TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing.

PURPOSE: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services. METHODS: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at baseline, after pretest education/counseling, and after GT result disclosure. The primary end point was noninferiority in reducing decisional conflict between webtool and GC using the validated Decisional Conflict Scale. Mixed-effects regression modeling was used to compare decisional conflict between groups. Participants opting for GT received a 51-gene panel, with results delivered to participants and their providers. RESULTS: The analytic data set includes primary outcome data from 315 participants (GC [n = 162] and webtool [n = 153]). Mean difference in decisional conflict score changes between groups was -0.04 (one-sided 95% CI, -∞ to 2.54; P = .01), suggesting the patient-driven webtool was noninferior to GC. Overall, 145 (89.5%) GC and 120 (78.4%) in the webtool arm underwent GT, with pathogenic variants in 15.8% (8.7% in PCA genes). Satisfaction did not differ significantly between arms; knowledge of cancer genetics was higher but attitudes toward GT were less favorable in the webtool arm. CONCLUSION: The results of the TARGET study support the use of patient-driven digital webtools for expanding access to pretest genetic education for PCA GT. Further studies to optimize patient experience and evaluate them in diverse patient populations are warranted.

Technology-enhanced AcceleRation of Germline Evaluation for Therapy (TARGET): A randomized controlled trial of a pretest patient-driven webtool vs. genetic counseling for prostate cancer germline testing.

BACKGROUND: Germline testing has an increasingly important role in prostate cancer care. However, a relative shortage of genetic counselors necessitates alternate strategies for delivery of pre-test education for germline testing. This study, funded by the Prostate Cancer Foundation, seeks to address the need for novel methods of delivery of pre-test germline education beyond traditional germline counseling to facilitate informed patient decision-making for germline testing. METHODS: This is a two-armed randomized controlled trial (RCT) with a target enrollment of 173 participants with prostate cancer per study arm (total anticipated n = 346). Patients who meet criteria for germline testing based on tumor features, family history or Ashkenazi Jewish ancestry are being recruited from 5 US sites including academic, private practice and Veterans healthcare settings. Consenting participants are randomized to the interactive pretest webtool or germline counseling with assessment of key patient-reported outcomes involved in informed decision-making for germline testing. RESULTS: Participants complete surveys at baseline, after pretest education/counseling, and following disclosure of germline results. The primary outcome of the study is decisional conflict for germline testing. Secondary outcomes include genetic knowledge, satisfaction, uptake of germline testing, and understanding of results. CONCLUSION: Our hypothesis is that the web-based genetic education tool is non-inferior to traditional genetic counseling regarding key patient-reported outcomes involved in informed decision-making for germline testing. If proven, the results would support deploying the webtool across various practice settings to facilitate pre-test genetic education for individuals with prostate cancer and developing collaborative care strategies with genetic counseling. CLINICALTRIALS: gov Identifier: NCT04447703.

Five-alpha reductase inhibitors in men undergoing active surveillance for prostate cancer: impact on treatment and reclassification after 6 years follow-up.

OBJECTIVES: To evaluate the impact of 5-alpha reductase inhibitors (5-ARIs) on definitive treatment (DT) and pathological progression (PP) in patients on active surveillance (AS) for prostate cancer. METHODS: We identified 361 consecutive patients, from an IRB-approved database, on AS for prostate cancer with minimum 2 years follow-up. Patients were grouped into two cohorts, those using 5-ARIs (5-ARI; n = 119) or not using 5-ARIs (no 5-ARI; n = 242). Primary and secondary endpoints were treatment-free survival (TFS) and PP-free survival (PPFS), which were evaluated by Kaplan-Meier analysis. Univariate and multivariable cox regression analysis were used to identify predictors for PP and DT. A p value < 0.05 was considered statistically significant. RESULTS: Baseline characteristics and the prostate biopsy rate were similar between the two groups. Median (range) follow-up was 5.7 (2.0-17.2) years. Five-year and 10-year TFS was 92% and 59% for the 5-ARI group versus 80% and 51% for the no 5-ARI group (p = 0.005), respectively. Five-year and 10-year PPFS was 77% and 41% for the 5-ARI group versus 70% and 32% for the no 5-ARI group (p = 0.04), respectively. Independent predictors for treatment and PP were not taking 5-ARIs (p = 0.005; p = 0.02), entry PSA > 2.5 ng/mL (p = 0.03; p = 0.01) and Gleason pattern 4 on initial biopsy (p < 0.001; p < 0.001), respectively. The main limitation is the retrospective study design. CONCLUSIONS: 5-ARIs reduces reclassification and cross-over to treatment in men on active surveillance for prostate cancer. Further, taking 5-ARIs was an independent predictor for prostate cancer progression and definitive treatment.

