Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Johnen G

PROVIDER: S-EPMC6156219 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Johnen Georg G Burek Katarzyna K Raiko Irina I Wichert Katharina K Pesch Beate B Weber Daniel G DG Lehnert Martin M Casjens Swaantje S Hagemeyer Olaf O Taeger Dirk D Brüning Thomas T

Scientific reports 20180925 1

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 ...[more]

PMID: 30254313

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Project description:BackgroundThe current reference test for the detection of respiratory abnormalities in asbestos-exposed workers is spirometry. However, spirometry has several shortcomings that greatly affect the efficacy of current asbestos control programs. The forced oscillation technique (FOT) represents the current state-of-the-art technique in the assessment of lung function. This method provides a detailed analysis of respiratory resistance and reactance at different oscillatory frequencies during tidal breathing. Here, we evaluate the FOT as an alternative method to standard spirometry for the early detection and quantification of respiratory abnormalities in asbestos-exposed workers.Methodology/principal findingsSeventy-two subjects were analyzed. The control group was composed of 33 subjects with a normal spirometric exam who had no history of smoking or pulmonary disease. Thirty-nine subjects exposed to asbestos were also studied, including 32 volunteers in radiological category 0/0 and 7 volunteers with radiological categories of 0/1 or 1/1. FOT data were interpreted using classical parameters as well as integer (InOr) and fractional-order (FrOr) modeling. The diagnostic accuracy was evaluated by investigating the area under the receiver operating characteristic curve (AUC). Exposed workers presented increased obstruction (resistance p<0.001) and a reduced compliance (p<0.001), with a predominance of obstructive changes. The FOT parameter changes were correlated with the standard pulmonary function analysis methods (R = -0.52, p<0.001). Early respiratory abnormalities were identified with a high diagnostic accuracy (AUC = 0.987) using parameters obtained from the FrOr modeling. This accuracy was significantly better than those obtained with classical (p<0.001) and InOr (p<0.001) model parameters.ConclusionsThe FOT improved our knowledge about the biomechanical abnormalities in workers exposed to asbestos. Additionally, a high diagnostic accuracy in the diagnosis of early respiratory abnormalities in asbestos-exposed workers was obtained. This makes the FOT particularly useful as a screening tool in the context of asbestos control and elimination. Moreover, it can facilitate epidemiological research and the longitudinal follow-up of asbestos exposure and asbestos-related diseases.

Project description:BackgroundMalignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection.Methodology/principal findingsWe conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99±0.01 in training, 0.98±0.04 in independent blinded verification and 0.95±0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy.SignificanceThe SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease.

Project description:Malignant 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.For 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.Calretinin 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).Calretinin 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.

Dataset Information

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

Publications

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

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