PROJECT SUMMARY/ABSTRACT: There is currently a technological gap in high-dose-rate brachytherapy (HDR-BT) that has stunted the efficacy of single-fraction HDR-BT monotherapy for prostate cancer patients and is preventing a shift away from invasive interstitial brachytherapy to an intracavitary-only approach for cervical cancer patients. The gap is due to the radiation dose conformity limitations of HDR-BT, and, until a solution is developed, prostate cancer HDR-BT will continue to have dose conformity limitations due to geometric constraints, requiring multiple needle implants and/or a hospital stay, and cervical cancer treatments will continue to be invasive, challenging, and time-con- suming, with limited patient access. The long-term goal is to transfer a technology, called ReNeu, for generating 169Yb sources that can dramatically improve radiation dose conformity, into clinical usage using a business model based on the substantial cost savings achieved through re-activation in a nuclear reactor. The overall objective of this project is to demonstrate the technical merit, feasibility, and commercial potential of ReNeu, which is expected to enable the rotating shield brachytherapy (RSBT) approach to improving dose conformity. 169Yb is an ideal isotope for RSBT since its specific activity is high enough to match the dose rate of conventional 192Ir in a similar source volume, and the emitted gamma ray energy is low enough for partial shielding. The proposed approach for making 169Yb commercially feasible is to simply increase source volume from 1 mm3 to 3 mm3, while maintaining the conventional source diameter. The source could be (re)activated up to 11 times, and, based on preliminary work, this process could reduce the overall cost per clinic-year of 169Yb sources by 75%. The rationale for this work is that ReNeu will provide the framework that will make RSBT commercially viable, enabling brachytherapy improvements that could benefit tens of thousands of patients per year. A demonstration of feasibility for the ReNeu approach will be addressed by carrying out two specific aims: (1) Develop a mechan- ical prototype ReNeu source/wire that enables clinical usage and (2) Develop the (re)activation model for ReNeu to validate its clinical and commercial potential. Under aim 1, a 169Yb source will be constructed with a 3 mm3 volume that, along with its controlling guidewire, will be capable of re-activation. The expectation is that the source/wire will successfully pass the tests needed for FDA clearance. Under aim 2, the 169Yb (re)activation model based on preliminary data will be experimentally calibrated, which will apply for up to 11 (re)activations. The expectation is that each (re)activation will take 9 days on average, with an average clinical source lifetime after each (re)activation of 41 days. This contribution is expected to be significant because it removes a major impediment to improving brachytherapy that could benefit prostate and cerv...