A Multi-Institutional Study of Magnetic Resonance/Ultrasound Fusion-Guided Nanoparticle-Directed Focal Therapy for Prostate Ablation.

PURPOSE: Focal therapy aims to provide a durable oncologic treatment option for men with prostate cancer (PCa), while preserving their quality of life. Most focal therapy modalities rely on the direct tissue effect, resulting in a possible nontargeted approach to ablation. Here, we report the results of the first human feasibility trial utilizing nanoparticle-directed focal photothermal ablation for PCa. MATERIALS AND METHODS: A prospective, open-label, single-arm, multicenter study of men with localized PCa in Gleason Grade Group 1 to 3 was conducted. Men received a single infusion of gold nanoparticles (AuroShells), followed by magnetic resonance (MR)/ultrasound (US) fusion-guided laser excitation of the target tissue to induce photothermal ablation. MRI was used to assess the effectiveness of prostate tissue ablation at 48 to 96 hours, 3 months, and 12 months post treatment. At 3 months, a targeted fusion biopsy of the lesion(s) was conducted. At 12 months, a targeted fusion biopsy and standard templated biopsy were performed. Treatment success was determined based on a negative MR/US fusion biopsy outcome within the treated area. RESULTS: Forty-six men were enrolled in the study, and 44 men with 45 lesions completed nanoparticle infusion and laser treatment. The mean PSA level at baseline was 9.5 ng/mL, which decreased to 5.9 ng/mL at 3 months and to 4.7 ng/mL at 12 months (P < .0001). The oncologic success rates at 3 and 12 months resulted in 29 (66%) and 32 (73%) of 44 patients, respectively, being successfully treated, confirmed with negative MR/US fusion biopsies within the ablation zone. Among Gleason Grade Group, maximum lesion diameter on MRI, prostate volume, and Prostate Imaging Reporting and Data System scoring, the maximum lesion diameter was significantly associated with the odds of treatment failure at 12 months (P = .046). CONCLUSIONS: Nanoparticle-directed focal laser ablation of neoplastic prostate tissue resulted in 73% of patients with successful treatment at 12 months post treatment, confirmed by negative MR/US fusion biopsy of the treated lesion and a systematic biopsy. CLINICAL TRIAL REGISTRATION NO.: 02680535.

Urothelial Differences in the Exstrophy-Epispadias Complex: Potential Implications for Management.

PURPOSE: The authors examined the urothelium of exstrophy-epispadias complex spectrum patients for histological differences and expression of terminal markers of urothelial differentiation. MATERIALS AND METHODS: Between 2012 and 2017 bladder biopsies were obtained from 69 pediatric exstrophy-epispadias complex patients. These specimens were compared to bladder specimens from normal controls. All bladder specimens underwent histological assessment followed by immunohistochemical staining for uroplakin-II and p63. Expression levels of uroplakin-II and p63 were then assessed by a blinded pathologist. RESULTS: Forty-three classic bladder exstrophy biopsies were obtained (10 newborn closures, 22 delayed closures, and 11 repeat closures). Additional biopsies from 18 cloacal exstrophy patients and 8 epispadias patients were also evaluated. These specimens were compared to 8 normal control bladder specimens. Overall, uroplakin-II expression was lower in exstrophy-epispadias complex patients compared to controls (p <0.0001). Among classic bladder exstrophy patients, there was reduced expression of uroplakin-II in the delayed and repeat closures in comparison to newborn closures (p=0.045). Expression of p63 was lower in patients with exstrophy-epispadias complex compared to controls (p <0.0001). Expression of p63 was similar among classic bladder exstrophy patients closed as newborns when compared to delayed or repeat closures. Classic bladder exstrophy patients had a higher rate of squamous metaplasia when compared to controls (p=0.044). Additionally, there was a higher rate of squamous metaplasia in the patients undergoing delayed closure in comparison to those closed in the newborn period (p <0.001). CONCLUSIONS: The urothelium in the exstrophy-epispadias complex bladder is strikingly different than that of healthy controls. Uroplakin-II expression is greatly reduced in exstrophy-epispadias complex bladders and is influenced by the timing of bladder closure. Reduced uroplakin-II expression and increased rates of squamous metaplasia in exstrophy-epispadias complex patients undergoing delayed closure suggests that exposure of the urothelium may induce these changes. These findings shed light on the molecular changes in exstrophy-epispadias complex bladders and may have implications on the appropriate timing of primary bladder closure, as those closed in the newborn period appear to have a greater potential for growth and differentiation.

Urinary Continence Outcomes in Classic Bladder Exstrophy: A Long-Term Perspective.