Heterotopic Bone Formation in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma is associated with calcium deposition in a significant percentage of patients. However, frank ossification within a tumor is extremely rare. We report a case of a 41-year-old male with a slow-growing left renal mass who underwent minimally invasive nephron-sparing surgery. Final pathology revealed clear cell renal cell carcinoma with focal areas of heterotopic bone formation. While prognostic implications of this variant are unclear, patients with renal cell carcinoma with osseous metaplasia can present with slow growth kinetics and early-stage disease.

Urinary Retention in Spinal Cord Injury.

A 43-year-old woman with paralysis and neurogenic bladder secondary to a gunshot wound presented with worsening urinary incontinence and urinary tract infections. On workup she was found to have two large bladder stones with diameters of around 11 cm. She was managed with antibiotics and surgical removal. This case highlights the importance of a multidisciplinary team in managing patients with spinal cord injuries.

Robotic Renal Artery Aneurysm Repair.

BACKGROUND: Renal artery aneurysm (RAA) is a rare condition, traditionally managed with endovascular or open surgical techniques. OBJECTIVE: To report our experience with robotic RAA repair. DESIGN, SETTING, AND PARTICIPANTS: Nine consecutive patients underwent intracorporeal robotic surgery for 10 RAAs. SURGICAL PROCEDURE: Two patients underwent concomitant robotic partial nephrectomy. One patient had RAA in a solitary kidney. Median RAA diameter was 2.2 (1.8-3)cm. Intracorporeal transarterial hypothermic renal perfusion was performed in five patients. Robotic techniques included tailored aneurysmectomy and repair (n=5), excision with end-to-end anastomosis (n=2), aneurysmectomy with branch reimplantation (n=1), prosthetic interposition graft repair (n=1), and simple nephrectomy (n=1; this patient's data were excluded from analysis). MEASUREMENTS: Demographics, RAA characteristics, intraoperative techniques, perioperative outcomes, and follow up data were analyzed. Aneurysms were diagnosed by computed tomography, angiography, or incidentally during the performance of a partial nephrectomy. RESULTS AND LIMITATIONS: All cases were performed robotically, without conversion to open surgery. Median (range) operative time was 3.8 (3-6)h, warm ischemia time 26 (19-32)min, hypothermic renal perfusion time 34 (29-69)min, and estimated blood loss 100 (25-400)ml. No intraoperative blood transfusion was required. Median hospital stay was 3 (2-6)d. One patient had a Clavien-Dindo grade II complication. At median follow-up of 16 (2-67)mo, all patients had preserved renal function. Follow-up imaging confirmed normal caliber reconstructed renal arteries with globally perfused kidneys, except for two kidneys with small segmental infarcts due to an intentionally ligated small polar vessel. Limitations include the small number of patients and the retrospective nature of the study. CONCLUSIONS: Robotic repair of complex RAAs is feasible. Surgical expertise, patient selection, and RAA-specific vascular reconstruction are critical for success. Greater experience is needed to evaluate the proper place of robotic repair of RAAs. PATIENT SUMMARY: We report intracorporeal robotic repair for complex renal artery aneurysms. This robotic operation is feasible and safe, and replicates open principles. However, it requires considerable experience and expertise.

Torin2 Exploits Replication and Checkpoint Vulnerabilities to Cause Death of PI3K-Activated Triple-Negative Breast Cancer Cells.

Frequent mutation of PI3K/AKT/mTOR signaling pathway genes in human cancers has stimulated large investments in targeted drugs but clinical successes are rare. As a result, many cancers with high PI3K pathway activity, such as triple-negative breast cancer (TNBC), are treated primarily with chemotherapy. By systematically analyzing responses of TNBC cells to a diverse collection of PI3K pathway inhibitors, we find that one drug, Torin2, is unusually effective because it inhibits both mTOR and other PI3K-like kinases (PIKKs). In contrast to mTOR-selective inhibitors, Torin2 exploits dependencies on several kinases for S-phase progression and cell-cycle checkpoints, thereby causing accumulation of single-stranded DNA and death by replication catastrophe or mitotic failure. Thus, Torin2 and its chemical analogs represent a mechanistically distinct class of PI3K pathway inhibitors that are uniquely cytotoxic to TNBC cells. This insight could be translated therapeutically by further developing Torin2 analogs or combinations of existing mTOR and PIKK inhibitors.

