George R. Schade

Histotripsy methods in mechanical disintegration of tissue: towards clinical applications.

Abstract In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti-tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery.

Histotripsy focal ablation of implanted prostate tumor in an ACE-1 canine cancer model.

PURPOSE Histotripsy is a nonthermal ablative focused ultrasound technology with possible future applications for prostate cancer focal therapy. We used the ACE-1 prostate tumor model and evaluated the feasibility of treating prostate tumors with histotripsy. MATERIALS AND METHODS A total of 10 immunosuppressed (cyclosporine treated) canine subjects received transrectal ultrasound guided percutaneous intraprostatic injection of ACE-1 canine prostate cancer cells. Prostates were serially imaged with transrectal ultrasound to monitor tumor growth. Subjects were sham treated (3) or underwent transabdominal histotripsy of the prostate, which targeted implanted tumor and adjacent parenchyma using a 750 kHz piezoelectric ultrasound therapy transducer. Prostates were examined histologically to confirm tumor and the histotripsy treatment effect. RESULTS ACE-1 tumors were visualized on transrectal ultrasound in all 10 subjects within 2 weeks of tumor injection. Lesions demonstrated growth in the prostatic capsule, glandular lobules, fibrous septa and periurethral stroma with significant desmoplastic reaction and areas of central necrosis on histology. Lymph node and/or pulmonary metastases developed in 4 subjects. Ultrasound tumor localization and initiation of cavitation during histotripsy therapy were feasible in all treated subjects. Histologically there was evidence of homogenization of tumor and prostatic parenchyma in all 4 acute subjects with necrosis and hemorrhage in the 3 chronic subjects. CONCLUSIONS This study shows the feasibility of histotripsy destruction of prostate tumors in a canine ACE-1 model. It suggests a potential role for histotripsy based focal therapy for prostate cancer. Further studies are needed to better characterize the effects of histotripsy on malignant tissues.

Ex-Vivo Ureteroscopy at the Time of Live Donor Nephrectomy

BACKGROUND AND PURPOSE Potential transplant renal allograft recipients exceed the number of donors. Our institution now considers patients with small, unilateral, nonobstructing, incidental renal calculi for possible renal donation. We adopted ex-vivo ureteroscopy (ExURS) to render these kidneys stone free at the time of renal transplantation. We examined the safety and efficacy of ExURS. PATIENTS AND METHODS After confirming a lack of significant metabolic defects on 24-hour urinalysis, 23 patients with small nonobstructing unilateral nephrolithiasis detected on preoperative CT angiography underwent donor nephrectomy. Immediately after cold perfusion, ExURS was performed with ice cold saline irrigation. Retrospective review was performed. RESULTS Pyeloscopy was successfully performed in all 23 patients. A total of 28 calculi, mean largest diameter 3.9 mm (range 3-6 mm), were visualized in 19 kidneys. Basket extraction and holmium laser lithotripsy was performed in 12 and 6 kidneys, respectively. Treatment rendered 17/19 stone-containing kidneys stone free with a mean treatment time of 6.2 minutes (3-10 min). There were no intraoperative complications. Median serum creatinine level of recipients at 1 month and 1 year were 1.4 ± 1.8 mg/dL and 1.3 ± 0.6 mg/dL, respectively. At a median follow-up of 63 ± 47.2 months, there were no transplant urinary calculi among the recipients. CONCLUSIONS ExURS safely renders live donor kidney allografts stone free with low risk of recurrence. When used appropriately, ExURS could safely increase the number of potential kidney donors and minimize the risk of adverse stone events.

A novel canine model for prostate cancer

No existing animal model fully recapitulates all features of human prostate cancer. The dog is the only large mammal, besides humans, that commonly develops spontaneous prostate cancer. Canine prostate cancer features many similarities with its human counterpart. We sought to develop a canine model of prostate cancer that would more fully represent the features of human prostate cancer than existing models.

Endoscopic Assessment and Prediction of Prostate Urethral Disintegration After Histotripsy Treatment in a Canine Model

BACKGROUND AND PURPOSE Histotripsy is a nonthermal focused ultrasound technology that uses acoustic cavitation to homogenize tissue. Previous research has demonstrated that the prostatic urethra is more resistant to histotripsy effects than prostate parenchyma, a finding that may complicate the creation of transurethral resection of the prostate-like treatment cavities. The purpose of this study was to characterize the endoscopic appearance of the prostatic urethra during and after histotripsy treatment and to identify features that are predictive of urethral disintegration. MATERIALS AND METHODS Thirty-five histotripsy treatments were delivered in a transverse plane traversing the prostatic urethra in 17 canine subjects (1-3/prostate ≥1 cm apart). Real-time endoscopy was performed in the first four subjects to characterize development of acute urethral treatment effect (UTE). Serial postprocedure endoscopy was performed in all subjects to assess subsequent evolution of UTE. RESULTS Endoscopy during histotripsy was feasible with observation of intraurethral cavitation, allowing characterization of the real-time progression of UTE from normal to frank urethral disintegration. While acute urethral fragmentation occurred in 3/35 (8.6%) treatments, frank urethral disintegration developed in 24/35 (68.5%) within 14 days of treatment. Treating until the appearance of hemostatic pale gray shaggy urothelium was the best predictor of achieving urethral fragmentation within 14 days of treatment with positive and negative predictive values of 0.91 and 0.89, respectively. CONCLUSION Endoscopic assessment of the urethra may be a useful adjunct to prostatic histotripsy to help guide therapy to ensure urethral disintegration, allowing drainage of the homogenized adenoma and effective tissue debulking.