PURPOSE: We investigated surgical approaches to urinary incontinence and long-term continence outcomes after successful bladder reconstruction in a heterogeneous patient population with classic bladder exstrophy. We hypothesized that while most patients will achieve urinary continence after surgery, only a select group will void volitionally per urethra. MATERIALS AND METHODS: An institutional database of 1,323 patients with exstrophy-epispadias complex was reviewed for patients with classic bladder exstrophy who underwent successful bladder closure and a subsequent continence procedure between 1975 and 2017. Procedures included bladder neck reconstruction, bladder neck reconstruction with augmentation cystoplasty or continent catheterizable stoma, and bladder neck closure with continent catheterizable stoma. Cloacal exstrophy, epispadias and variant exstrophy cases were excluded from analysis. Continence at last followup was defined as a dry interval of 3 or more hours without nighttime leakage. Those patients with more than 3 months of followup were assessed. RESULTS: Overall 432 patients underwent successful bladder closure (primary 71.5%, repeat 28.5%) and a urinary continence procedure. At last followup 162 (37%) underwent bladder neck reconstruction, 76 (18%) underwent bladder neck reconstruction with augmentation cystoplasty or continent catheterizable stoma, 173 (40%) underwent bladder neck closure with continent catheterizable stoma and 18 underwent other procedures. Median followup from the first continence procedure was 7.2 years (IQR 2.3-13.7). Continence was assessed in 350 patients. After isolated bladder neck reconstruction 91 of 142 patients were continent (64%, 95% CI 56-72). After bladder neck closure with continent catheterizable stoma 124 of 133 patients evaluated were continent (93%, 95% CI 87-97). CONCLUSIONS: Most patients with classic bladder exstrophy require multiple reconstructive procedures to achieve continence. Only about 25% of patients are expected to void normally per urethra without reliance on catheterization or urinary diversion.

3-Dimensional Magnetic Resonance Imaging Guided Pelvic Floor Dissection for Bladder Exstrophy: A Single Arm Trial.

PURPOSE: We determined the safety and efficacy of intraoperative magnetic resonance imaging guided surgical reconstruction of bladder exstrophy for the identification of the urogenital diaphragm fibers and the thickened muscular attachments between the posterior urethra, bladder plate and pubic rami. MATERIALS AND METHODS: Institutional review board and U.S. Food and Drug Administration approval was obtained for the use of Brainlab (Munich, Germany) intraoperative magnetic resonance imaging guided navigation of the pelvic floor anatomy during closure of classic bladder exstrophy and cloacal exstrophy at our institution. Preoperative pelvic 3-dimensional magnetic resonance imaging was obtained 1 day before closure in patients undergoing pelvic osteotomies. Intraoperative registration was performed after preoperative planning with a pediatric radiologist using 5 anatomical landmarks immediately before initiation of surgery. Accuracy of pelvic anatomy identification was assessed by 2 pediatric urological surgeons and 1 pediatric radiologist. RESULTS: In 43 patients with classic bladder exstrophy and 4 patients with cloacal exstrophy closed at our institution, Brainlab technology was used successfully to navigate and guide the dissection of the pelvic floor intraoperatively. In all patients there was 100% accuracy in the correlation of gross anatomical landmarks with 3-dimensional magnetic resonance imaging identified landmarks intraoperatively, and all patients had successful closure without any major complications. CONCLUSIONS: Brainlab intraoperative 3-dimensional magnetic resonance imaging guided pelvic floor navigation and dissection is an effective way to accurately identify pelvic anatomy during classic bladder exstrophy and cloacal exstrophy closure. This technology offers a unique opportunity for surgical skill education in this complex reconstructive operation.

Beyond transrectal ultrasound-guided prostate biopsies: available techniques and approaches.

OBJECTIVES: Recent advances have led to the use of magnetic resonance imaging (MRI) alone or with fusion to transrectal ultrasound (TRUS) images for guiding biopsy of the prostate. Our group sought to develop consensus recommendations regarding MRI-guided prostate biopsy based on currently available literature and expert opinion. METHODS: The published literature on the subject of MRI-guided prostate biopsy was reviewed using standard search terms and synthesized and analyzed by four different subgroups from among the authors. The literature was grouped into four categories-MRI-guided biopsy platforms, robotic MRI-TRUS fusion biopsy, template mapping biopsy and transrectal MRI-TRUS fusion biopsy. Consensus recommendations were developed using the Oxford Center for Evidence Based Medicine criteria. RESULTS: There is limited high level evidence available on the subject of MRI-guided prostate biopsy. MRI guidance with or without TRUS fusion can lead to fewer unnecessary biopsies, help identify high-risk (Gleason ≥ 3 + 4) cancers that might have been missed on standard TRUS biopsy and identify cancers in the anterior prostate. There is no apparent significant difference between MRI biopsy platforms. Template mapping biopsy is perhaps the most accurate method of assessing volume and grade of tumor but is accompanied by higher incidence of side effects compared to TRUS biopsy. CONCLUSIONS: Magnetic resonance imaging-guided biopsies are feasible and better than traditional ultrasound-guided biopsies for detecting high-risk prostate cancer and anterior lesions. Judicious use of MRI-guided biopsy could enhance diagnosis of clinically significant prostate cancer while limiting diagnosis of insignificant cancer.