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

Robotic Intracorporeal Continent Cutaneous Diversion.

PURPOSE: Robotic intracorporeal urinary diversion has mostly been done for ileal conduit or orthotopic neobladder diversion. We present what is to our knowledge the initial series, detailed technique and outcomes of the robotic intracorporeal Indiana pouch with a minimum 1-year followup. MATERIALS AND METHODS: Ten patients underwent robotic radical cystectomy, pelvic lymphadenectomy and intracorporeal Indiana pouch urinary diversion for cancer in 9 and benign disease in 1. Data were collected prospectively. Baseline demographics, pathology data, and 1-year complication rates and functional outcomes were assessed. RESULTS: All 10 cases were successfully completed intracorporeally without open conversion. Median total operative time was 6 hours, including 3.5 hours for pouch creation. Median blood loss was 200 cc and median hospital stay was 10 days. Four Clavien grade 1-2 and 3 Clavien 3-5 complications occurred. None of the patients had a bowel leak. One noncompliant patient requested undiversion to an ileal conduit. The remaining 9 patients successfully catheterized the ileal channel and were completely continent at the last followup at a median of 13.7 months (range 12.3 to 15.2). Study limitations include small sample size and short followup. CONCLUSIONS: We present what is to our knowledge the initial series of robotic completely intracorporeal Indiana pouch diversion. Early perioperative data indicate acceptable operative efficiency and complication rates. Longer followup is required to assess the functional outcomes of this less commonly performed diversion.

Robot-Assisted Laparoscopic Resection of a Pelvic Schwannoma.

There is minimal data within the literature demonstrating the use of robotics to resect pelvic, benign schwannoma(s). Herein, we describe a case of a 46-year-old transgender male that presented with complaints of left-sided pelvic pain. Pre-operatively, the etiology was unknown. The patient underwent robotic-assisted laparoscopic excision of the pelvic mass, including a 5-6 cm resection of the obturator nerve, successfully. Final pathology found a benign schwannoma. Schwannomas are difficult to diagnose pre- and intra-operatively and are thus frequently misdiagnosed as urologic or gynecologic lesions. This report demonstrates that robotics can be used safely to resect benign, pelvic schwannoma(s).

Identifying aggressive prostate cancer foci using a DNA methylation classifier.

BACKGROUND: Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland. RESULTS: Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages. CONCLUSIONS: Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.

Robotic Partial Nephrectomy: Expanding Utilization, Advancing Innovation.

Robotic partial nephrectomy (RPN) is gaining increasing prominence for nephron-sparing surgery in the treatment of patients with localized kidney tumors. RPN offers the benefits of minimally invasive surgery with a shorter learning curve compared with its laparoscopic counterpart. While long-term data are awaited, RPN does provide short-term oncologic and functional outcomes comparable to open and laparoscopic partial nephrectomy. Furthermore, robotic surgery has facilitated technical innovation, including the elimination of warm ischemia, provided minimally invasive alternatives to patients with complex tumors, and importantly, has fuelled increased dissemination of partial nephrectomy surgery among community urologists.

Evolution of robot-assisted orthotopic ileal neobladder formation: a step-by-step update to the University of Southern California (USC) technique.

OBJECTIVE: To describe our, step-by-step, technique for robotic intracorporeal neobladder formation. PATIENTS AND METHODS: The main surgical steps to forming the intracorporeal orthotopic ileal neobladder are: isolation of 65 cm of small bowel; small bowel anastomosis; bowel detubularisation; suture of the posterior wall of the neobladder; neobladder-urethral anastomosis and cross folding of the pouch; and uretero-enteral anastomosis. Improvements have been made to these steps to enhance time efficiency without compromising neobladder configuration. RESULTS: Our technical improvements have resulted in an improvement in operative time from 450 to 360 min. CONCLUSION: We describe an updated step-by-step technique of robot-assisted intracorporeal orthotopic ileal neobladder formation.

Improving needle biopsy accuracy in small renal mass using tumor-specific DNA methylation markers.

