Malignant pleural mesothelioma (MPM), a devastating asbestos-induced cancer, has <10% 5-yr survival. Treatments are few and limited. Aggressive surgery (extra-pleural pneumonectomy (EPP) or pleurectomy/decortication (PD)) followed by chemotherapy is effective in a subset of patients, yielding 20%-30% 5-yr survival, but identifying the patients who will benefit from this treatment is a significant challenge. Surgery of any type for MPM is associated with considerable morbidity and some mortality. The primary goal is to enhance and validate prognostic biomarkers and a robust risk score to identify only those patients who will be long-term survivors to undergo surgery. We previously developed and prospectively validated a 4-factor pathology staging score (MPS=MPM Prognostic Score) that is the best reliable prognostic test after surgery for MPM. We extended this effort to develop a pre-treatment clinical prognostic score to inform patients in their decisions regarding therapy. Herein we propose for multicenter clinical evaluation this risk score (MRiS = MPM Risk Score) based on 4 simple tests (Chest CT, CBC, 2 molecular tests on pleural biopsy). We will leverage 4 unique prospective patient cohorts (total: 1101 patients) with clinical data and specimens for the proposed work. These cohorts constitute a one-of-a-kind resource that also allows to generate, evaluate and validate new candidate biomarkers. In a recent study published in Nat. Genetics, we defined 4 robust, distinct and more homogeneous expression clusters consistent with the epithelial to mesenchymal transformation and demonstrated that expression cluster I (defined by CLDN15/VIM ratio) can be a surrogate for the histological- subtype-diagnosis in MRiS and we propose to expand this to the other clusters. We also constructed and validated a derivative of a simple existing blood test (neutrophil/lymphocyte ratio) that is prognostic and a part of MRiS representing the immune response. We hypothesize that 1) adding new genetic and clinical test information to our current prognostic models will enable more accurate allocation of MPM patients into more homogeneous pre-treatment subpopulations, allowing for rational assignment of therapies; 2) our new prognostic models can be successfully transferred to FFPE and be used clinically. The Aims are: 1. Prospectively validate a new pre-treatment prognostic algorithm to predict survival for MPM patients, by enrolling all new patients with MPM into a clinical trial where the MRiS is determined prior to treatment and outcome is measured by follow up. We will also: a. Determine test and specimens properties for the molecular tests in pleural biopsies; and b. Develop, explore and test new diagnostic, prognostic and predictive signatures for MPM based on expression clusters membership and response to specific therapies. 2. Transfer the molecular tests to FFPE preserved pleural biopsy samples and determine concordance, specimen and test properties of propose...