Re-evaluation of potential predictors of calretinin and mesothelin in a population-based cohort study using assays for the routine application in clinical medicine

Our plain-English summary of Re-evaluation of potential predictors of calretinin and mesothelin in a population-based cohort study using assays for the routine application in clinical medicine, by S. Casjens, G. Johnen, I. Raiko, et al (BMJ Open, 2021).

The study

• Authors: S. Casjens, G. Johnen, I. Raiko, B. Pesch, D. Taeger, C. Töpfer, S. Schonefeld, S. Moebus, K.H. Jöckel, T. Brüning, D. Weber
• Journal: BMJ Open
• Published: 2021;11(2):e039079
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: Calretinin and mesothelin are molecular markers for the detection of malignant mesothelioma at early stages. Our objective was the re-evaluation of factors influencing calretinin and mesothelin concentrations in plasma of cancer-free men in order to minimise false-positive tests when using commercial assays approved for clinical diagnostics.

Setting: This re-evaluation used data and archived blood samples of the population-based Heinz Nixdorf Recall Study (HNRS) collected from 2011 to 2014.

Participants: The present analysis comprised of 569 cancer-free men at the time of blood sampling (median age 70 years) from HNRS.

Primary And Secondary Outcomes: Mesothelin plasma concentration was determined using ELISA and CLEIA (chemiluminescent enzyme immunoassay). Calretinin plasma concentration was assessed using ELISA.

Results: Compared with the previous determination of concentrations, we detected less false-positive tests using the commercial assays. In this analysis, we found nine false-positive calretinin tests using the ELISA (specificity 98.4%, 95% CI 97.0% to 99.2%) and 24 false-positive mesothelin tests using both ELISA and CLEIA (specificity 95.8%, 95% CI 93.8% to 97.2%). We confirmed renal dysfunction as major predictor of elevated marker concentrations. Mesothelin was additionally affected by bronchitis. Furthermore, elevated inflammation values and hypertension only affected the mesothelin concentration determined by ELISA.

