Profile of soluble factors in pleural effusions predict prognosis in mesothelioma

Our plain-English summary of Profile of soluble factors in pleural effusions predict prognosis in mesothelioma, by I.M. Dick, Y.C.G. Lee, H.M. Cheah, et al (Cancer Biomarkers, 2022).

The study

• Authors: I.M. Dick, Y.C.G. Lee, H.M. Cheah, A. Miranda, B.W.S. Robinson, J. Creaney
• Journal: Cancer Biomarkers
• Published: 2022;33(1):159-169
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma is a deadly asbestos induced cancer. Less than 10% of mesothelioma patients survive 5 years post diagnosis. However survival can range from a few months to a number of years. Accurate prediction of survival is important for patients to plan for their remaining life, and for clinicians to determine appropriate therapy. One unusual feature of mesothelioma is that patients frequently present with tumor-associated pleural effusions early in the course of the disease.

Objective: To study whether cells and molecules present in pleural effusions provide prognostic information for mesothelioma.

Methods: We profiled the cellular constituents and concentrations of 40 cytokines, chemokines and cellular factors (collectively "soluble factors") involved in inflammatory and immune signalling pathways in pleural effusion samples from 50 mesothelioma patients.Associations with survival were evaluated by Cox proportional hazards regression methods. Results for the two soluble factors most significantly and independently associated with survival were validated in an independent set of samples (n= 51) using a separate assay system.

Results: Survival analysis revealed that IL8, IL2Ra (CD25) and PF4 were independent determinants of a more negative prognosis in mesothelioma patients, independent of other known prognostic factors. Lipocalin2 and IL4 were associated with better prognosis.

Conclusions: This study demonstrates that pleural effusions rich in a range of soluble factors are associated with poor prognosis. These findings will enhance our ability to prognosticate outcomes in mesothelioma patients.

In plain English

The authors studied whether pleural effusion, the fluid around the lung, holds clues to survival in pleural mesothelioma. They measured 40 immune and inflammation-related substances, and cell types, in fluid taken before treatment from 50 patients. They then measured IL8 and PF4 in a separate, randomly chosen group of 51 patients using a different test. Asbestos exposure was not examined. In the first group, 14 of the 40 substances were each linked to survival. Analysed together, higher IL8, IL2Ra and PF4 were linked to shorter survival, and higher lipocalin-2 and IL4 to longer survival. Grouping patients by the share of lymphocytes, macrophages or neutrophils in their fluid showed no significant link with survival. In the second group, with the two substances adjusted for each other, higher PF4 was linked to shorter survival (hazard ratio 1.687 per standard deviation increase, 95% CI 1.157 to 2.461). The IL8 result in that analysis (1.501, 0.988 to 2.279) was not statistically significant. The authors concluded that fluid rich in a range of soluble factors is associated with poorer prognosis, and they called for confirmation studies.

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: Observational biomarker (prognosis) study with a discovery cohort and an independent validation cohort drawn from a biobank
• Who was studied: People with pathologically confirmed pleural mesothelioma at a specialist referral centre, enrolled in the NCARD Biobanking program (National Centre for Asbestos Related Disease, University of Western Australia). The discovery cohort was 50 patients, 42 male and 8 female. The validation cohort was 51 patients, 40 male and 11 female, selected randomly at a later time. Study dates are not given.
• Exposure: Asbestos exposure was not assessed. The factors studied were the cell composition of pleural effusion fluid and the concentrations of 40 cytokines, chemokines and cellular factors involved in inflammation and immune signalling, measured with a multiplex assay. IL8 and PF4 were re-measured by separate ELISA tests in the validation cohort.
• Main results:
  • Discovery cohort (50 patients), each factor analysed alone: 14 of the 40 molecules (35%) were significantly associated with survival. For each of these, a higher value was associated with poorer prognosis.
  • Discovery cohort, factors analysed together (multivariate). Higher levels of three factors were linked to poorer prognosis: IL8 (HR 2.688, 95% CI 1.690 to 4.273, p less than 0.001), IL2Ra (HR 2.223, 1.275 to 3.877, p = 0.005) and PF4 (HR 1.936, 1.311 to 2.859, p = 0.001). Higher levels of two factors were linked to more favourable prognosis: lipocalin-2 (HR 0.419, 0.275 to 0.640, p less than 0.001) and IL4 (HR 0.615, 0.395 to 0.956, p = 0.031).
  • Discovery cohort: under a more stringent statistical threshold, IL8 was the only pleural effusion cytokine significantly associated with prognosis.
  • Discovery cohort: cluster analysis grouped 11 patients whose fluid had overall higher concentrations of soluble factors. These patients had poorer prognosis than the other two clusters (17 and 22 patients) (HR 3.549, 1.557 to 8.089, p less than 0.001).
  • Discovery cohort: when patients were grouped by the percentage of lymphocytes, macrophages or neutrophils in their fluid, none of these groupings was significantly associated with survival.
  • Validation cohort (51 patients, ELISA tests), with IL8 and PF4 adjusted for each other. PF4 was significantly associated with poorer prognosis (HR 1.687 per SD increase, 1.157 to 2.461, p = 0.007). IL8 was not statistically significant (HR 1.501 per SD increase, 0.988 to 2.279, p = 0.057).
  • Validation cohort: for separating survival under 9 months from survival of 9 months or more, the area under the curve (AUC) was 0.712 for IL8 (0.543 to 0.881, p = 0.019) and 0.756 for PF4 (0.600 to 0.912, p = 0.005).
  • Although the validation cohort was randomly selected, its median survival was significantly shorter than the discovery cohort's: 12.53 months (7.37 to 17.70) versus 22.1 months (16.98 to 27.22), p = 0.003.
• The authors' conclusion: The authors concluded that mesothelioma patients whose pleural effusion has high concentrations of a range of soluble factors have relatively poor prognosis, independent of other prognostic factors. They stated that measuring IL8, PF4, IL2Ra, lipocalin-2 and IL4 in pleural fluid will add prognostic information.
• Limitations the authors state:
  • The study does not explain why these factor levels are associated with prognosis.
  • The IL4 association with prognosis is weak and is confounded by its correlation with other cytokines.
  • Confirmation studies are still needed to evaluate these factors as biomarkers and to set threshold values for clinical use.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Prognosis, Mesothelioma, Pleural Mesothelioma, Cytokine.

Related studies

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• Diagnostic value of soluble mesothelin-related peptides in pleural effusion for malignant pleural mesothelioma: An updated meta-analysis — R. Gao, F. Wang, et al. (2019)
• Multiplex Soluble Biomarker Analysis from Pleural Effusion — J. Javadi, K. Dobra, et al. (2020)
• Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions — H.I. Pass, A. Wali, et al. (2008)
• Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum — J. Creaney, S. Sneddon, et al. (2013)
• Pleural effusions and pneumothorax: Beyond simple plumbing: Expert opinions on knowledge gaps and essential next steps — R. Thomas, N.M. Rahman, et al. (2020)

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