Previous Asbestos Exposure Research Articles

Prise en charge diagnostique et thérapeutique du mésothéliome pleural en 2024

Pleural mesothelioma (PM) is a quite rare tumor, usually due to previous asbestos exposure. Its global prognosis is poor, without validated curative treatment to date. Diagnosis relies ideally on thoracoscopy with pleural biopsies, ± combined with (immediate) talc pleurodesis. Surgery with curative intent, included with multimodal treatment and restrained to highly selected patients, was recently rechallenged. As frontline treatment, standard pemetrexed/platinum-based chemotherapy was lightly improved by addition of bevacizumab. It is currently challenged by the immunotherapy combination of Nivolumab + Ipilimumab, and perhaps soon by combinations of chemotherapy + immunotherapy. No standard treatment is firmly validated beyond first line treatment, even if anti-PD-1/PD-L1 ± anti-CTLA-4 checkpoint inhibitors also exhibited some interesting results in this setting, in phase II and III clinical trials. Therefore, the search of new treatments, strategies and biomarkers is a crucial goal, and recruitment of patients in clinical trials strongly encouraged. Other immunotherapies alone or combined with standard treatments and/or targeted therapies, multimodal strategies are currently assessed. In France, the national network of expert centers for PM management, “NETMESO” (labelled by INCa), aims at proposing an optimal management to all patients systematically discussed in regional (± national) MTB dedicated to PM, and at stimulating clinical and translational research in collaboration with its partners including patients advocating associations.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Atypical presentation of testicular mesothelioma

Mesothelioma is a rare cancer that generally affects the lining of the lungs. However, in more rare cases, there are extra-pleural involvement of organs that are lined with mesothelial cells, including the testicle. Mesothelioma of the tunica vaginalis of the testicle typically presents with a painless scrotal mass with accompanying hydrocele of the affected side. The most common predisposition to mesothelioma of the tunica vaginalis is previous asbestos exposure, long-standing hydrocele, and previous scrotal surgeries. In this case we present a patient with isolated left tunica vaginalis mesothelioma of the testicle, yet without classic risk factors or other sites of disease. Left radical orchiectomy was performed and subsequent follow-up imaging did not reveal any sites of recurrence or metastasis. Although, mesothelioma of the tunica vaginalis is a rare cancer, it should be seen as a possible differential when evaluating new testicular masses.

Does previous asbestos exposure increase the risk of a post coronary artery bypass graft (CABG) pleural effusion – a routine data study?

BackgroundDevelopment of pleural effusion (PE) following CABG is common. Post-CABG PE are divided into early- (within 30 days of surgery) and delayed-onset (30 days–1 year) which are likely due to distinct pathological processes. Some experts suggest asbestos exposure may confer an independent risk for late-onset post-CABG PE, however no large studies have explored this potential association.Research questionTo explore possible association between asbestos exposure and post-CABG PE using routine data.MethodsAll patients who underwent CABG 01/04/2013–31/03/2018 were identified from the Hospital Episode Statistics (HES) Database. This England-wide population was evaluated for evidence of asbestos exposure, pleural plaques or asbestosis and a diagnosis of PE or PE-related procedure from 30 days to 1 year post-CABG. Patients with evidence of PE three months prior to CABG were excluded, as were patients with a new mesothelioma diagnosis.Results68,150 patients were identified, of whom 1,003 (1%) were asbestos exposed and 2,377 (3%) developed late-onset PE. After adjusting for demographic data, Index of Multiple Deprivation and Charlson Co-morbidity Index, asbestos exposed patients had increased odds of PE diagnosis or related procedure such as thoracentesis or drainage (OR 1.35, 95% CI 1.03–1.76, p = 0.04). In those with evidence of PE requiring procedure alone, the adjusted OR was 1.66 (95% CI 1.14–2.40, p = 0.01). Additional subgroup analysis of the 518 patients coded for pleural plaques and asbestosis alone revealed an adjusted OR of post-CABG PE requiring a procedure of 2.16 (95% CI 1.38–3.37, p = 0.002).InterpretationThis large-scale study demonstrates prior asbestos exposure is associated with modestly increased risk of post-CABG PE development. The risk association appears higher in patients with assigned clinical codes indicative of radiological evidence of asbestos exposure (pleural plaques or asbestosis). This association may fit with a possible inflammatory co-pathogenesis, with asbestos exposure ‘priming’ the pleura resulting in greater propensity for PE evolution following the physiological insult of CABG surgery. Further work, including prospective studies and clinicopathological correlation are suggested to explore this further.

