Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma

Our plain-English summary of Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma, by P. Stockhammer, T. Ploenes, D. Theegarten, et al (Lung Cancer, 2020).

The study

• Authors: P. Stockhammer, T. Ploenes, D. Theegarten, M. Schuler, S. Maier, C. Aigner, B. Hegedus
• Journal: Lung Cancer
• Published: 2020;139:124-132
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with dismal prognosis but variable course of disease. To support diagnosis and to risk stratify patients, more reliable biomarkers are warranted. Emerging evidence underlines a functional role of transforming growth factor-beta (TGF-β) in MPM tumorigenesis though its utility as a clinical biomarker remains unexplored.

Materials And Methods: Corresponding pleural effusions and serum samples taken at primary diagnosis were analyzed for TGF-β by ELISA, and for mesothelin (SMRP) by chemiluminescence enzyme immunoassay. Tumor load was quantified in MPM patients by volumetric analysis of chest CT scans. All findings were correlated with clinicopathological characteristics.

Results: In total 48 MPM patients, 24 patients with non-malignant pleural disease (NMPD) and 30 patients with stage IV lung cancer were enrolled in this study. Pleural effusions from MPM patients had significantly higher TGF-β levels than from NMPD or lung cancer patients (p < 0.0001; AUC for MPM vs NMPD: 0.78, p = 0.0001). Both epithelioid and non-epithelioid MPM were associated with higher TGF-β levels (epithelioid: p < 0.05; non-epithelioid: p < 0.0001) and levels of TGF-β correlated with disease stage (p = 0.003) and with tumor volume (p = 0.002). Interestingly, high TGF-β levels in pleural effusion, but not in serum, was significantly associated with inferior overall survival (TGF-beta ≥14.36 ng/mL: HR 3.45, p = 0.0001). This correlation was confirmed by multivariate analysis. In contrast, effusion SMRP levels were exclusively high in epithelioid MPM, negatively correlated with effusion TGF-β levels and did not provide prognostic information.

Conclusion: TGF-β levels determined in pleural effusion may be a promising biomarker for diagnosis and prognostic stratification of MPM.

Copyright © 2019 Elsevier B.V. All rights reserved.

In plain English

This single-center study in Essen, Germany, measured transforming growth factor-beta (TGF-beta) in pleural fluid from 48 consecutive malignant pleural mesothelioma patients included from July 2016 to November 2018, and in blood from 22 of them. Controls were 24 patients with non-malignant pleural disease and patients with stage IV lung cancer. The article reports no asbestos exposure data. Mean fluid TGF-beta was 14.36 ng/mL in mesothelioma, 6.04 in non-malignant disease and 3.09 in lung cancer. Levels were higher in non-epithelioid than epithelioid mesothelioma and in late-stage than early-stage disease. They rose with tumor volume in the 18 patients measured. Mesothelioma patients with fluid levels of 14.36 ng/mL or more had worse survival (hazard ratio 3.45, CI 1.47 to 8.33), also in multivariate analysis. Blood TGF-beta, measured in 22 mesothelioma and 19 non-malignant disease patients, did not differ significantly between those groups and was not significantly associated with survival. Fluid mesothelin (SMRP) was high mainly in epithelioid tumors and was not significantly associated with survival. The authors concluded that pleural fluid TGF-beta may be a promising diagnostic and prognostic biomarker.