Urinary Tract Stones

Urinary tract stone disease is one of the most common urologic conditions in the US, with a lifetime prevalence of about 13% for men and 7% for women. In this article we review the management of urinary tract stones and discuss when to seek urologic consultation. We cover epidemiologic data, stone types, presenting symptoms, imaging, metabolic evaluation and risk factors, and medical management strategies. We also discuss the indications for surgical intervention and the common operative procedures currently available.

Prostate Cancer Expression Profiles of Cytoplasmic ERβ1 and Nuclear ERβ2 are Associated with Poor Outcomes following Radical Prostatectomy

PURPOSE Existing data regarding the expression of estrogen receptors (ERs) and prostate cancer outcomes have been limited. We evaluated the relationship of expression profiles of ERβ subtypes and the ER GPR30 (G-protein-coupled receptor-30) with patient factors at diagnosis and outcomes following radical prostatectomy. MATERIALS AND METHODS Tissue microarrays constructed using samples from 566 men with long-term clinical followup were analyzed by immunohistochemistry targeting ERβ1, ERβ2, ERβ5 and GPR30. An experienced pathologist scored receptor distribution and staining intensity. Tumor staining characteristics were evaluated for associations with patient characteristics, recurrence-free survival and prostate cancer specific mortality following radical prostatectomy. RESULTS Prostate cancer cells had unique receptor subtype staining patterns. ERβ1 demonstrated predominantly nuclear localization while ERβ2, ERβ5 and GPR30 were predominantly cytoplasmic. After controlling for patient factors intense cytoplasmic ERβ1 staining was independently associated with time to recurrence (HR 1.7, 95% CI 1.1-2.6, p = 0.01) and prostate cancer specific mortality (HR 6.6, 95% CI 1.8-24.9, p = 0.01). Intense nuclear ERβ2 staining was similarly independently associated with prostate cancer specific mortality (HR 3.9, 95% CI 1.1-13.4, p = 0.03). Patients with cytoplasmic ERβ1 and nuclear ERβ2 co-staining had significantly worse 15-year prostate cancer specific mortality than patients with expression of only cytoplasmic ERβ1, only nuclear ERβ2 and neither ER (16.4%, 4.3%, 0.0% and 2.0 %, respectively, p = 0.001). CONCLUSIONS Increased cytoplasmic ERβ1 and nuclear ERβ2 expression is associated with worse cancer specific outcomes following radical prostatectomy. These findings suggest that tumor ERβ1 and ERβ2 staining patterns provide prognostic information on patients treated with radical prostatectomy.

Characterizing the Morbidity of Postchemotherapy Retroperitoneal Lymph Node Dissection for Testis Cancer in a National Cohort of Privately Insured Patients

OBJECTIVE To characterize morbidity of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testis cancer, we analyze a contemporary national database. PC-RPLND is the standard for residual radiographic masses ≥1 cm (nonseminoma) and positron emission tomography-avid masses ≥3 cm (seminoma). Morbidity for PC-RPLND is greater than primary RPLND, which may be mitigated by performing surgery at a high-volume cancer center. METHODS Current Procedural Terminology and International Classification of Diseases, Ninth Edition codes identified men with testis cancer undergoing PC- or primary RPLND in MarketScan (2007-2012). Multivariable logistic regression assessed factors associated with receiving adjunctive procedures (ie, nephrectomy, vascular reconstruction), prolonged hospitalization, and 90-day readmission. Geographic variables assessed regionalization of PC-RPLND. RESULTS Of 559 men with claims for PC- or primary RPLND (206, 37% PC-RPLND), 19% of PC-RPLND underwent adjunctive procedures (vs 1% among RPLND, P  <  .01). For PC-RPLND, the nephrectomy rate was 10% and the vascular reconstruction rate was 8%. On multivariable analysis, PC-RPLND was associated with undergoing adjunctive procedures (odds ratio 41.9; 95% confidence interval 11.7, 150) and prolonged hospitalization (odds ratio 3.75; 95% confidence interval 1.68, 8.42) compared to primary RPLND. PC-RPLND was not associated with 90-day readmission. Up to 29% of PC-RPLNDs are performed in centers, billing just a single case through MarketScan in the 6 years studied. CONCLUSION PC-RPLND is associated with adjunctive procedures and longer hospitalizations. Given the morbidity of PC-RPLND in this young patient population, efforts are needed to establish quality benchmarks for, reduce the morbidity of, and to accurately discriminate risk during patient discussions prior to this complex, specialized surgery.

Boiling histotripsy of the kidney: Preliminary studies and predictors of treatment effectiveness

Boiling histotripsy (BH), an ultrasound technique to mechanically homogenize tissue, has been described in ex vivo liver and myocardium. As a noninvasive, non-thermal based approach, BH may have advantages over clinically available thermal ablative technologies for renal masses. We aimed to characterize BH exposures in human and porcine ex vivo kidneys using a 7-element 1 MHz transducer (duty factor 1–3%, 5–10 ms pulses, 98 MPa in situ shock amplitude, 17 MPa peak negative). Lesions were successfully created in both species, demonstrating focally homogenized tissue above treatment thresholds (pulse number) with stark transition between treated and untreated cells on histologic assessment. Human tissue generally required more pulses to produce similar effect compared to porcine. Similarly, kidneys displayed tissue specific resistance to BH with increasing resistance from cortex to medulla to the collecting system. Tissue properties that predict resistance to renal BH were evaluated demonstrating correlatio...

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

To assess the impact of histotripsy treatment parameters (pulse number and pulse‐repetition frequency [PRF]) on the efficiency of histotripsy induced homogenisation of the prostatic urethra.