Author(s): Tsim S.; Blyth K.G.; Kelly C.; Alexander L.; Evison M.; Holme J.; Cameron E.J.; Wright A.; Grundy S.; Grieve D.; Ionescu A.; Breen D.; Paramasivan E.; Psallidas I.; McCormick C.; Thomson F.; Ostroff R.; Maskell N.
Source: American Journal of Respiratory and Critical Care Medicine; 2018; vol. 197
Publication Date: 2018
Publication Type(s): Conference Abstract
Available at American Journal of Respiratory and Critical Care Medicine – from Edge Hill Aintree LIRC (lib302411) Local Print Collection [location] : Edge Hill Aintree LIRC.
Abstract:Introduction An accurate, diagnostic blood biomarker for Malignant Pleural Mesothelioma (MPM) would be a major clinical advance. Previous studies have been limited by size, retrospective design, inconsistent sampling and inappropriate comparators. Fibulin-3 (F-3), a secreted glycoprotein and SOMAscan (SS), a 13-protein proteomic classifier, have demonstrated >90% sensitivity and specificity in retrospective series. Mesothelin has been widely studied in MPM, but in meta-analyses offers insufficient sensitivity for clinical use. Methods DIAPHRAGM (ISRCTN10079972) was an adequately-powered, prospective observational study, funded by the Chief Scientist Office Scotland (ETM/285), that recruited an ‘intention-to-diagnose’ population from 22 UK/Irish centres (December 2013 – December 2016). The primary objective was to determine if F-3 and SS protein measurements offered clinically useful diagnostic performance, defined as high sensitivity (>90% for SS, >80% for F-3) at high specificity (>90% for both). F-3 and SS performance will be compared to Mesothelin. Correlation between F-3 and SS protein levels and tumour volume was tested using contrast-enhanced Magnetic Resonance Imaging (MRI) in a cohort of patients with MPM recruited to an exploratory sub-study. Patients were recruited at first presentation with suspected pleural malignancy (SPM). Biomarker sampling was designed to simulate clinical use and diagnostic assessment was robust and consistent (Figure 1). Inclusion criteria were SPM (unilateral pleural effusion/mass), fitness for sampling and consent. Patients with an in-situ or recent chest drain were excluded. Target sample size was 600 SPM cases (including at least 120 MPM), in addition to 109 asbestos-exposed controls (AECs). This assured a standard error around all estimates, for all markers of <5%. Results 639 SPM and 109 AECs were recruited. Of the SPMs, 75% (n=478) were male, mean age was 72 (SD 10) years, 70% were current/ex-smokers. 85% (n=540) presented with breathlessness, 27% (n=171) with chest pain and 42% (n=270) as an acute admission. 156/639 patients had MPM (24%), 213/639 (33%) had secondary pleural malignancy and 241/639 (38%) had benign pleural disease. Final diagnoses are awaited in 29/639 (5%) at time of writing. 31 MPM patients underwent volumetric MRI. Median pleural volume in these patients was 346mls (IQR 265-461). F-3, SS and Mesothelin assays are currently in progress. Conclusion DIAPHRAGM is an appropriately-designed, multi-centre study that will clearly define the diagnostic performance of F-3, SS and Mesothelin in MPM. A large, well-phenotyped bioresource (serum, plasma, DNA +/-pleural fluid) has been created for future biomarker discovery/validation studies.