Anatomy of Classic Bladder Exstrophy: MRI Findings and Surgical Correlation.

PURPOSE OF REVIEW: The exstrophy-epispadias complex (EEC) represents a group of congenitally acquired malformations involving the musculoskeletal, gastrointestinal, and genitourinary systems. Classic bladder exstrophy (CBE) is the most common and best studied entity within the EEC. In this review, imaging features of CBE anatomy will be presented with surgical correlation. RECENT FINDINGS: Magnetic resonance imaging (MRI) has emerged as a useful modality for pre- and postnatal assessment of the abdominal wall, pelvic floor, and gastrointestinal and genitourinary systems of children with CBE. The authors' experience supports use of preoperative MRI, in conjunction with navigational software, as a method for identifying complex CBE anatomy. Imaging facilitates surgical approach and improves visualization of complex anatomy, potentially helping to avoid complications. Continued investigation of imaging guidance in CBE repair is needed as surgical techniques improve.

Novel Anatomical Observations of the Prostate, Prostatic Vasculature and Penile Vasculature in Classic Bladder Exstrophy Using Magnetic Resonance Imaging.

PURPOSE: We used magnetic resonance imaging to define the innate pelvic neurovascular course and prostatic anatomy in infants with classic bladder exstrophy before the pelvis was altered by surgery. MATERIALS AND METHODS: Pelvic magnetic resonance imaging was performed in male infants with classic bladder exstrophy and compared to a group of age matched controls. Data collected included prostatic dimensions as well as course of the prostatic artery, periprostatic vessels and pudendal neurovasculature. RESULTS: The prostate was larger in the transverse (p <0.001) and anteroposterior (p <0.001) dimensions in patients with classic bladder exstrophy compared to those with normal prostates but was smaller in the craniocaudal dimension (p <0.001). This finding resulted in a larger calculated prostate volume in patients with classic bladder exstrophy compared to controls (p = 0.015). The pelvic vasculature and prostatic artery followed a similar course in patients with classic bladder exstrophy and controls. Relative to each other, the lateral to medial course of the prostatic arteries in males with classic bladder exstrophy was less pronounced than in normal males. A similar externally rotated pattern was seen when both sides of the pudendal vasculature were compared in males with classic bladder exstrophy. CONCLUSIONS: The prostate in infants with classic bladder exstrophy has a consistent configuration and dimensions that differ from those in normal infants. When both sides are compared, the periprostatic vasculature and penile sensory neurovascular bundles are externally rotated in infants with classic bladder exstrophy. However, these components course along the same landmarks as in normal patients.

Risk of Upgrading from Prostate Biopsy to Radical Prostatectomy Pathology-Does Saturation Biopsy of Index Lesion during Multiparametric Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy Help?

PURPOSE: We sought to determine whether saturation of the index lesion during magnetic resonance imaging-transrectal ultrasound fusion guided biopsy would decrease the rate of pathological upgrading from biopsy to radical prostatectomy. MATERIALS AND METHODS: We analyzed a prospectively maintained, single institution database for patients who underwent fusion and systematic biopsy followed by radical prostatectomy in 2010 to 2016. Index lesion was defined as the lesion with largest diameter on T2-weighted magnetic resonance imaging. In patients with a saturated index lesion transrectal fusion biopsy targets were obtained at 6 mm intervals along the long axis of the index lesion. In patients with a nonsaturated index lesion only 1 target was obtained from the lesion. Gleason 6, 7 and 8-10 were defined as low, intermediate and high risk, respectively. RESULTS: Included in the study were 208 consecutive patients, including 86 with a saturated and 122 with a nonsaturated lesion. Median patient age was 62.0 years (IQR 10.0) and median prostate specific antigen was 7.1 ng/ml (IQR 8.0). The median number of biopsy cores per index lesion was higher in the saturated lesion group (4 vs 2, p <0.001). The risk category upgrade rate from systematic only, fusion only, and combined fusion and systematic biopsy results to prostatectomy was 40.9%, 23.6% and 13.8%, respectively. The risk category upgrade from combined fusion and systematic biopsy results was lower in the saturated than in the nonsaturated lesion group (7% vs 18%, p = 0.021). There was no difference in the upgrade rate based on systematic biopsy between the 2 groups. However, fusion biopsy results were significantly less upgraded in the saturated lesion group (Gleason upgrade 20.9% vs 36.9%, p = 0.014 and risk category upgrade 14% vs 30.3%, p = 0.006). CONCLUSIONS: Our results demonstrate that saturation of the index lesion significantly decreases the risk of upgrading on radical prostatectomy by minimizing the impact of tumor heterogeneity.