Malignant peritoneal mesothelioma with unresolving haemorrhagic ascites- A case report

Peritoneal mesothelioma being a rare tumor is difficult to diagnose and start treatment. Pleura is the most common area being affected by mesothelioma, peritoneum being the second common site, and in some cases synchronous pleural and peritoneal mesotheliomas are observed (30–45% of the cases). The presentation of mesothelioma is not up to mark leading to difficulty in diagnosis due to lack of specific symptoms and clinical findings. In addition, in the absence of previous asbestos exposure a delay in the diagnosis is not rare. Here we report a case of malignant peritoneal mesotheliomas. The diagnostic and therapeutic approaches for these rare neoplasms are discussed. A 24 year old male patient was admitted with complaints of pain abdomen (on & off) and abdominal distension since 15 days, with no inhalational exposure to asbestos, causing diagnostic confusion. He had history of unresolving haemorrhagic ascites. No drug allergy was noted. Diagnostic laproscopy was done, shows multiple omental nodules. Omental biopsy along with immunohistochemistry leads to diagnosis of malignant peritoneal mesothelioma. Peritoneal mesotheliomas are infrequent clinical entities. However, patients presenting with prolonged abdominal pain and ascitis should be considered to have atypical pathologies with peritoneal mesotheliomas being one of the differentials.

Identification of a new potential plasmatic biomarker panel for the diagnosis of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare highly aggressive tumor strongly associated with asbestos exposure and characterized by poor prognosis. Currently, diagnosis is based on invasive techniques, thus there is a need of identifying non-invasive biomarkers for early detection of the disease among asbestos-exposed subjects. In the present study, we measured the plasmatic concentrations of Mesothelin, Fibulin-3, and HMGB1 protein biomarkers, and of hsa-miR-30e-3p and hsa-miR-103a-3p Extracellular-Vesicles- embedded micro RNAs (EV-miRNAs). We tested the ability of these biomarkers to discriminate between MPM and PAE subjects alone and in combination. the study was conducted on a population of 26 patients with MPM and 54 healthy subjects with previous asbestos exposure (PAE). Mesothelin, Fibulin-3, and HMGB1 protein biomarkers were measured by the enzyme-linked immunosorbent assay (ELISA) technique; the levels of hsa-miR-30e-3p and hsa-miR-103a-3p EV-miRNAs was assessed by quantitative real-time PCR (qPCR). the most discriminating single biomarker resulted to be Fibulin-3 (AUC 0.94 CI 95% 0.88-1.0; Sensitivity 88%; Specificity 87%). After investigating the different possible combinations, the best performance was obtained by the three protein biomarkers Mesothelin, Fibulin-3, and HMGB1 (AUC 0.99 CI 95% 0.97-1.0; Sensitivity 96%; Specificity 93%). the results obtained contribute to identifying new potential non-invasive biomarkers for the early diagnosis of MPM in high-risk asbestos-exposed subjects. Further studies are needed to validate the evidence obtained, in order to assess the reliability of the proposed biomarker panel.

Understanding clinical decision-making in mesothelioma care: a mixed methods study

IntroductionMalignant pleural mesothelioma is a rare, incurable cancer arising from previous asbestos exposure; patients have a poor prognosis, with a median survival rate of 8–14 months. Variation in mesothelioma clinical...

Aquaporin-6 May Increase the Resistance to Oxidative Stress of Malignant Pleural Mesothelioma Cells.

Malignant pleural mesothelioma (MPM) is an aggressive cancer of the pleural surface and is associated with previous asbestos exposure. The chemotherapy drug is one of the main treatments, but the median survival ranges from 8 to 14 months from diagnosis. The redox homeostasis of tumor cells should be carefully considered since elevated levels of ROS favor cancer cell progression (proliferation and migration), while a further elevation leads to ferroptosis. This study aims to analyze the functioning/role of aquaporins (AQPs) as a hydrogen peroxide (H2O2) channel in epithelial and biphasic MPM cell lines, as well as their possible involvement in chemotherapy drug resistance. Results show that AQP-3, -5, -6, -9, and -11 were expressed at mRNA and protein levels. AQP-6 was localized in the plasma membrane and intracellular structures. Compared to normal mesothelial cells, the water permeability of mesothelioma cells is not reduced by exogenous oxidative stress, but it is considerably increased by heat stress, making these cells resistant to ferroptosis. Functional experiments performed in mesothelioma cells silenced for aquaporin-6 revealed that it is responsible, at least in part, for the increase in H2O2 efflux caused by heat stress. Moreover, mesothelioma cells knocked down for AQP-6 showed a reduced proliferation compared to mock cells. Current findings suggest the major role of AQP-6 in providing mesothelioma cells with the ability to resist oxidative stress that underlies their resistance to chemotherapy drugs.

