Impact of Variant Histology on Oncological Outcomes in Upper Tract Urothelial Carcinoma: Results From the ROBUUST Collaborative Group.

INTRODUCTION: Oncologic implications of variant histology (VH) have been extensively studied in bladder cancer; however, further investigation is needed in upper tract urothelial carcinoma (UTUC). Our study aims to evaluate the impact of VH on oncological outcomes in UTUC patients treated with radical nephroureterectomy (RNU). METHODS: A retrospective analysis was performed on patients who underwent a robotic or laparoscopic RNU for UTUC using the ROBUUST database, a multi-institutional collaborative including 17 centers worldwide. Logistic regression was used to assess the effect of VH on urothelial recurrence (bladder, contralateral upper tract), metastasis, and survival following RNU. RESULTS: A total of 687 patients were included in this study. Median (IQR) age was 71 (64-78) years and 470 (68%) had organ confined disease. VH was present in 70 (10.2%) patients. In a median follow-up of 16 months, the incidence of urothelial recurrence, metastasis, and mortality was 26.8%, 15.3%, and 11.8%, respectively. VH was associated with increased risk of metastasis (HR 4.3, P <.0001) and death (HR 2.0, P =.046). In multivariable analysis, VH was noted to be an independent risk factor for metastasis (HR 1.8, P =.03) but not for urothelial recurrence (HR 0.99, P =.97) or death (HR 1.4, P =.2). CONCLUSION: Variant histology can be found in 10% of patients with UTUC and is an independent risk factor for metastasis following RNU. Overall survival rates and the risk of urothelial recurrence in the bladder or contralateral kidney are not affected by the presence of VH.

Outcomes of Robot-Assisted Laparoscopic Pyeloplasty Based on Degree of Obstruction on Preoperative Tc-99 MAG-3 Renal Scintigraphy.

Objective: Management of symptomatic ureteropelvic junction (UPJ) obstruction with hydronephrosis and discordant Tc-99 mercaptoacetyltriglycine (MAG-3) renal scintigraphy is challenging. In this study we describe long-term outcomes of patients who underwent robot-assisted laparoscopic pyeloplasty for the correction of symptomatic UPJ obstruction with discordant preoperative Tc-99m MAG-3 renal scintigraphy. Methods: Patients undergoing robot-assisted laparoscopic pyeloplasty for symptomatic UPJ obstruction at a single academic center from 2009 to 2021 were retrospectively reviewed. Patients were categorized into three groups with varying degrees of obstruction based on preoperative MAG-3 imaging: Group 1: no obstruction (Lasix T1/2 clearance <10 minutes), Group 2: equivocal obstruction (Lasix T1/2 clearance 10-20 minutes), and Group 3: obstruction (Lasix T1/2 clearance >20 minutes. Pyeloplasty success was defined as resolution of symptoms and improvement/stable computed tomography (CT) imaging or MAG-3 scintigraphy. Failure was defined as persistence of symptoms with either obstruction on functional imaging, worsening hydronephrosis, or subsequent intervention. Results: A total of 125 cases were identified, with a median patient age of 35 years. Dismembered pyeloplasty technique was performed in 98.4% of cases. Median preoperative split renal function on MAG-3 scintigraphy was the only statistically significant (p = 0.003) difference in preoperative characteristics between the three groups. There were 15 postoperative complications, with a rate of Clavien-Dindo grade 3 or higher complications of 4.8%. Overall pyeloplasty success was 92.8%, with success rates of 100% (15/15) and 97% (32/33) in the no obstruction and equivocal obstruction groups, respectively. Median time to pyeloplasty failure was 20.4 months. Conclusion: Robot-assisted laparoscopic pyeloplasty is a safe and effective surgical intervention for correcting UPJ obstruction. Patients with symptoms of UPJ obstruction and discordant functional imaging studies demonstrate similar or improved success rates after pyeloplasty compared with patients with documented high-grade obstruction. Based on these findings preoperative renal scan may not be reliable in appropriate selection of candidacy for pyeloplasty.

Practice trends for perioperative intravesical chemotherapy in upper tract urothelial carcinoma: Low but increasing utilization during minimally invasive nephroureterectomy.