PURPOSE: The clinical management of small renal masses (SRMs) is challenging since the current methods for distinguishing between benign masses and malignant renal cell carcinomas (RCCs) are frequently inaccurate or inconclusive. In addition, renal cancer subtypes also have different treatments and outcomes. High false negative rates increase the risk of cancer progression and indeterminate diagnoses result in unnecessary and potentially morbid surgical procedures. EXPERIMENTAL DESIGN: We built a predictive classification model for kidney tumors using 697 DNA methylation profiles from six different subgroups: clear cell, papillary and chromophobe RCC, benign angiomylolipomas, oncocytomas, and normal kidney tissues. Furthermore, the DNA methylation-dependent classifier has been validated in 272 ex vivo needle biopsy samples from 100 renal masses (71% SRMs). RESULTS: In general, the results were highly reproducible (89%, n=70) in predicting identical malignant subtypes from biopsies. Overall, 98% of adjacent-normals (n=102) were correctly classified as normal, while 92% of tumors (n=71) were correctly classified malignant and 86% of benign (n=29) were correctly classified benign by this classification model. CONCLUSIONS: Overall, this study provides molecular-based support for using routine needle biopsies to determine tumor classification of SRMs and support the clinical decision-making.

Partial Prostatectomy for Anterior Cancer: Short-term Oncologic and Functional Outcomes.

BACKGROUND: Focal ablative therapy may be a suboptimal option for anterior prostate cancers (APCs) reaching the prostate apex due to concerns for thermal injury to the external sphincter. OBJECTIVE: To explore the technical feasibility of anterior partial prostatectomy (APP) for isolated APCs detected by magnetic resonance imaging (MRI), and to report short-term oncologic and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: Following institutional review board approval, over an 8-yr period (2008-2015) 17 consenting patients were enrolled in a prospective single-arm single-center Innovation, Development, Exploration, Assessment, Long-term (IDEAL) phase 2a study. Inclusion criteria comprised preurethral, low- to intermediate-risk APC diagnosed by MRI, and targeted biopsies. Robotic template APP was performed; posterolateral aspect of the submontanal urethra, peripheral zone, and periprostatic tissues were preserved intact. Median follow-up was 30 mo (interquartile range [IQR]: 25-70). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We noted the incidence of perioperative complications and examined reports of pathology, prostate-specific antigen (PSA), imaging, biopsies, and questionnaires. RESULTS AND LIMITATIONS: Preoperatively, median PSA was 9.8 ng/ml, Gleason score was 6-7 (3 + 4), and cancer volume was 3.7cm3 (IQR: 1.7-4.6). The technique was feasible in all cases. Perioperative complications included anastomotic leak (12%; G2), urinary tract infection (6%; G2), and transient intestinal ileus in one case (6%; G2). At 3 mo, continence and potency rates were 100% and 83%, respectively. Median nadir PSA was 0.4 ng/ml (IQR: 0.3-0.7). All margins and posterolateral margins rates were 55% and 35%, respectively. APC recurrence-free survival at 2 yr was 0.86 (95% confidence interval [CI], 0.55-0.96). Four patients (24%) who recurred underwent an uncomplicated completion of robot-assisted prostatectomy. Regarding limitations, CIs are quite wide for reported outcomes. CONCLUSIONS: Robotic partial prostatectomy for isolated APC is feasible with good functional results. While promising, much more research is needed to verify our initial outcomes and appropriately position APP in the treatment paradigms for APC. PATIENT SUMMARY: We explored a novel approach for partial prostatic surgical ablation for prostate cancer located in the anterior part of the prostate as an alternative to other focal ablative techniques.

Robot-assisted Level II-III Inferior Vena Cava Tumor Thrombectomy: Step-by-Step Technique and 1-Year Outcomes.

