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.

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In this study we evaluate the suitability of two methods of RNA conservation in blood samples, PAXgene and RNAlater, in combination with variable shipping conditions for their application in multicenter studies and biobanking. RNA yield, integrity, and purity as well as levels of selected mRNA and microRNA species were analyzed in peripheral human blood samples stabilized by PAXgene or RNAlater and shipped on dry ice or at ambient temperatures from the study centers to the central analysis laboratory. Both examined systems were clearly appropriate for RNA stabilization in human blood independently of the shipping conditions. The isolated RNA is characterized by good quantity and quality and well suited for downstream applications like quantitative RT-PCR analysis of mRNA and microRNA. Superior yield and integrity values were received using RNAlater. It would be reasonable to consider the production and approval of blood collection tubes prefilled with RNAlater to facilitate the use of this excellent RNA stabilization system in large studies.

Objectives-To examine if the occurrence of diVerent cancers was increased among rubber workers, as the highest known exposures of humans to nitrosamines have occurred in the rubber industry. Methods-A cohort of 8933 rubber workers (hired after 1 January 1950, still active or retired on 1 January 1981 and employed for at least 1 year in one of five study factories) was followed up for mortality from 1 January 1981 to 31 December 1991. Work histories were reconstructed with routinely documented cost centre codes, which allowed identification by employment in specific work areas. For each cost centre code time and factory specific, semi-quantitative exposures to nitrosamines (three levels: low, medium, high) and other compounds were estimated by industrial hygienists. Rate ratios for medium (RR m ) and high (RR h ) exposures and 95% confidence intervals (95% CIs) were calculated with Cox's proportional hazards models with the low exposure as reference. Results-Exposure to nitrosamines was significantly associated with an increased mortality from cancers of the oesophagus (13 deaths: RR m 1.7, 95% CI 0.3 to 10.3; RR h 7.3, 95% CI 1.9 to 27.8) and of the oral cavity and pharynx (17 deaths: RR m 0.8, 95% CI 0.2 to 4.1; RR h 3.9, 95% CI 1.4 to 11.1). A non-significant trend of increasing mortality with exposure to higher concentrations of nitrosamines was found for mortality from cancer of the prostate (26 deaths: RR m 1.4, 95% CI 0.5 to 3.8; RR h 2.2, 95% CI 0.9 to 5.6), and the brain (six deaths: RR m 3.9, 95% CI 0.3 to 42.6; RR h 6.0, 95% CI 0.6 to 57.6). No association was found between exposure to nitrosamines and cancer of the stomach (RR m 0.8, 95% CI 0.4 to 1.8; RR h 1.2, 95% CI 0.5 to 2.5) or lung (RR m 1.0, 95% CI 0.6 to 1.5; RR h 1.0, 95% CI 0.7 to 1.6). Conclusions-Exposure to high concentrations of nitrosamines is associated with increased mortality from cancers of the oesophagus, oral cavity, and pharynx, but not with increased mortality from cancers of the stomach or lung.

BackgroundMalignant mesothelioma (MM) is a deadly cancer mainly caused by previous exposure to asbestos. With a latency period up to 50 years the incidence of MM is still increasing, even in countries that banned asbestos. Secondary prevention has been established to provide persons at risk regular health examinations. An earlier detection with tumor markers might improve therapeutic options. Previously, we have developed a new blood-based assay for the protein marker calretinin. Aim of this study was the verification of the assay in an independent study population and comparison with the established marker mesothelin.MethodsFor a case-control study in men, a total of 163 cases of pleural MM and 163 controls were available from Australia, another 36 cases and 72 controls were recruited in Germany. All controls had asbestosis and/or plaques. Calretinin and mesothelin were determined by ELISA (enzyme-linked immunosorbent assay) in serum or plasma collected prior to therapy. We estimated the performance of both markers and tested factors potentially influencing marker concentrations like age, sample storage time, and MM subtype.ResultsCalretinin was able to detect all major subtypes except for sarcomatoid MM. Calretinin showed a similar performance in Australian and German men. At a pre-defined specificity of 95% the sensitivity of calretinin reached 71% and that of mesothelin 69%, when excluding sarcomatoid MM. At 97% specificity, the combination with calretinin increased the sensitivity of mesothelin from 66% to 75%. Sample storage time did not influence the results. In controls the concentrations of calretinin increased 1.87-fold (95% CI 1.10–3.20) per 10 years of age and slightly more for mesothelin (2.28, 95% CI 1.30–4.00).ConclusionsCalretinin could be verified as a blood-based marker for MM. The assay is robust and shows a performance that is comparable to that of mesothelin. Retrospective analyses would not be limited by storage time. The high specificity supports a combination of calretinin with other markers. Calretinin is specific for epithelioid and biphasic MM but not the rarer sarcomatoid form. Molecular markers like calretinin and mesothelin are promising tools to improve and supplement the diagnosis of MM and warrant further validation in a prospective study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3375-5) contains supplementary material, which is available to authorized users.