Precision Epigenomics Inc, is a University of Arizona Cancer Center and Department of Pathology, spin out, aiming to launch molecular diagnostic tests for cancer patients. The product of this SBIR is Sentinel-MPE liquid biopsy assay, which is a multi-cancer detection test. Our Sentinel-MPE test can identify over twenty different cancer types. Here, we apply the Sentinel- MPE test to the differential diagnosis of pleural effusions. In clinical practice, it remains a challenge to distinguish between malignant pleural effusion (MPE) and benign pleural effusion (BPE). Cytology remains the gold standard for the detection of malignant cells in pleural effusion. However, its sensitivity is limited. Because of the limitations of conventional cytology methods, there is an urgent need to develop a more accurate and effective method for the efficient diagnosis of MPE. In collaboration with the University of Arizona, Precision Epigenomics has generated significant feasibility and clinical utility data using pleural effusion. Our pilot studies indicate that our Sentinel-MPE test has the potential to be an effective complimentary tool for cytology in the process of differential diagnosis. The aim of this project is to conduct a multi-site clinical validation study to establish the Sentinel-MPE test as a new commercial molecular test for the diagnosis of MPE. The aims of this project are: 1) To establish the diagnostic value of the Sentinel-MPE liquid biopsy assay to identify cancer in pleural effusion and 2) To validate the Sentinel-MPE liquid biopsy assay for cancer detection in pleural effusion. The long-term goal of this project is to bring the field of pathology a new diagnostic tool for the diagnosis of malignant pleural effusions.