Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas

Our plain-English summary of Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas, by K.B. Sriram, V. Relan, B.E. Clarke, et al (BMC Cancer, 2012).

The study

• Authors: K.B. Sriram, V. Relan, B.E. Clarke, E.E. Duhig, M.N. Windsor, K.S. Matar, R. Naidoo, L. Passmore, E. McCaul, D. Courtney, I.A. Yang, R.V. Bowman, K.M. Fong
• Journal: BMC Cancer
• Published: 2012;12:428
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The diagnosis of malignant pleural effusions (MPE) is often clinically challenging, especially if the cytology is negative for malignancy. DNA integrity index has been reported to be a marker of malignancy. The aim of this study was to evaluate the utility of pleural fluid DNA integrity index in the diagnosis of MPE.

Methods: We studied 75 pleural fluid and matched serum samples from consecutive subjects. Pleural fluid and serum ALU DNA repeats [115bp, 247bp and 247bp/115bp ratio (DNA integrity index)] were assessed by real-time quantitative PCR. Pleural fluid and serum mesothelin levels were quantified using ELISA.

Results: Based on clinico-pathological evaluation, 52 subjects had MPE (including 16 mesotheliomas) and 23 had benign effusions. Pleural fluid DNA integrity index was higher in MPE compared with benign effusions (1.2 vs. 0.8; p<0.001). Cytology had a sensitivity of 55% in diagnosing MPE. If cytology and pleural fluid DNA integrity index were considered together, they exhibited 81% sensitivity and 87% specificity in distinguishing benign and malignant effusions. In cytology-negative pleural effusions (35 MPE and 28 benign effusions), elevated pleural fluid DNA integrity index had an 81% positive predictive value in detecting MPEs. In the detection of mesothelioma, at a specificity of 90%, pleural fluid DNA integrity index had similar sensitivity to pleural fluid and serum mesothelin (75% each respectively).

Conclusion: Pleural fluid DNA integrity index is a promising diagnostic biomarker for identification of MPEs, including mesothelioma. This biomarker may be particularly useful in cases of MPE where pleural aspirate cytology is negative, and could guide the decision to undertake more invasive definitive testing. A prospective validation study is being undertaken to validate our findings and test the clinical utility of this biomarker for altering clinical practice.

In plain English

This Australian study tested whether a laboratory measure called the DNA integrity index (the ratio of longer to shorter DNA fragments) in pleural fluid could help tell malignant (cancer-related) pleural effusions from benign ones. The authors studied pleural fluid and matched blood serum from 75 consecutive patients with undiagnosed effusions at The Prince Charles Hospital, Brisbane, between February 2010 and September 2011. Fifty-two had malignant effusions, including 16 mesotheliomas and 22 lung cancers. Twenty-three had benign effusions, four of them asbestos-related. The median pleural fluid index was 1.1 in malignant effusions and 0.8 in benign effusions (p less than 0.001). In serum, the index did not differ between the two groups. Cytology combined with a raised index gave 81% sensitivity and 87% specificity. Among 46 patients whose cytology was negative, a raised index had an 81% positive predictive value. For mesothelioma, at 90% specificity, the index, pleural fluid mesothelin and serum mesothelin each had 75% sensitivity. The authors called the index a promising biomarker. They described the work as a single-centre pilot study with relatively few subjects and said its results need confirmation.

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: Diagnostic biomarker study (described by the authors as a translational study to be interpreted as a pilot study) of consecutive patients with pleural effusions
• Who was studied: 75 consecutive patients with undiagnosed pleural effusions at The Prince Charles Hospital, Brisbane, Australia, February 2010 to September 2011. 52 had malignant effusions (22 lung cancer, 16 mesothelioma, 14 other cancers) and 23 had benign effusions.
• Exposure: The study did not measure asbestos exposure. It measured cell-free DNA fragments (ALU 115bp and 247bp) and mesothelin in pleural fluid and serum. Four benign effusions were classed as asbestos-related, defined by asbestos exposure, pleural plaques and/or rounded atelectasis, with no evidence of mesothelioma.
• Main results:
  • The median pleural fluid DNA integrity index was 1.1 in all malignant effusions and 0.8 in benign effusions (p less than 0.001).
  • In the mesothelioma subgroup, the median pleural fluid index was 1.2, compared with 0.8 in benign effusions (p less than 0.001).
  • The serum DNA integrity index did not differ between malignant and benign effusions (median 0.9 vs. 0.9, p=0.461).
  • At 90% specificity for distinguishing all malignant effusions from benign ones, sensitivity was 57% for the pleural fluid index, 37% for pleural fluid mesothelin and 44% for serum mesothelin.
  • Cytology combined with a raised pleural fluid index (above 1.02) gave 81% sensitivity and 87% specificity for malignant versus benign effusions.
  • In 46 cytology-negative patients, 23 of whom were eventually diagnosed with a malignant effusion, a raised pleural fluid index had 57% sensitivity, 87% specificity, 81% positive predictive value and 67% negative predictive value.
  • For mesothelioma versus benign effusions, the area under the ROC curve was highest for serum mesothelin (0.94, 95% CI 0.87-1.00), followed by pleural fluid mesothelin (0.89) and the pleural fluid index (0.82).
  • For mesothelioma, at 90% specificity, the pleural fluid index, pleural fluid mesothelin and serum mesothelin each had 75% sensitivity.
  • Median pleural fluid mesothelin was 38 nM in patients with mesothelioma and 4.6 nM in patients with benign effusions (p less than 0.001).
• The authors' conclusion: The authors concluded that the pleural fluid DNA integrity index is a promising diagnostic biomarker for malignant pleural effusions and that its findings warrant confirmation in a large prospective study.
• Limitations the authors state:
  • The method used to measure DNA integrity is only one of several reported in the literature.
  • The number of subjects was relatively small, and the mix of diagnoses (including a high proportion of mesothelioma, 31%) came from a single Australian tertiary referral centre.
  • DNA was extracted from a mixture of cell types in pleural fluid, and the influence of non-tumour cells is not known.
  • Serum mesothelin results could not be obtained for 10 of 75 subjects (13%).

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Mesothelioma, Cytology, Mesothelin, Biomarker, Aspirate.

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