Christopher R. Hempel

Histotripsy of the Prostate: Dose Effects in a Chronic Canine Model

OBJECTIVES To develop the technique of histotripsy ultrasound therapy as a noninvasive treatment for benign prostatic hyperplasia and to examine the histotripsy dose-tissue response effect over time to provide an insight for treatment optimization. We have previously demonstrated the feasibility of prostate histotripsy fractionation in a canine model. METHODS Various doses of histotripsy were applied transabdominally to the prostates of 20 canine subjects. Treated prostates were then harvested at interval time points from 0 to 28 days and assessed for histologic treatment response. RESULTS The lowest dose applied was found to produce only scattered cellular disruption and necrosis, whereas higher doses produced more significant regions of tissue effect that resulted in sufficient fractionation of tissue so the material could be voided with urination. Urethral tissue was more resistant to the lower histotripsy doses than was parenchymal tissue. Treatment of the urethra at the lowest doses appeared to heal, with minimal long-term sequelae. CONCLUSIONS Histotripsy was effective at fractionating parenchymal and urethral tissue in the prostate, in the presence of a sufficient dose. Further development of this technique could lead to a noninvasive method for debulking the prostate to relieve symptoms associated with benign prostatic hyperplasia.

Histotripsy fractionation of prostate tissue: local effects and systemic response in a canine model.

PURPOSE Histotripsy is an extracorporeal ultrasound technology that uses cavitational mechanisms to produce nonthermal tissue destruction. Previously we reported the feasibility of histotripsy for prostate tissue fractionation and immediate debulking. In this study we characterized the local effects and systemic response after histotripsy treatment of prostate tissue in an in vivo canine model. MATERIALS AND METHODS Histotripsy was applied transabdominally to the prostate in 18 intact male canine subjects under general anesthesia. Acoustic bursts (4 μseconds) were delivered at a 300 Hz pulse repetition rate from a highly focused 750 kHz piezoelectric ultrasound transducer with a 15 cm aperture and 3 × 3 × 8 mm focal volume. Specimens of the prostate and surrounding structures were obtained at prescribed time points (0, 7, 28 or 56 days) after histotripsy. Blood and urine parameters were assessed periodically while clinical evaluation incorporating a validated veterinary pain scale was performed daily. RESULTS Conventional transrectal ultrasound facilitated targeting of the focal volume and provided real-time assessment of cavitation activity. Fractionation of the targeted volume and clearance of the resultant debris with urination produced a treatment cavity in each prostate. No acoustic collateral damage was seen and urothelialization of the treatment cavity developed within 28 days of treatment. Only transient laboratory value abnormalities and minimal hematuria were noted after treatment. Pain scores revealed only mild posttreatment discomfort. CONCLUSIONS Histotripsy produced consistent tissue fractionation and prostate debulking without collateral acoustic injury or clinical side effects and it was well tolerated in the canine model.

Acoustic Access to the Prostate for Extracorporeal Ultrasound Ablation

This study aimed to measure acoustic access to the prostate for extracorporeal ultrasound ablation. Both transabdominal and transperineal approaches were considered. The objective was to measure the size and shape of the aperture available for unobstructed targeting of the prostate. CT images of 17 randomly selected men > 56 years of age were used to create 3D reconstructions of the lower abdomen and pelvis. Rays were traced from target locations in the prostate toward the perineum and the abdomen. The maximum CT density encountered along each path was recorded; those paths that traversed structures with CT density exceeding a soft tissue threshold were considered to be blocked by bone. Unblocked rays comprised the accessible aperture. The aperture through the perineum was found to be a triangular-shaped region bounded by the lower bones of the pelvis varying significantly in size between subjects. The free aperture through the abdomen was wedge shaped limited by the pubis and also with great subject-to-subject variability. Average unblocked fractions of an f/1 transducer to target base, middle, and apex of the prostate along the urethra from the perineum were 77.0%, 94.4%, and 99.6%, respectively. Averages targeting from the abdomen were 86.1%, 52.3%, and 11.0%. Acoustic access to the prostate for therapy through the perineum was judged to be feasible. Access from the abdomen was judged to be sufficient for the base of the prostate, but likely inadequate for the middle and apex.

Prostate histotripsy for BPH: initial canine results

Histotripsy is an extracorporeal ablative technology that utilizes microsecond pulses of intense ultrasound (< 1% duty cycle) to produce nonthermal, mechanical fractionation of targeted tissue. We have previously demonstrated the feasibility of histotripsy prostate ablation. In this study we sought to assess the chronic tissue response, tolerability and safety of histotripsy in a chronic in vivo canine model. Five acute and thirteen chronic canine subjects were anesthetized and treated with histotripsy targeting the prostate. Pulses consisted of 3 cycle bursts of 750 kHz ultrasound at a repetition rate of 300 Hz delivered transabdominally from a highly focused 15 cm aperture array. Transrectal ultrasound imaging provided accurate targeting and real-time monitoring of histotripsy treatment. Prostates were harvested at 0, 7, 28, or 56 days after treatment. Consistent mechanical tissue fractionation and debulking of prostate tissue was seen acutely and at delayed time points without collateral injury. Urothelialization of the treatment cavity was apparent 28 days after treatment. Canine subjects tolerated histotripsy with minimal hematuria or discomfort. Only mild transient lab abnormalities were noted. Histotripsy is a promising non-invasive therapy for prostate tissue fractionation and debulking that appears safe and well tolerated without systemic side effects in the canine model.

Analysis of Acoustic Access to the Prostate Through the Abdomen and Perineum for Extracorporeal Ablation

As part of the development of a noninvasive treatment for BPH using histotripsy, this study aimed to measure acoustic access for extracorporeal ablation of the prostate. Both transabdominal and transperineal approaches were considered. The objective was to measure the size and shape of a transducer aperture that could target the prostate without obstruction. CT images obtained from 17 subjects >56 years of age were used to create 3D reconstructions of the lower abdomen and pelvis. Target locations on the urethra at the base, mid, and apex in the prostate were marked along with a transrectal imaging probe. Evenly space rays spanning were traced from each target location towards the perineum and separately towards the abdomen with the maximum x‐ray density encountered along each path recorded. The overall free aperture through the perineum was found to be a triangular shaped region bounded by the lower bones of the pelvis and the transrectal probe varying significantly in size between subjects. The free ape...

Histotrispy: Urologic applications.

Histotripsy is an extracorporeal ablative technology that utilizes microsecond pulses of intense ultrasound to produce nonthermal, mechanical fractionation of targeted tissue. We have previously demonstrated the feasibility of histotripsy ablation in in vivo renal and prostate models. We sought to assess the chronic tissue response, tolerability, and safety of prostate histotripsy in a chronic in vivo canine model. Five acute and thirteen chronic canine subjects were anesthetized and treated with histotripsy targeting the prostate. Pulses consisting of three cycle bursts of 750‐kHz ultrasound at a repetition rate of 300 Hz were delivered from a highly focused 15‐cm aperture array. Prostates were harvested at 0, 7, 28, or 56 days after treatment. Transrectal ultrasound imaging provided accurate targeting and real‐time monitoring of histotripsy treatment. Consistent mechanical tissue fractionation and debulking of prostate tissue was seen acutely and at delayed time points without collateral injury. Canine ...