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Open Access Research article

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

Krishna B Sriram12*, Vandana Relan12, Belinda E Clarke3, Edwina E Duhig3, Morgan N Windsor4, Kevin S Matar4, Rishendran Naidoo4, Linda Passmore12, Elizabeth McCaul12, Deborah Courtney12, Ian A Yang12, Rayleen V Bowman12 and Kwun M Fong12

Author Affiliations

1 UQ Thoracic Research Centre, School of Medicine, The University of Queensland, Queensland, Australia

2 Department of Thoracic Medicine, The Prince Charles Hospital, Queensland, Australia

3 Department of Anatomical Pathology, The Prince Charles Hospital, Queensland, Australia

4 Department of Thoracic Surgery, The Prince Charles Hospital, QLD, Australia

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BMC Cancer 2012, 12:428  doi:10.1186/1471-2407-12-428

Published: 25 September 2012

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.

Keywords:
Malignant pleural effusions; Mesothelioma; Lung cancer; DNA integrity index; Mesothelin