Immunothérapie et autres stratégies dans le traitement du mésothéliome pleural: Immunotherapy and other strategies in the treatment of pleural mesothelioma

Management of malignant pleural mesothelioma (MPM), a rare tumor, usually due to previous asbestos exposure, with a globally poor prognosis and no validated curative treatment to date, is highly evolving. Recent major improvements in a better knowledge of MPM pathogenesis stimulate the search of new treatments, strategies and biomarkers to drive precision medicine in the future. Multimodal treatment and surgery with curative intent, included was well as radiotherapy, are highly discussed and restrained to selected patients, even if these indications could change with the combination of immunotherapies. As front line treatment, standard chemotherapy doing quite poorly, even if slightly improved by addition of bevacizumab, is now highly challenged by an immunotherapy combining nivolumab + ipilimumab. Therapeutic options beyond first line treatment are limited even if anti-PD-1/PD-L1 ± anti-CTLA-4 antibodies also exhibited promising results in phase II and III trials. Thus the search of new treatments, strategies and biomarkers is a crucial goal, and recruitment of patients in clinical trials is strongly encouraged. Other immunotherapies alone or combined with standard treatments and/or targeted therapies, multimodal strategies including intrapleural therapy are currently assessed.In France, the national cancer institute INCa labelled the national network of expert centers for MPM NETMESO (combining MESOCLIN and MESOPATH) and requests that to all patients should be discussed during regional (± national) NETMESO multidisciplinary board MPM at least at the time of diagnosis, in order to propose them an optimal management and to join clinical research studies.© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

A multicentric analysis of prognostic factors in malignant pleural mesothelioma

Background: Malignant pleural mesothelioma is a rare entity with poor prognosis, linked to previous asbestos exposure. The main goal of this study was to analyse the impact of clinical factors on mesothelioma prognosis. Methods: Retrospective cohort study of patients with malignant pleural mesothelioma in three Portuguese institutions, from 1999 to 2020. Statistical analysis was performed with Kaplan–Meier method and Cox regression using IBM SPSS® v25. Results: 60 patients were included, with male predominance (70%) and a median age of 69 years old. At diagnosis, 61% had advanced TNM stage (TNM III-IV) and 18% had an ECOG-PS ≥ 2. Asbestos exposure was stated in 48%. Epithelioid mesothelioma was the most prevalent histological subtype (81%). The majority received first line chemotherapy, in 10% combined with surgery, and two patients received immunotherapy after progression. Median overall survival (OS) was 13 months and median progression free survival was 10 months. A lower OS was observed in patients with ECOG-PS ≥ 2, age ≥ 70 years, TNM stage III-IV, anaemia, and hypoalbuminemia. Applying the decision tree model proposed by Brims et al. in our population, a significant difference in median OS was observed between the risk groups. In a multivariate analysis using Cox regression, Brims risk group 4, older age and advanced TNM stage were identified as independent negative prognostic factors. Conclusion: Recognition of these prognostic factors at diagnosis and use of specific prognostic models can help guide malignant pleural mesothelioma management.

Old Habits Die Hard - Asbestos Exposure.

Although the damages to health that are caused by asbestos exposure are known, the mineral continues to be in use. Our main purpose in the study was to determine the relationship between awareness and asbestos use. A total of 100 residents from the Armutova village of Ergani District in the Diyarbakir province of Turkey, with previous asbestos exposure were studied between January 2010 and December 2010. Exposure to asbestos was questioned in all participants. Asbestos doses were measured in the setting where they lived. The pulmonary function tests (PFTs) including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were performed, and chest radiography was taken. The duration of asbestos exposure was found to be associated with reduced PFTs and the pathological lung findings on radiology. Although 97% of the participants were aware of asbestos and its health risks, the rates of its use were significantly higher, and associated with excessive exposure levels. Longer duration of asbestos exposure was significantly associated with reduced FVC. There were more prominent reductions in FEV1 with longer durations of asbestos exposure. The high rates of asbestos use indicate that changing habits, particularly among individuals residing in rural areas, is difficult. In our country, the main route of asbestos exposure is through the environment, which is at least as hazardous as occupational exposure.

