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The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009–2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally via image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including BAP-1 and CDKN2A (p16) for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pre-therapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.

Purpose: Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinicobiological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies.Experimental Design: Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels.Results: Unsupervised hierarchical clustering on transcriptomic data defined two robust MPM subgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype.Conclusions: A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established. Clin Cancer Res; 20(5); 1323-34. Ó2014 AACR.

aaAsbestos comprises a group of six hydrated silicate minerals capable of forming very thin fibres: chrysotile, crocidolite, amosite, anthophyllite, tremolite and actinolite [1]. Chrysotile belongs to the serpentine group and the other five to the amphibole group of minerals. Chrysotile fibre bundles split easily and magnesium can be leached under weak acid conditions. These factors may contribute to the lower biopersistence of chrysotile in the lungs.

A hospital-based case-control study of the association between past occupational exposure to asbestos and pleural mesothelioma was carried out in five regions of France. Between 1987 and 1993, 405 cases and 387 controls were interviewed. The job histories of these subjects were evaluated by a group of experts for exposure to asbestos fibers according to probability, intensity, and frequency. A cumulative exposure index was calculated as the product of these three parameters and the duration of the exposed job, summed over the entire working life. Among men, the odds ratio increased with the probability of exposure and was 1.2 (95% confidence interval (CI) 0.8-1.9) for possible exposure and 3.6 (95% CI 2.4-5.3) for definite exposure. A dose-response relation was observed with the cumulative exposure index: The odds ratio increased from 1.2 (95% CI 0.8-1.8) for the lowest exposure category to 8.7 (95% CI 4.1-18.5) for the highest. Among women, the odds ratio for possible or definite exposure was 18.8 (95% CI 4.1-86.2). We found a clear dose-response relation between cumulative asbestos exposure and pleural mesothelioma in a population-based case-control study with retrospective assessment of exposure. A significant excess of mesothelioma was observed for levels of cumulative exposure that were probably far below the limits adopted in most industrial countries during the 1980s.

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BackgroundAlthough major concerns exist regarding the potential consequences of human exposure to nanoparticles (NP), no human toxicological data is currently available. To address this issue, we took welders, who present various adverse respiratory outcomes, as a model population of occupational exposure to NP.The aim of this study was to evaluate if welding fume-issued NP could be responsible, at least partially, in the lung alterations observed in welders.MethodsA combination of imaging and material science techniques including ((scanning) transmission electron microscopy ((S)TEM), energy dispersive X-ray (EDX), and X-ray microfluorescence (μXRF)), was used to characterize NP content in lung tissue from 21 welders and 21 matched control patients. Representative NP were synthesized, and their effects on macrophage inflammatory secretome and migration were evaluated, together with the effect of this macrophage inflammatory secretome on human lung primary fibroblasts differentiation.ResultsWelding-related NP (Fe, Mn, Cr oxides essentially) were identified in lung tissue sections from welders, in macrophages present in the alveolar lumen and in fibrous regions. In vitro macrophage exposure to representative NP (Fe2O3, Fe3O4, MnFe2O4 and CrOOH) induced the production of a pro-inflammatory secretome (increased production of CXCL-8, IL-1ß, TNF-α, CCL-2, −3, −4, and to a lesser extent IL-6, CCL-7 and −22), and all but Fe3O4 NP induce an increased migration of macrophages (Boyden chamber). There was no effect of NP-exposed macrophage secretome on human primary lung fibroblasts differentiation.ConclusionsAltogether, the data reported here strongly suggest that welding-related NP could be responsible, at least in part, for the pulmonary inflammation observed in welders. These results provide therefore the first evidence of a link between human exposure to NP and long-term pulmonary effects.

WRA declined in France over the study period. The only significant increase concerned WRA related to exposure to quaternary ammonium compounds. Zero-inflated negative binomial and logistic regression models appear to describe adequately these data.