wool, and special-purpose glass fibers. RCFs are more durable and biopersistent than several other SVFs, although very much less biopersistent than either amosite or crocidolite asbestos. Chronic inhalation studies indicated that rats and hamsters exposed to RCF fibers developed fibrosis and tumors. Epidemiological studies at the University of Cincinnati funded by the Industry indicated that exposed workers; (1) exhibited symptoms (e.g., dyspnea) similar to those reported in other dust-exposed populations, (2) developed statistically, but not clinically, significant deficits in certain measures of pulmonary function in a cross sectional study, but no excessive decline in a longitudinal study, and (3) a dose related increase in pleural plaques, but no interstitial fibrosis. The 2003 mortality study indicated no incremental lung cancer and no cases of mesothelioma. RCF producers developed a comprehensive industry wide product stewardship program (PSP) beginning in the late 1980s. In conjunction with the PSP, there has been a progressive decrease in the TWA concentration of fibers by manufacturers and end-users. The research program has successfully produced more soluble fibers and undertaken efforts to develop larger diameter fibers. The results of the ongoing epidemiology studies confirm that occupational exposure to RCF is associated with the development of pleural plaques and minor decrements in lung function, but no interstitial fibrosis or incremental lung cancer.

RevDate: 2018-07-14

Tweedale G, B Castleman (2018)

Jock McCulloch (1945-2018): A Tribute.

International journal of health services : planning, administration, evaluation, 48(3):586-591.

Jock William McCulloch, who died at Melbourne, Australia, in January 2018, was one of the foremost historians of occupational health of his generation. This tribute reviews his career and oeuvre, which was tragically ended by his death from mesothelioma.

RevDate: 2018-06-05

Barbiero F, Zanin T, Pisa FE, et al (2018)

Cancer incidence in a cohort of asbestos-exposed workers undergoing health surveillance.

International archives of occupational and environmental health pii:10.1007/s00420-018-1326-3 [Epub ahead of print].

OBJECTIVES: To compare a local cohort of 2488 men occupationally exposed to asbestos and enrolled in a public health surveillance program with the 1995-2009 cancer incidence of the general population of Friuli Venezia Giulia (FVG) region, Northeast Italy, we conducted a historical cohort study.

METHODS: Standardized incidence ratios (SIRs), with 95% confidence interval (95% CI), for specific cancer sites were estimated in the cohort and in subgroups of workers employed in shipbuilding between 1974 and 1994. For internal comparisons, we calculated incidence rate ratios (IRRs) for all cancers, lung cancer and mesothelioma, by level of exposure to asbestos and sector of employment adjusted for smoking habits and age at start of follow-up.

RESULTS: Among cohort members the SIR was 8.82 (95% CI 5.95-12.61) for mesothelioma and 1.61 (95% CI 1.26-2.04) for lung cancer. In subgroup analyses, the SIR for lung cancer in subjects hired in shipbuilding between 1974 and 1984 was 2.09 (95% CI 1.32-3.13). In the overall cohort, a borderline increased incidence was also found for stomach cancer (SIR = 1.53 95% CI 0.96-2.31). Internal comparisons within the cohort show that among men with high asbestos exposure level the relative risk was almost threefold for lung cancer (IRR = 2.94 95% CI 1.01-8.57).

CONCLUSIONS: This cohort experienced an excess in the incidence of both mesothelioma and lung cancer, showing increasing incidence rates at higher level of asbestos exposure. For lung cancer, the relative incidence was highest among workers hired in shipbuilding between 1974 and 1984.

RevDate: 2018-06-01

Fujimoto N, Aoe K, Kozuki T, et al (2018)

A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol.

Clinical lung cancer pii:S1525-7304(18)30106-2 [Epub ahead of print].

BACKGROUND: The purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM).

PATIENTS AND METHODS: Patients with untreated, advanced, or metastatic MPM who meet the inclusion and exclusion criteria will be included. A total of 18 patients will be enrolled from 4 Japanese institutions within 1 year. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/person) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient's condition meets the withdrawal criteria. The primary end point is the centrally reviewed overall response rate. The secondary end points include the disease control rate, overall survival, progression-free survival, and adverse events.

CONCLUSION: This phase II trial evaluating first-line combination chemotherapy for unresectable MPM commenced in January 2018. This is the first prospective trial to evaluate the effect of an anti-programmed death-1 antibody combined with cisplatin and pemetrexed for unresectable MPM.

RevDate: 2018-06-03

Ahmadzada T, Reid G, S Kao (2018)

Biomarkers in malignant pleural mesothelioma: current status and future directions.

Journal of thoracic disease, 10(Suppl 9):S1003-S1007.

RevDate: 2018-07-13

Saji T, Nishita M, Ogawa H, et al (2018)

Critical role of the Ror-family of receptor tyrosine kinases in invasion and proliferation of malignant pleural mesothelioma cells.

Genes to cells : devoted to molecular & cellular mechanisms, 23(7):606-613.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis and closely related to exposure to asbestos. MPM is a heterogeneous tumor with three main histological subtypes, epithelioid, sarcomatoid, and biphasic types, among which sarcomatoid type shows the poorest prognosis. The Ror-family of receptor tyrosine kinases, Ror1 and Ror2, is expressed in various types of tumor cells at higher levels and affects their aggressiveness. However, it is currently unknown whether they are expressed in and involved in aggressiveness of MPM. Here, we show that Ror1 and Ror2 are expressed in clinical specimens and cell lines of MPM with different histological features. Studies using MPM cell lines indicate that expression of Ror2 is associated tightly with high invasiveness of MPM cells, whereas Ror1 can contribute to their invasion in the absence of Ror2. However, both Ror1 and Ror2 promote proliferation of MPM cells. We also show that promoted invasion and proliferation of MPM cells by Ror signaling can be mediated by the Rho-family of small GTPases, Rac1, and Cdc42. These findings elucidate the critical role of Ror signaling in promoting invasion and proliferation of MPM cells.

RevDate: 2018-05-31

Tartarone A, Lerose R, M Aieta (2018)

Is there a role for immunotherapy in malignant pleural mesothelioma?.

Medical oncology (Northwood, London, England), 35(7):98 pii:10.1007/s12032-018-1156-x.

Malignant pleural mesothelioma (MPM) is a very aggressive malignancy, mainly caused by asbestos exposure. Patients with MPM have a poor prognosis that remained substantially unchanged in the last few years and limited effective therapeutic options with no recognized second or further-line therapy. In this context, also in view of the positive results observed in other tumor types, immunotherapy could play a relevant role. This review focuses on the most promising immunotherapies being investigated in MPM.

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