Prise en charge diagnostique et thérapeutique du mésothéliome pleural malin en 2021: Diagnostic and therapeutic management of malignant pleural mesothelioma in 2021

Malignant pleural mesothelioma (MPM) is a rare tumor, usually due to previous asbestos exposure. Its global prognosis is poor, without validated curative treatment to date. Diagnosis relies ideally on thoracoscopy with pleural biopsies, ± combined with talc pleurodesis. Surgery with curative intent, included with multimodal treatment, is restrained to highly selected patients. Radiotherapy is also of limited indication in MPM. As front line treatment, standard chemotherapy doing quite poorly, even if slightly improved by addition of bevacizumab, is now challenged by an immunotherapy combining Nivolumab + Ipilimumab. No treatment is firmly validated beyond first line treatment even if anti-PD-1/PD-L1 ± anti-CTLA-4 antibodies also exhibited some promising results in this setting, in phase II and III trials. Thus the search of new treatments, strategies and biomarkers is a crucial goal, and recruitment of patients in clinical trials is strongly encouraged. Other immunotherapies alone or combined with standard treatments and/ or targeted therapies, multimodal strategies including intrapleural therapy are currently assessed.In France, the national network of expert centers for MPM “NETMESO” (labelled by INCa, and combining MESOCLIN and MESOPATH), aims at proposing an optimal management to all patients systematically discussed in regional (± national) MTB dedicated to MPM, and at stimulating clinical and translational research in collaboration with its partners: Mesobank, IFCT… and patients associations.© 2021 SPLF. Published by Elsevier Masson SAS. All rights reserved.

The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3.

Simple SummaryMalignant pleural mesothelioma is an aggressive cancer most commonly associated with asbestos exposure. Its prognosis is very poor, and the current treatments have only a limited impact on survival. Therefore, there is an urgent need to develop new treatment strategies. We investigated combinations of different immune checkpoint blocking antibodies that have already shown promising results in several cancer types. We suggested that the effect of a combination treatment might even be better than one, single therapy. Based on our in vitro results about the secretion of several immune related molecules we selected promising treatments for further investigation in a mesothelioma mouse model. We found that monotherapy with an immune checkpoint blocking antibody against programmed death-1 (PD-1), and its combination with another blocking antibody against lymphocyte activation gene-3 (LAG-3), resulted in delayed tumor growth and survival benefit in our mice. Further research is warranted to optimize the treatment schedule of the combination therapy.Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9–12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.

Sarcomatoid malignant peritoneal mesothelioma presenting as a localized mesenteric tumor with no previous asbestos exposure

Sarcomatoid malignant peritoneal mesothelioma is the rarest and most lethal form of peritoneal mesothelioma. We present the case of a sarcomatoid malignant peritoneal mesothelioma presenting as a localized mesenteric tumor in a 54-year-old female with no previous asbestos exposure. This clinical presentation is extremely rare and is the first documented in Cameroon.

Prise en charge diagnostique et thérapeutique du mésothéliome pleural malin en 2020: Diagnostic and therapeutic management of malignant pleural mesothelioma in 2020

AbstractMalignant pleural mesothelioma (MPM) is a rare tumor, usually due to previous asbestos exposure. Its glob prognosis is poor, without validated curative treatment to date. Diagnosis relies ideally on thoracoscopy with pleural biopsies, ± combined with talc pleurodesis. Surgery with curative intent, included with multimodal treatment, is restrained to highly selected patients. Radiotherapy is also of limited indication in MPM. Standard first line chemotherapy does quite poorly, improved by addition of bevacizumab. No treatment is validated as second line or further even if anti-PD-1/PD-L1 ± anti-CTLA-4 antibodies exhibited promising results in phase II trials (MAPS-2…). Thus the search of new treatments, strategies and biomarkers is a crucial goal, and recruitment of patients in clinical trials is strongly encouraged. Other immunotherapies alone or combined with standard treatments and/or targeted therapies, multimodal strategies including intrapleural therapy are currently assessed.In France, the national network of clinical expert centers for MPM, “MESOCLIN” then “NET-MESO” by its recent association with the pathologist network “MESOPATH”, aims at proposing an optimal treatment to all patients systematically discussed in regional (±national) MTB dedicated to MPM, and at stimulating clinical and translational research in close collaboration with its partners: Mesobank, IFCT… and patients associations.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Abstract B096: Predictors of survival in black and white patients with malignant pleural mesothelioma