BACKGROUND: Level II-III inferior vena cava (IVC) tumor thrombectomy for renal cell carcinoma is among the most challenging urologic oncologic surgeries. In 2015, we reported the initial series of robot-assisted level III caval thrombectomy. OBJECTIVE: To describe our University of Southern California technique in a step-by-step fashion for robot-assisted IVC level II-III tumor thrombectomy. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five selected patients with renal neoplasm and level II-III IVC tumor thrombus underwent robot-assisted surgery with a minimum 1-yr follow-up (July 2011 to March 2015). SURGICAL PROCEDURE: Our standardized anatomic-based "IVC-first, kidney-last" technique for robot-assisted IVC thrombectomy focuses on minimizing the chances of an intraoperative tumor thromboembolism and major hemorrhage. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline demographics, pathology data, 90-d and 1-yr complications, and oncologic outcomes at last follow-up were assessed. RESULTS AND LIMITATIONS: Robot-assisted IVC thrombectomy was successful in 24 patients (96%) (level III: n=11; level II: n=13); one patient was electively converted to open surgery for failure to progress. Median data included operative time of 4.5h, estimated blood loss was 240ml, hospital stay 4 d; five patients (21%) received intraoperative blood transfusion. All surgical margins were negative. Complications occurred in four patients (17%): two were Clavien 2, one was Clavien 3a, and one was Clavien 3b. All patients were alive at a 16-mo median follow-up (range: 12-39 mo). CONCLUSIONS: Robotic IVC tumor thrombectomy is feasible for level II-III thrombi. To maximize intraoperative safety and chances of success, a thorough understanding of applied anatomy and altered vascular collateral flow channels, careful patient selection, meticulous cross-sectional imaging, and a highly experienced robotic team are essential. PATIENT SUMMARY: We present the detailed operative steps of a new minimally invasive robot-assisted surgical approach to treat patients with advanced kidney cancer. This type of surgery can be performed safely with low blood loss and excellent outcomes. Even patients with advanced kidney cancer could now benefit from robotic surgery with a quicker recovery.

Feasibility of expert and crowd-sourced review of intraoperative video for quality improvement of intracorporeal urinary diversion during robotic radical cystectomy.

INTRODUCTION: Development of uretero-ileal stricture (UIS) after robotic-assisted radical cystectomy (RARC) may be dependent on surgical technique. Video review of intraoperative technique is an emerging paradigm for surgical quality improvement. We examined whether surgeon-perceived risk of UIS or crowd-sourced assessment of robotic skill are associated with the development of UIS. METHODS: We conducted a case-control study comparing the operative technique of uretero-ileal anastomoses resulting in clinically significant UIS with the contralateral anastomosis for the same patient. De-identified videos were analyzed by 1) five high-volume surgeons; and 2) crowd workers (Crowd-Sourced Assessment of Technical Skill, C-SATS) to determine Global Evaluative Assessment of Robotic Skill (GEARS) score. Mantel-Haenszel common odds ratio (OR) estimates were calculated to assess the association between surgeon performance and the development of UIS. Logistic regression models were used to examine the association between GEARS scores and the development of UIS. RESULTS: A total of 10 UIS videos were compared to eight control videos by five surgeons and 2142 crowd workers. Expert surgeons systematically evaluated intraoperative footage, however, no association between the expert mode response and UIS (OR 0.42; 95% confidence interval [CI] 0.05-3.45; p=0.91) was identified. Crowd-sourced assessment was not predictive of UIS (p=0.62). CONCLUSIONS: We used video review to systematically analyze procedure-specific content and technique. The inability of surgeons to predict UIS may reflect the questionnaire, uncontrolled patient factors, or a lack of power. Crowd-sourced GEARS score was unsuccessful in predicting UIS after RARC.

Transvaginal bowel evisceration following robot-assisted radical cystectomy.

Transvaginal evisceration of the bowel has been found to most commonly occur following hysterectomy. To date, the reports of this complication following radical cystectomy are minimal. Herein, we report a case of transvaginal bowel evisceration 45 days following robotic-assisted radical cystectomy (RARC) in a postmenopausal woman.

Feasibility of robotic radical prostatectomy for medication refractory chronic prostatitis/chronic pelvic pain syndrome: Initial results.

Four patients diagnosed with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), met criteria for National Institute of Health (NIH) Category III prostatitis, failed multiple medicinal treatments and underwent robotic radical prostatectomy (RRP). Median operative time (range): 157 (127-259) min. Validated functional questionnaires responses and NIH CP symptom index (NIH-CPSI) score were collected for each patient's status at different time points pre- and post-operatively. Median decreases (range) were: International Prostate Symptom Score - 14 (1-19); Sexual Health Inventory for Men - 6 (-14-22); and NIH-CPSI total - 23.5 (13-33). Median length of follow-up (range) was 34 (24-43) months. RRP appears to be an option for carefully selected patients with medication-refractory CP/CPPS who understand that baseline sexual function may not be restored postoperatively.