Prostate histotripsy: evaluation of prostatic urethral treatment parameters in a canine model.

Objective - To assess the impact of histotripsy treatment parameters (pulse number and pulse-repetition frequency [PRF]) on the efficiency of histotripsy induced homogenization of the prostatic urethra. Material and Methods - A total of 34 transabdominal prostate histotripsy treatments were applied along a perpendicular plane traversing the prostatic urethra of 21 canine subjects. - Prostate histotripsy was applied with 1) escalating pulse number with fixed PRF or 2) at fixed pulse number with varying PRFs. - The development of urethral homognization within 14 days of histotripsy was evaluated endoscopically and confirmed histologically. Results - Within 14 days of histotripsy 50%, 83%, 83%, and 100% of subjects receiving 12.5k, 25k, 50k, and 100k pulses per mm of treatment path (delivered at 500Hz PRF), respectively developed prostatic urethral disintegration. - Delivery of 100k pulses per mm was required to achieve urethral disintegration in all subjects within 24 hours of histotripsy treatment. - Increasing histotripsy PRF from 50Hz to 500Hz to 2,000Hz while applying a constant dose of 25k pulses per mm treatment was associated with increased rate of urethral disintegration (50% vs 75% vs 100% at 14 days, respectively). Conclusions - Increasing the number of histotripsy pulses and/or increasing the PRF of histotripsy treatment applied to the urethra may improve the rate and efficiency of prostatic urethral disintegration in the canine model. - This understanding will aid in the development of treatment strategies for prostate histotripsy for BPH in human trials. Keywords: Benign Prostatic Hyperplasia (BPH), Focused Ultrasound, Prostate Introduction Histotripsy is a focused ultrasound technology that delivers short ( 99.9% of particles are less than 6 µm in size.(8) Volumetric ablation greater than the size of a single focal volume is accomplished by moving the bubble cloud throughout the targeted region. Histotripsy therapy can be guided and monitored in real-time with conventional ultrasound because the bubble cloud appears as a distinct hyperechoic (bright) focus and targeted tissue echogenicity decreases (becomes darker) corresponding to progressive tissue disintegration.(9, 10) The overarching objective of this research is to develop a histotripsy therapy for benign prostatic hyperplasia (BPH) that replicates the debulking capability of transurethral resection of the prostate (TURP) yet is less invasive and hence more widely applicable to patients with significant co-morbidity and/or suitable for use outside the operating room. Towards this goal, histotripsy has been evaluated in an in vivo canine model, demonstrating the ability to homogenize prostate tissue.(11) In this model, transabdominal histotripsy of the prostate appears safe and effective(12) producing dose dependent tissue debulking of targeted prostatic tissue(13) with minimal hematuria, even in anticoagulated subjects.(14) The strategy for effective histotripsy treatment of BPH is to produce a TURP-like defect by homogenizing parenchymal tissue as well as the adjacent prostatic urethra in order to facilitate drainage of the resultant homogenate with voiding.(12) However, the prostatic urethra is more resilient to mechanical forces than the prostate parenchyma and requires a greater number of acoustic pulses to achieve tissue disintegration.(13) In vitro studies have also demonstrated that substrate stiffness is inversely correlated with histotripsy susceptibility and lesion size(15) and that altering the pulse repetition frequency (PRF) can affect the efficiency of cavitation induced tissue homogenization.(16) As a result, the purpose of this study was to explore the efficiency of prostatic urethra homogenization in the in vivo canine model when varying the number and rate (PRF) of applied histotripsy pulses in order to better optimize treatment parameters in anticipation of future clinical applications.