Abstract Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer, particularly among black patients, with a very poor prognosis. There is only one study directly examining prognostic factors of survival in white and black patients with MPM, based on SEER. The goal of this study was to use a large, nationwide cancer database to examine factors associated with survival in black and white patients with MPM. Methods: We used the National Cancer Database (NCDB) to identify black and white patients diagnosed with MPM from 2004-2013. Multivariable Cox proportional hazards models, stratified by race, were used to assess factors associated with overall survival (OS), using adjusted hazards ratios (HRadj) and 95% confidence intervals (CI). Covariates included age, gender, ethnicity, zip-code level education and income, insurance, Charlson-Deyo comorbidity score, histology, laterality, stage, receipt of treatment (surgery, chemotherapy, radiotherapy), hospital characteristics, and year of diagnosis. Results: There were 15,828 patients included; 15,109 white (95.5%) and 719 black (4.5%). After adjustment, black patients were significantly younger, living in areas characterized by lower educational attainment and income, more likely to be on Medicaid, to be from the South and to live closer to their hospital. Though not significant, black patients were less likely to receive surgery, radiotherapy, and chemotherapy than white patients. There were several differences in factors associated with OS for black and white patients. OS was significantly worse for older patients, but the association was stronger in black patients (HRadj [white]: 1.86, 95% CI: 1.56-2.21; HRadj [black]: 7.18, 95% CI: 3.39-15.20 for ≥80 vs. <50 years). A higher comorbidity score was associated with worse OS (HRadj [white]: 1.28, 95% CI: 1.19-1.37; HRadj [black]: 1.53, 95% CI: 1.12-2.09 for comorbidity score ≥2 vs.0). Among white patients, women had significantly better survival (HRadj: 0.81, 95% CI: 0.77-0.85), but not so among black patients (HRadj: 0.95, 95% CI: 0.74-1.21). Both groups derived benefit from radiotherapy (HRadj [white]: 0.84, 95% CI: 0.75-0.94; HRadj [black]: 0.41, 95% CI: 0.21-0.82) and chemotherapy (HRadj [white]: 0.67, 95% CI: 0.64-0.70; HRadj [black]: 0.75, 95% CI: 0.60-0.94); only white patients had significantly better OS with surgery (HRadj [white]: 0.78, 95% CI: 0.74-0.83; HRadj [black]: 1.06, 95% CI: 0.76-1.48). Conclusion: Prognostic factors associated with better OS vary by race. Some of these differences may reflect poorer access to quality healthcare among black patients and compounded socioeconomic effects. Differences in previous asbestos exposure with race could also play a role in the biology of the disease. Further work is needed to untangle these differences to determine best care practices and improve prognosis for all patients. Citation Format: Naomi Alpert, Maaike van Gerwen, Nisha Ohri, Raja Flores, Emanuela Taioli. Predictors of survival in black and white patients with malignant pleural mesothelioma [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B096.

Clinical Features in Patients With Malignant Pleural Mesothelioma With 5-Year Survival and Evaluation of Original Diagnoses

IntroductionMalignant pleural mesothelioma (MPM) is a fatal malignancy strongly associated with previous asbestos exposure. Overall survival remains dismal, partly owing to poor response to available treatment. The aims of this study were to evaluate diagnostic accuracy in a group of patients with MPM with an unusually long survival time and to assess the factors related to this prolonged survival. Materials and MethodsForty-three patients with overall survival exceeding 5 years were accepted to the long-term survivor (LTS) group, and these patients were compared with 84 patients with epithelial MPM. Data were collected from various national registries and electronic medical records. In addition, all available histopathologic diagnostic samples and computed tomography studies were re-evaluated by experienced specialists. ResultsOur study showed a good diagnostic accuracy, with only 1 (0.5%) patient having an incorrect MPM diagnosis. Two (0.9%) localized malignant mesotheliomas and 2 (0.9%) well-differentiated papillary mesotheliomas were also found. LTS patients were younger, more frequently female, had a better performance status at time of diagnosis, and had less evidence of prior asbestos exposure. In multivariate analysis, we showed tumor size, Eastern Cooperative Oncology Group performance status, and first-line treatment (both surgery and chemotherapy) to be associated with survival time. ConclusionWe confirmed the diagnosis of MPM in an overwhelming majority of patients in the LTS group. An epithelial subtype of MPM behaving clinically more indolently seems to exist, but further tumor and genetic characterization is needed. The prolonged survival time is most likely explained by a combination of tumor-, patient-, and treatment-related factors.