INTRODUCTION: Perioperative intravesical chemotherapy (IVC) at or around the time of radical nephroureterectomy (RNU) reduces the risk of intravesical recurrence. Guidelines since 2013 have recommended its use. The objective of this study is to examine IVC utilization and determine predictors of its administration within a large international consortium. METHODS AND MATERIALS: Data was collected from 17 academic centers on patients who underwent robotic/laparoscopic RNU between 2006 and 2020. Patients who underwent concomitant radical cystectomy and cases in which IVC administration details were unknown were excluded. Univariate and multivariate analyses were utilized to determine predictors of IVC administration. A Joinpoint regression was performed to evaluate utilization by year. RESULTS: Six hundred and fifty-nine patients were included. A total of 512 (78%) did not receive IVC while 147 (22%) did. Non-IVC patients were older (P < 0.001), had higher ECOG scores (P = 0.003), and had more multifocal disease (23% vs. 12%, P = 0.005). Those in the IVC group were more likely to have higher clinical T stage disease (P = 0.008), undergone laparoscopic RNU (83% vs. 68%, P < 0.001), undergone endoscopic management of the bladder cuff (20% vs. 4%, P = 0.008). Multivariable regression showed that decreased age (OR 0.940, P < 0.001), laparoscopic approach (OR 2.403, P = 0.008), and endoscopic management of the bladder cuff (OR 7.619, P < 0.001) were significant predictors favoring IVC administration. Treatment at a European center was associated with lower IVC use (OR 0.278, P = 0.018). Overall utilization of IVC after the 2013 European Association of Urology (EAU) guideline was 24% vs. 0% prior to 2013 (P < 0.001). Limitations include limited data regarding IVC timing/agent and inclusion of minimally invasive RNU patients only. CONCLUSIONS: While IVC use has increased since being added to the EAU UTUC guidelines, its use remains low at academic centers, particularly within Europe.

Outcomes of Lymph Node Dissection in Nephroureterectomy in the Treatment of Upper Tract Urothelial Carcinoma: Analysis of the ROBUUST Registry.

PURPOSE: We sought to evaluate outcomes of lymph node dissection (LND) in patients with upper tract urothelial carcinoma. MATERIALS AND METHODS: We performed a multicenter retrospective analysis utilizing the ROBUUST (for RObotic surgery for Upper Tract Urothelial Cancer Study) registry for patients who did not undergo LND (pNx), LND with negative lymph nodes (pN0) and LND with positive nodes (pN+). Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS). Multivariable analyses evaluated predictors of outcomes and pathological node positivity. Kaplan-Meier analyses (KMAs) compared survival outcomes. RESULTS: A total of 877 patients were analyzed (LND performed in 358 [40.8%]/pN+ in 73 [8.3%]). Median nodes obtained were 10.2 for pN+ and 9.8 for pN0. Multivariable analyses noted increasing age (OR 1.1, p <0.001), pN+ (OR 3.1, p <0.001) and pathological stage pTis/3/4 (OR 3.4, p <0.001) as predictors for all-cause mortality. Clinical high-grade tumors (OR 11.74, p=0.015) and increasing tumor size (OR 1.14, p=0.001) were predictive for lymph node positivity. KMAs for pNx, pN0 and pN+ demonstrated 2-year OS of 80%, 86% and 42% (p <0.001) and 2-year RFS of 53%, 61% and 35% (p <0.001), respectively. KMAs comparing pNx, pN0 ≥10 nodes and pN0 <10 nodes showed no significant difference in 2-year OS (82% vs 85% vs 84%, p=0.6) but elicited significantly higher 2-year RFS in the pN0 ≥10 group (60% vs 74% vs 54%, p=0.043). CONCLUSIONS: LND during nephroureterectomy in patients with positive lymph nodes provides prognostic data, but is not associated with improved OS. LND yields ≥10 in patients with clinical node negative disease were associated with improved RFS. In high-grade and large tumors, lymphadenectomy should be considered.

Robotic vs Laparoscopic Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Multicenter Propensity-Score Matched Pair "tetrafecta" Analysis (ROBUUST Collaborative Group).

