Despite aggressive surgical, radiological, and chemotherapeutic interventions, patients with primary and metastatic brain malignancies have poor prognoses. Primary treatment often includes surgical debulking followed by chemoradiation. In the post-therapy brain, there is commonly distortion of tissue and treatment-induced reactive/healing changes, which are sometimes identified as pseudo-progression. Distinguishing these features from true progression of residual or recurrent cancer is perplexing. Accurate clinical distinction between these two cases is essential, since it drives treatment and monitoring strategies in these patients. Magnetic resonance imaging (MRI) is the standard of reference in the evaluation of brain tumors. In recent years, multiparametric MRI (mpMRI) has become helpful in distinguishing pseudo-progression from true progression; although, the diagnostic performance of these methods needs further improvement. Positron emission tomography (PET) imaging of factors associated with cellular proliferation provides valuable, complementary information that can more accurately differentiate posttreatment reactive changes from residual brain tumor. Our group has extensive expertise in the clinical evaluation of an emerging PET tracer known as 18F-2’-fluoro-5-methyl-1- beta-D-arabinofuranosyluracil (FMAU). FMAU is a thymidine analog that is phosphorylated by both cytosolic thymidine kinase 1 (TK1) and mitochondrial TK2. Thus, this PET tracer incorporates into the DNA synthetic pathway at a rate proportional to proliferation. As a contrast agent, it provides information specific to cellular proliferation, which has the potential to differentiate between true progression and pseudo-progression. We have ample experience with FMAU synthesis, pharmacokinetic studies, and performing PET studies in humans under a currently approved protocol by the USC Radioactive Drug Research Committee (RDRC) Protocol No. RAD-UN-10-10). The overall goal of this proposal is to test the hypothesis: combined structural, functional, and cellular proliferation imaging information provided by mpMRI and dynamic FMAU PET kinetic analysis more accurately characterize lesions in patients who have undergone primary treatment for brain malignancy. Our specific aims are: Aim 1) Correlate radiomics mpMRI and dynamic FMAU PET kinetic parameters to identify multimodality imaging features that discriminate recurrent brain tumor from post-treatment reactive changes; Aim 2) Associate the combined imaging feature set to immunohistopathology and assess impact on clinical management. This translationalclinical, interdisciplinary project will employ the unique expertise of 3 experienced investigators from 3 USC Schools, Hossein Jadvar, MD, PhD (PI), from KSOM Department of Radiology, who is an expert in molecular imaging and theranostics, Krishna Nayak, PhD (Co-PI), from VSOE Department of Electrical and Computer Engineering, who is an expert in MRI acquisition and analysis, and J. Andrew MacKay, PhD (Co-PI), from School of Pharmacy, who is an expert in image-driven pharmacokinetics. Our recently FDA-approved Investigational New Drug application (#129512) and pilot human data that will be obtained in this project will facilitate the expanded use of this novel diagnostic tool more rapidly to the clinic where it can have a major impact on patient care. Potential commercialization is facilitated since the intellectual property (US patent 7,273,600 B2) for FMAU radiochemistry preparation has been assigned to USC and our Molecular Imaging Center is now near the final stages of renovation into an approved cGMP PET radiopharmaceutical production facility.