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

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

Prise en charge diagnostique et thérapeutique du mésothéliome pleural malin en 2019

Malignant pleural mesothelioma (MPM) is a rare tumor, usually due to previous asbestos exposure. Its glob prognosis is poor, without validated curative treatment to date. Diagnosis relies ideally on thoracoscopy with pleural biopsies, ± combined with talc pleurodesis. Surgery with curative intent, included with multimodal treatment, is restrained to highly selected patients. Radiotherapy is also of limited indication in MPM. Standard first line chemotherapy does quite poorly, improved by addition of bevacizumab. No treatment is validated as second line or further even if anti-PD-1/PD-L1 ± anti-CTLA-4 antibodies exhibited promising results in phase II trials (MAPS-2…). Thus the search of new treatments, strategies and biomarkers is a crucial goal, and recruitment of patients in clinical trials is strongly encouraged. Other immunotherapies alone or combined with standard treatments and/or targeted therapies, multimodal strategies including intrapleural therapy are currently assessed.In France, the national network of clinical expert centers for MPM, “MESOCLIN”, aims at proposing an optimal treatment to all patients systematically discussed in regional (±national) MTB dedicated to MPM, and at stimulating clinical and translational research in close collaboration with its partners: Mesopath, Mesobank, IFCT… and patients associations.

Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin \u2013 a case-control comparison nested into a prospective cohort of asbestos-exposed workers

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.

PO-274 Tumour subtype-specific cells of origin of malignant mesothelioma

IntroductionMalignant Mesothelioma (MM) is an aggressive malignancy of the lining of the thoracic and peritoneal cavity. The primary cause is previous asbestos exposure. The pathological diagnosis of MM is rather complex due to a lack of useful biological markers and because multiple cell types are involved in the development of MM. We aimed to investigate to what extent the tumour subtype is determined by the cell of origin rather than the somatically acquired driver mutations.Material and methodsCo-deletion of the conditional tumour suppressors, NF2, p53 and Cdkn2a in freshly isolated mesothelial cells using Cre viruses allowed us to establish clonal cell lines with epithelial, sacomatoid and biphasic morphology as also observed in human MM. Cells were analysed for clinical relevant protein marker profiles, tumorigenic potential and RNA expression. Results were compared to (poly)clonal cell lines obtained from conditional mice injected intra-thoracically with lentiviruses expressing Cre-recombinase driven by tissue-specific promoters.Results and discussionsUsing the ex vivo approach we were able to obtain clonal cell lines that upon transplantation gave rise to the main three MM tumour epithelial, sarcomatoid and biphasic subtypes. The epithelial and sarcomatoid phenotypes observed in vitro retained in the tumours, also after serial transplantation of the cell lines. Clonal biphasic cells co-expressed both epithelial and sarcomatoid markers and external factors could skew these biphasic cells towards a more epithelial or sarcomatoid phenotype. Transplantation of clonal biphasic cells only gave rise to tumours when the cells were grafted in immune-deficient mice, this in contrast to the epithelial and sarcomatoid cell lines that effectively gave tumours in syngeneic immunocompetent recipients. Analysis of tumour cell populations and derived clonal cell lines induced by lentiviral Cre-mediated switching of the same tumour suppressors in the mesothelial lining of conditional mice showed a high level of heterogeneity that included the same tumour subtypes also obtained using the ex vivo procedure.ConclusionA set of the same genetic mutations is able to drive heterogeneous MM development suggesting that the specific phenotype of the resulting tumour depends on the specific cell-of-origin. Therefore, epigenetic differences rather than acquired mutations appear a determining factor for the subtype of MM that arises. This epigenetic state appears relative stability as interconversion of the tumour subtypes was not observed.