PROJECT SUMMARY: Renal cell carcinoma (RCC) is the sixth most common cancer in the United States, with ~ 82k new diagnoses estimated for 2023. Surgery is the preferred option for initial management of RCC, but the number of patients who qualify is reduced each year due to the aging, comorbid population. Histotripsy is a noninvasive, focused ultrasound therapy used for tissue ablation via bubble activity, and is an attractive alternative to surgery. Indeed, a pilot clinical trial to test histotripsy for the treatment of RCC is scheduled for 2023. Standard B-mode ultrasound imaging is used to monitor histotripsy via the detection of hyperintense bubble pixels. In the kidney, histotripsy bubbles are obscured on B-mode due to artifacts, image degradation at depth, and a lack of contrast specificity. Patients will be disqualified from receiving treatment with histotripsy when bubbles cannot be located and monitored with imaging. Further, B-mode bubble imaging does not provide the information necessary to assess the likelihood of successful oncological outcomes. Real-time feedback to adjust the histotripsy exposure and ensure ablation is of particular importance for heterogenous tumors common to RCC. Hence, there is a need for improved histotripsy bubble detection to enable therapy automation. To address this gap, we have developed ultrafast, bubble-specific ultrasound imaging for monitoring histotripsy. Using this imaging sequence, we can assess the diffusive properties of histotripsy bubbles, a key marker of ablation outcomes, with sub-millisecond resolution. The scientific premise of this study is that ultrafast imaging will elevate histotripsy bubble monitoring, and provide feedback to ensure effective and safe RCC ablation. We have demonstrated strong translational potential to monitor histotripsy with ultrafast imaging in vitro, ex vivo, and in murine renal tumors on a pre-clinical system. Our objective is to refine and integrate this sequence onto a clinical-grade imager, develop and test feedback algorithms in RCC tissues and a relevant large animal model, and rapidly translate this imaging protocol into use in patients. To test our scientific premise, we will investigate the following aims: We will develop a translational histotripsy system for RCC in Specific Aim 1. We will integrate our ultrafast sequence onto a clinical-grade imaging platform, and evaluate its sensitivity and accuracy for bubble detection. In Specific Aim 2, methods to monitor and modulate the bubble cloud lifetime will be developed. These methods will be used to adjust the histotripsy pulsing rate to enhance the efficacy of histotripsy ablation. Specific Aim 3 will use information on the bubble cloud dissolution rate to provide real-time feedback of treatment outcomes using an in vivo porcine kidney ablation model. The rate of urological sequelae will be determined in short-term survival studies. This study will deliver validated ultrafast sequences on a commercial histotripsy imaging system to improve RCC ablation and ensure safety. Following these validation steps, the sequence will be translated immediately in a clinical trial for histotripsy RCC.

PROJECT NARRATIVE Our long-term objective is to develop monitoring for histotripsy with ultrafast, bubble-specific ultrasound imaging for effective, safe, and rapid ablation of renal cell carcinoma to decrease patient morbidity and mortality. In this project, we aim to refine and integrate ultrafast imaging onto a clinical-grade platform to facilitate rapid adoption, and develop and test feedback algorithms in ex vivo malignant renal tissues and a relevant large animal model.