The TOPAS TOol for PArticle Simulation, launched on NCI funding in 2009, is a breakthrough software project that struck down a usability barrier that was limiting cancer research and treatment. Improvements to radiotherapy and imaging require understanding how subatomic particles travel through apparatus and tissue. The most precise calculations of such motion follow the Monte Carlo (MC) method. Yet MC's painstaking specialized computer programming techniques had limited its availability to a small number of specialists. TOPAS brings a reliable, experimentally validated and easy-to-use MC tool within reach of every physicist. Requiring no programming knowledge, TOPAS provides nearly unlimited flexibility. It enables both clinical applications (e.g. high precision patient dose calculation) and cutting edge research (e.g. four dimensional time-of-flight simulations for detector developments), while its design promotes inter-institutional collaboration. In 2013, on a second NCI award, TOPAS was expanded from its initial focus on proton therapy physics to also cover radiation biology. TOPAS has been widely accepted in proton therapy physics and biology with 272 users at 121 institutions in 24 countries, but those working on other radiotherapy modalities and medical imaging lack such a tool. We seek to address these needs, creating the only fully integrated platform for advanced radiotherapy including multi-modality treatments and a broad range of image guidance. We shall: Specific Aim 1: Enhance the TOPAS Environment for User-Friendly Interactive Modeling and Simulation · Expand support for multi-processor, cluster, cloud and grid environments · Improve I/O compatibility with other medical physics standards · Improve computational speed and Graphical User Interface Specific Aim 2: Extend TOPAS Capabilities for Translational and Clinical Applications · Library of radiotherapy and imaging components, simplify simulation of complex therapy, QA and shielding · Biological models for radiation protection and pre-clinical research · Imaging systems and patient simulation, including more complex patient models Specific Aim 3: Maintain TOPAS for all User Communities · Respond to changes in underlying software packages and operating systems · Expand automated regression testing system for quality control Specific Aim 4: Disseminate TOPAS with Full Participation in ITCR Program Activities · Disseminate TOPAS through workshops at key conferences and web site · Provide user support through online user forum, web-based training and twice-yearly in-person trainings · Develop TOPAS user collaboration, initiate projects to address key user needs identified post-award, maintain depository for users to exchange customizations and extensions, move TOPAS to open source