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: single-center biomarker study of consecutive patients with comparison (control) groups
• Who was studied: 48 consecutive malignant pleural mesothelioma patients included at the Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, Germany, between July 2016 and November 2018. Pleural fluid was collected from all 48 at diagnosis; serum was available for 22. Controls were 24 patients with non-malignant pleural diseases (17 pleuritis, 4 pneumothorax, 2 pericardial cyst, 1 paravertebral cyst), 19 of whom had serum. There were also patients with newly diagnosed stage IV lung cancer: 29 in the methods and 30 in the abstract.
• Exposure: Asbestos exposure was not studied. The study measured TGF-beta (by ELISA) and mesothelin/SMRP (by chemiluminescent enzyme immunoassay) in pleural effusion and serum taken at diagnosis.
• Main results:
  • Mean pleural effusion TGF-beta was 14.36 plus or minus 1.77 ng/mL in mesothelioma patients, 6.04 plus or minus 1.18 ng/mL in non-malignant pleural disease patients, and 3.09 plus or minus 0.57 ng/mL in lung cancer patients (p less than 0.0001).
  • For distinguishing mesothelioma from non-malignant pleural disease, effusion TGF-beta had an AUC of 0.78 (95% CI 0.66-0.90). At a cut-off of 6.59 ng/mL, it gave 75.0% sensitivity and 77.1% specificity.
  • Effusion TGF-beta was higher in non-epithelioid mesothelioma (22.72 plus or minus 4.23 ng/mL) than in epithelioid mesothelioma (11.25 plus or minus 1.59 ng/mL), p=0.002.
  • Mesothelioma patients with late-stage disease had higher effusion TGF-beta than early-stage patients (20.51 plus or minus 3.42 vs 8.89 plus or minus 0.93 ng/mL, p=0.003).
  • Effusion TGF-beta correlated with tumor volume measured on CT. Volume measurements were available in 18 of 48 mesothelioma patients (Spearman r 0.67, p=0.002).
  • In all 48 mesothelioma patients, those with effusion TGF-beta at or above 14.36 ng/mL had worse overall survival than those below it (HR 3.45, CI 1.47-8.33, p=0.0001).
  • In epithelioid mesothelioma patients, using a histotype-specific cut-off, high effusion TGF-beta was associated with worse survival (HR 4.19, CI 1.54-11.38, p=0.0002).
  • In the 13 non-epithelioid patients there was only a non-significant trend (HR 1.65, CI 0.46-5.95, p=0.41).
  • In multivariate Cox regression for the full mesothelioma cohort, low effusion TGF-beta was independently associated with better overall survival (HR 0.22, CI 0.08-0.60, p=0.003). Multimodality treatment was also independently associated (HR 0.11).
  • Serum (blood) TGF-beta was measured in mesothelioma and non-malignant pleural disease patients only. It was not significantly different between these groups (p=0.103) and was not significantly associated with survival when the serum mean of 23.17 ng/mL was used as cut-off (p=0.98). It did not correlate with effusion levels (p=0.594).
  • Effusion SMRP was higher in mesothelioma than in non-malignant pleural disease patients (39.55 plus or minus 5.25 vs 19.64 plus or minus 5.83 nmol/L, p=0.004; AUC 0.71). Levels were high mainly in epithelioid tumors. Effusion SMRP was not prognostic when the mean was used as cut-off (p=0.35).
  • Counting a patient as positive if either effusion TGF-beta or effusion SMRP was above its cut-off gave 93.8% sensitivity and 58.3% specificity for diagnosing mesothelioma.
• The authors' conclusion: The authors concluded that TGF-beta levels measured in pleural effusion may be a promising biomarker for diagnosis and prognostic stratification of malignant pleural mesothelioma.
• Limitations the authors state:
  • Matched blood samples were not available for all mesothelioma and control patients.
  • The non-epithelioid group was small, and larger non-epithelioid cohorts are needed to establish prognostic value.
  • Prospective validation is needed, particularly in asbestos-exposed high-risk people.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Pleural Mesothelioma, Prognosis, Biomarker, Transforming Growth Factor-beta (TGF-β), Tumorigenesis, Mesothelin, Soluble Mesothelin-Related Peptides (SMRP).

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• Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma — N. Hirayama, C. Tabata, et al. (2011)
• Circulating endothelial cell (CEC) as a diagnostic and prognostic marker in malignant pleural mesothelioma (MPM) — K. Yoneda, F. Tanaka, et al. (2012)
• Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples - a short report — N. Beije, J. Kraan, et al. (2017)
• Utility of hyaluronic acid in pleural fluid for differential diagnosis of pleural effusions: likelihood ratios for malignant mesothelioma — S. Atagi, M. Ogawara, et al. (1997)

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