title: Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: UQ Thoracic Research Centre, School of Medicine, The University of Queensland, Queensland, Australia. bajee.sriram@uqconnect.edu.au
authors.forename: Krishna B
authors.initials: KB
authors.lastname: Sriram
authors.forename: Vandana
authors.initials: V
authors.lastname: Relan
authors.forename: Belinda E
authors.initials: BE
authors.lastname: Clarke
authors.forename: Edwina E
authors.initials: EE
authors.lastname: Duhig
authors.forename: Morgan N
authors.initials: MN
authors.lastname: Windsor
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Matar
authors.forename: Rishendran
authors.initials: R
authors.lastname: Naidoo
authors.forename: Linda
authors.initials: L
authors.lastname: Passmore
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCaul
authors.forename: Deborah
authors.initials: D
authors.lastname: Courtney
authors.forename: Ian A
authors.initials: IA
authors.lastname: Yang
authors.forename: Rayleen V
authors.initials: RV
authors.lastname: Bowman
authors.forename: Kwun M
authors.initials: KM
authors.lastname: Fong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis* / Q000097:blood / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D008297:Male; D000090204:Mesothelin; D008654:Mesothelioma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009369:Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D010996:Pleural Effusion / Q000235:genetics* / Q000473:pathology*; D016066:Pleural Effusion, Malignant / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D012372:ROC Curve; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D044366:Transition Temperature
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D058851:GPI-Linked Proteins; D000090204:Mesothelin