Purpose: To compare the outcomes of robotic radical nephroureterectomy (RRNU) and laparoscopic radical nephroureterectomy (LRNU) within a large multi-institutional worldwide dataset. Materials and Methods: The ROBotic surgery for Upper tract Urothelial cancer STudy (ROBUUST) includes data from 17 centers worldwide regarding 877 RRNU and LRNU performed between 2015 and 2019. Baseline features, perioperative and oncologic outcomes, were included. A 2:1 nearest-neighbor propensity-score matching with a 0.001 caliper was performed. A univariable and a multivariable logistic regression model were built to evaluate the predictors of a composite "tetrafecta" outcome defined as occurrence of bladder cuff excision+LND+no complications+negative surgical margins. Results: After matching, 185 RRNU and 91 LRNU were assessed. Patients in the RRNU group were more likely to undergo bladder cuff excision (81.9% vs 63.7%; p < 0.001) compared to the LRNU group. A statistically significant difference was found in terms of overall postoperative complications (p = 0.003) and length of stay (p < 0.001) in favor of RRNU. Multivariable analysis demonstrated that LRNU was an independent predictor negatively associated with achievement of "tetrafecta" (odds ratio: 0.09; p = 0.003). Conclusions: In general, RRNU and LRNU offer comparable outcomes. While the rate of overall complications is higher for LRNU in this study population, this is mostly related to low-grade complications, and therefore with more limited clinical relevance. RRNU seems to offer shorter hospital stay, but this might also be related to the different geographical location of participating centers. Overall, the implementation of robotics might facilitate achievement of a "tetrafecta" outcome as defined in the present study.

Procedure: Laparoscopic Donor Nephrectomy.

Minimally invasive approaches for laparoscopic donor nephrectomy are necessary to limit surgical morbidity, and technical challenges differ from those encountered during other laparoscopic renal surgeries. Presented here is a step-by-step guide for laparoscopic donor nephrectomy-focusing on pure laparoscopic and hand-assisted techniques. Both straight laparoscopic and hand-assisted nephrectomies were performed in healthy donors who met transplantation criteria in terms of global health and psychologic well-being. Patient positioning, trocar placement, surgical steps, incision closure, and postoperative care are reviewed. Standard equipment used to complete this procedure is itemized. This guide outlines indications, preoperative preparation, and procedural steps for laparoscopic donor nephrectomy. The techniques and the evolution thereof represent our experience since 2002 for 510 cases. The attached videos demonstrate a high-volume surgeon's typical approach while factoring in anatomical variation. In both cases, the donor nephrectomies were without incident and the patient's postoperative courses were without complication. A basic framework for donor nephrectomy is presented highlighting surgical steps we believe to be essential for graft preservation and ultimately effective transplantation. Although no two cases are the same, systematic approaches will allow for timely case completion, fewer complications, and better donor/recipient outcomes.

Nephron-sparing management of upper tract urothelial carcinoma.

Urothelial carcinoma of the upper urinary tract is uncommon and presents unique challenges for diagnosis and management. Nephroureterectomy has been the preferred management option, but it is associated with significant morbidity. Nephron-sparing treatments are a valuable alternative and provide similar efficacy in select cases. A PubMed literature review was performed in English language publications using the following search terms: urothelial carcinoma, upper tract, nephron-sparing, intraluminal and systemic therapy. Contemporary papers published within the last 10 years were primarily included. Where encountered, systematic reviews and meta-analyses were given priority, as were randomized controlled trials for newer treatments. Core guidelines were referenced and citations reviewed for inclusion. A summary of epidemiological data, clinical diagnosis, staging, and treatments focusing on nephron-sparing approaches to upper tract urothelial carcinoma (UTUC) are outlined. Nephron-sparing management strategies are viable options to consider in patients with favorable features of UTUC. Adjunctive therapies are being investigated but the data remains mixed. Protocol variability and dosage differences limit statistical interpretation. New mechanisms to improve treatment dwell times in the upper tracts are being designed with promising preliminary results. Studies investigating systemic therapies are ongoing but implications for nephron-sparing management are uncertain. Nephron-sparing management is an acceptable treatment modality best suited for favorable disease. More work is needed to determine if intraluminal and/or systemic therapies can further optimize treatment outcomes beyond resection alone.

Autophagy as a modulator and target in prostate cancer.

Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.