Conclusions: The newly available assays of calretinin and mesothelin approved for clinical diagnostics showed high specificities in the population-based cohort of elderly men without a malignant disease. The current evaluation provides a basis to consider influencing factors in order to further improve the diagnostic procedure.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This study re-tested archived plasma from 569 cancer-free men sampled in 2011–2014 in the Heinz Nixdorf Recall Study, a population-based cohort in Germany's Ruhr area. They were recruited from the general population, not from an asbestos-worker cohort; median age was 70. The authors measured calretinin and mesothelin, blood markers for early detection of malignant mesothelioma. They used commercial assays approved for clinical diagnosis and sought factors linked to false positives. Nine men (1.6%) had a false-positive calretinin test, a specificity of 98.4% (95% CI 97.0% to 99.2%). Each mesothelin assay was positive in 24 men (4.2%), a specificity of 95.8% (95% CI 93.8% to 97.2%). In adjusted analyses, raised cystatin C, a blood measure of kidney function, was associated with positive tests for both markers. Current bronchitis was associated with positive mesothelin tests on both assays. Raised C reactive protein and current hypertension were associated with positive tests only on the mesothelin ELISA. The authors concluded the approved assays showed high specificities in these men. They noted that few false positives limited power to detect predictors, and only men were included.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Cross-sectional re-analysis of archived plasma samples from a prospective population-based cohort study. It re-evaluated an earlier analysis using commercial assays approved for clinical diagnostics, to find factors linked to false-positive tests for calretinin and mesothelin, which are markers for detecting malignant mesothelioma at early stages.
• Who was studied: 569 men from the second follow-up survey (2011–2014) of the Heinz Nixdorf Recall Study, a population-based cohort in the Ruhr area of Germany. All were without a malignant disease at blood collection. Median age was 70 years (range 56–84).
• Exposure: Asbestos exposure was not studied. The factors examined as possible predictors of raised marker levels were age, smoking status, self-reported diseases, cancer after blood sampling, current medication and 36 blood parameters. The markers were measured with a calretinin ELISA (positive above 0.6 ng/mL), a mesothelin CLEIA (positive at 1.5 nM or more) and a mesothelin ELISA (positive at 2.0 nM or more).
• Main results:
  • Calretinin ELISA: 9 of 569 men had a false-positive test (1.6%), a specificity of 98.4% (95% CI 97.0% to 99.2%).
  • Mesothelin: each of the two assays (CLEIA and ELISA) was positive in 24 men (4.2%), a specificity of 95.8% (95% CI 93.8% to 97.2%). Twenty-one men (3.7%) were positive on both mesothelin assays.
  • In the multiple regression models, calretinin was affected only by cystatin C above standard values: prevalence odds ratio 17.5 (95% CI 4.40 to 69.7).
  • Cystatin C above standard values was associated with positive mesothelin tests. The prevalence odds ratio was 12.1 (95% CI 4.46 to 33.0) with the CLEIA and 9.58 (95% CI 3.46 to 26.5) with the ELISA.
  • Current bronchitis was associated with positive mesothelin tests. The prevalence odds ratio was 6.13 (95% CI 1.10 to 34.1) with the CLEIA and 7.38 (95% CI 1.35 to 40.3) with the ELISA. This was based on 3 positive men with bronchitis on each assay.
  • Raised C reactive protein (prevalence odds ratio 3.00, 95% CI 1.17 to 7.67) and current hypertension (prevalence odds ratio 4.63, 95% CI 1.01 to 21.2) affected only the mesothelin result measured by ELISA.
  • Combining markers: 5 men were positive on both the calretinin ELISA and the mesothelin CLEIA (99.1% specificity). 4 men were positive on both the calretinin ELISA and the mesothelin ELISA (99.3% specificity).
• The authors' conclusion: The authors concluded that the newly available calretinin and mesothelin assays approved for clinical diagnostics showed high specificities in this cohort of elderly men without cancer. In their view, calretinin was affected only by renal dysfunction, while mesothelin was affected by renal dysfunction, hypertension, age and current bronchitis. They said the evaluation gives a basis for taking such influencing factors into account to improve diagnosis.
• Limitations the authors state:
  • The high specificities rested on small numbers of false positives, which limited the power to detect predictors.
  • Only men were included, so possible differences between men and women could not be studied.
  • Participants were recruited from the general population, not from a cohort of asbestos workers.
  • The authors noted that specificity might be lower in the target population of people formerly exposed to asbestos or with asbestos-related diseases.
  • The link between raised triglycerides and the mesothelin ELISA was based on small numbers and could be a chance finding.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Calretinin, Mesothelin, Cohort Study, Mesothelioma, Inflammation.

Related studies

• Assessment of potential predictors of calretinin and mesothelin to improve the diagnostic performance to detect malignant mesothelioma: results from a population-based cohort study — S. Casjens, D.G. Weber, et al. (2017)
• Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers — G. Johnen, K. Burek, et al. (2018)
• Mesothelin, Calretinin, and Megakaryocyte Potentiating Factor as Biomarkers of Malignant Pleural Mesothelioma — C. Jiménez-Ramírez, S. Casjens, et al. (2019)
• Assessment of miR-103a-3p in leukocytes-No diagnostic benefit in combination with the blood-based biomarkers mesothelin and calretinin for malignant pleural mesothelioma diagnosis — C. Jiménez-Ramírez, D. Gilbert Weber, et al. (2022)
• NPM2 in malignant peritoneal mesothelioma: from basic tumor biology to clinical medicine — H.L. Wu, Z.R. Yang, et al. (2022)
• Biomarkers for Predicting Malignant Pleural Mesothelioma in a Mexican Population — G. Aguilar-Madrid, B. Pesch, et al. (2018)

Browse more research in BMJ Open, or return to medical research.