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Background Pleural mesothelioma (PM) can be challenging to diagnose. Some patients require multiple invasive procedures with associated delays before diagnosis. The TARGET study showed that PET-CT-guided biopsy did not improve diagnostic yield compared with CT in patients with initial non-diagnostic biopsies. 1 Newer immunohistochemical (IHC) tests such as BAP1 and MTAP were not available at the time of TARGET. REPLICA aimed to use these newer IHC tests to determine whether performing BAP1 and MTAP IHC on historical samples could have increased the diagnostic yield.Methods Participants with suspected pleural malignancy and an initial non-diagnostic biopsy were recruited to the TARGET trial between 10/11/2015–19/09/2018. For REPLICA, BAP1 and MTAP IHC were performed on the original non-diagnostic and repeat biopsies for all PM diagnoses within TARGET. Histological analysis including MTAP1 and MTAP staining was performed independently by two thoracic pathologists. Diagnostic yields and time to diagnosis were compared with and without BAP1 and MTAP IHC.Results We present the results of the first 21 patients, with a total of 50 biopsies. Participant characteristics were as expected (19; 90.5% male; median age 75 (70–83 IQR), 14; 67% epithelioid). 10/21 (47.6%) patients would have achieved a diagnosis after one biopsy, and a further 10/21 on second biopsy. This would have resulted in fewer biopsies overall (31 vs 50,p=0.0005). The addition of BAP1 and MTAP IHC would have reduced time to diagnosis (median 22 vs 71 days,p=0.0005), and required fewer diagnostic MDT discussions (31 vs 52,p=0.0005) with a potential biopsy-related cost saving of £741.90 per patient.Conclusions This study demonstrates the potential benefit of BAP1 and MTAP IHC in diagnosing PM. These additional tests have the potential to reduce multiple biopsies and shorten time to diagnosis. Access to BAP1 and MTAP IHC should be available within every cancer network.Reference Fonseka DD, et al. PET-CT-guided versus CT-guided biopsy in suspected malignant pleural thickening: a randomised trial. European Respiratory Journal 2024;63(2):2301295.