Novel Observations of Female Genital Anatomy in Classic Bladder Exstrophy Using 3-Dimensional Magnetic Resonance Imaging Reconstruction.

PURPOSE: Understanding the distinct female anatomy in classic bladder exstrophy is crucial for optimal reconstructive and functional outcomes. We present novel quantitative anatomical data in females with classic bladder exstrophy before primary closure. MATERIALS AND METHODS: 3-Dimensional reconstruction was performed in patients undergoing pelvic magnetic resonance imaging, and pelvic anatomy was characterized, including measurements of the vagina, cervix and erectile bodies. RESULTS: We examined magnetic resonance imaging of 5 females (mean age 5.5 months) with classic bladder exstrophy and 4 age matched controls (mean age 5.8 months). Mean distance between the anal verge and vaginal introitus was greater in patients with classic bladder exstrophy (2.43 cm) than in controls (1.62 cm). Mean total vaginal length in patients with classic bladder exstrophy was half that of controls (1.64 cm vs 3.39 cm). All 4 controls had posterior facing cervical ora, while 4 of 5 females with exstrophy had anterior facing cervical ora located in the anterior vaginal wall. Lateral deviation of the cervical ora was also seen in all 5 patients with classic bladder exstrophy but in only 1 control. Clitoral body length was comparable in both groups (26.2 mm and 28.0 mm). However, the anterior cavernosa-to-posterior (pelvic rami associated) cavernosa ratio was much greater in patients with classic bladder exstrophy (6.4) compared to controls (2.5). CONCLUSIONS: This study uncovers the uniquely novel finding that contrary to their male counterparts, females with classic bladder exstrophy have the majority of the clitoral body anterior to the pelvic attachment. This discovery has surgical and embryological implications.

Magnetic Resonance Imaging-Transrectal Ultrasound Guided Fusion Biopsy to Detect Progression in Patients with Existing Lesions on Active Surveillance for Low and Intermediate Risk Prostate Cancer.

PURPOSE: Active surveillance is an established option for men with low risk prostate cancer. Multiparametric magnetic resonance imaging with magnetic resonance imaging-transrectal ultrasound fusion guided biopsy may better identify patients for active surveillance compared to systematic 12-core biopsy due to improved risk stratification. To our knowledge the performance of multiparametric magnetic resonance imaging in following men on active surveillance with visible lesions is unknown. We evaluated multiparametric magnetic resonance imaging and magnetic resonance imaging-transrectal ultrasound fusion guided biopsy to monitor men on active surveillance. MATERIALS AND METHODS: This retrospective review included men from 2007 to 2015 with prostate cancer on active surveillance in whom magnetic resonance imaging visible lesions were monitored by multiparametric magnetic resonance imaging and fusion guided biopsy. Progression was defined by ISUP (International Society of Urological Pathology) grade group 1 to 2 and ISUP grade group 2 to 3. Significance was considered at p ≤0.05. RESULTS: A total of 166 patients on active surveillance with 2 or more fusion guided biopsies were included in analysis. Mean followup was 25.5 months. Of the patients 29.5% had pathological progression. Targeted biopsy alone identified 44.9% of patients who progressed compared to 30.6% identified by systematic 12-core biopsy alone (p = 0.03). Fusion guided biopsy detected 26% more cases of pathological progression on surveillance biopsy compared to systematic 12-core biopsy. Progression on multiparametric magnetic resonance imaging was the sole predictor of pathological progression at surveillance biopsy (p = 0.013). Multiparametric magnetic resonance imaging progression in the entire cohort had 81% negative predictive value, 35% positive predictive value, 77.6% sensitivity and 40.5% specificity in detecting pathological progression. CONCLUSIONS: Multiparametric magnetic resonance imaging progression predicts the risk of pathological progression. Patients with stable multiparametric magnetic resonance imaging findings have a low rate of progression. Incorporating fusion guided biopsy in active surveillance nearly doubled our detection of pathological progression compared to systematic 12-core biopsy.