SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-ß-independent manner.

Histone-lysine N-methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial-to-mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor-beta-independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA-seq and assay for transposase-accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild-type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell-intrinsic and cell-extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.

Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome.

BACKGROUND: Clear cell renal cell cancer (ccRCC), the 8th leading cause of cancer-related death in the US, is challenging to treat due to high level intratumoral heterogeneity (ITH) and the paucity of druggable driver mutations. CcRCC is unusual for its high frequency of epigenetic regulator mutations, such as the SETD2 histone H3 lysine 36 trimethylase (H3K36me3), and low frequency of traditional cancer driver mutations. In this work, we examined epigenetic level ITH and defined its relationships with pathologic features, aspects of tumor biology, and SETD2 mutations. RESULTS: A multi-region sampling approach coupled with EPIC DNA methylation arrays was conducted on a cohort of normal kidney and ccRCC. ITH was assessed using DNA methylation (5mC) and CNV-based entropy and Euclidian distances. We found elevated 5mC heterogeneity and entropy in ccRCC relative to normal kidney. Variable CpGs are highly enriched in enhancer regions. Using intra-class correlation coefficient analysis, we identified CpGs that segregate tumor regions according to clinical phenotypes related to tumor aggressiveness. SETD2 wild-type tumors overall possess greater 5mC and copy number ITH than SETD2 mutant tumor regions, suggesting SETD2 loss contributes to a distinct epigenome. Finally, coupling our regional data with TCGA, we identified a 5mC signature that links regions within a primary tumor with metastatic potential. CONCLUSION: Taken together, our results reveal marked levels of epigenetic ITH in ccRCC that are linked to clinically relevant tumor phenotypes and could translate into novel epigenetic biomarkers.

Comparison of Robot-Assisted and Open Radical Cystectomy in Recovery of Patient-Reported and Performance-Related Measures of Independence: A Secondary Analysis of a Randomized Clinical Trial.

Importance: No data exist on time to recovery of patient-reported and performance-related measures of functional independence after radical cystectomy (open or robotic). Objective: To determine recovery of functional independence after radical cystectomy and whether robot-assisted radical cystectomy (RARC) is associated with any advantage over open procedures. Design, Setting, and Participants: Data for this secondary analysis from the RAZOR (Randomized Open vs Robotic Cystectomy) trial were used. RAZOR was a phase 3 multicenter noninferiority trial across 15 academic medical centers in the US from July 1, 2011, to November 18, 2014, with a median follow-up of 2 years. Participants included the per-protocol population (n = 302). Data were analyzed from February 1, 2017, to May 1, 2021. Interventions: Robot-assisted radical cystectomy or open radical cystectomy (ORC). Main Outcomes and Measures: Patient-reported (activities of daily living [ADL] and independent ADL [iADL]) and performance-related (hand grip strength [HGS] and Timed Up & Go walking test [TUGWT]) measures of independence were assessed. Patterns of postoperative recovery for the entire cohort and comparisons between RARC and ORC were performed. Exploratory analyses to assess measures of independence across diversion type and to determine whether baseline impairments were associated with 90-day complications or 1-year mortality were performed. Findings: Of the 302 patients included in the analysis (254 men [84.1%]; mean [SD] age at consent, 68.0 [9.7] years), 150 underwent RARC and 152 underwent ORC. Baseline characteristics were similar in both groups. For the entire cohort, ADL, iADL, and TUGWT recovered to baseline by 3 postoperative months, whereas HGS recovered by 6 months. There was no difference between RARC and ORC for ADL, iADL, TUGWT, or HGS scores at any time. Activities of daily living recovered 1 month after RARC (mean estimated score, 7.7 [95% CI, 7.3-8.0]) vs 3 months after ORC (mean estimated score, 7.5 [95% CI, 7.2-7.8]). Hand grip strength recovered by 3 months after RARC (mean estimated HGS, 29.0 [95% CI, 26.3-31.7] kg) vs 6 months after ORC (mean estimated HGS, 31.2 [95% CI, 28.8-34.2] kg). In the RARC group, 32 of 90 patients (35.6%) showed a recovery in HGS at 3 months vs 32 of 88 (36.4%) in the ORC group (P = .91), indicating a rejection of the primary study hypothesis for HGS. Independent ADL and TUGWT recovered in 3 months for both approaches. Hand grip strength showed earlier recovery in patients undergoing continent urinary diversion (mean HGS at 3 months, 31.3 [95% CI, 27.7-34.8] vs 33.9 [95% CI, 30.5-37.3] at baseline; P = .09) than noncontinent urinary diversion (mean HGS at 6 months, 27.4 [95% CI, 24.9-30.0] vs 29.5 [95% CI, 27.2-31.9] kg at baseline; P = .02), with no differences in other parameters. Baseline impairments in any parameter were not associated with 90-day complications or 1-year mortality. Conclusions and Relevance: The results of this secondary analysis suggest that patients require 3 to 6 months to recover baseline levels after radical cystectomy irrespective of surgical approach. These data will be invaluable in patient counseling and preparation. Hand grip strength and ADL tended to recover to baseline earlier after RARC; however, there was no difference in the percentage of patients recovering when compared with ORC. Further study is needed to assess the clinical significance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT01157676.

Learning Curve for Robotic-Assisted Laparoscopic Retroperitoneal Lymph Node Dissection.

Introduction: Robotic retroperitoneal lymph node dissection (R-RPLND) is a challenging procedure. We hypothesized that surgical times and operative complications would decrease as surgeons became more facile with R-RPLND. Materials and Methods: We retrospectively reviewed 121 consecutive R-RPLNDs performed at Naval Medical Center San Diego and Mayo Clinic Arizona by 4 fellowship trained robotic surgeons between 2008 and 2018. Linear regression was used to analyze independent predictors of setup time, operative time, and lymph node counts. Logistic regression was used to analyze open conversions, overall complications, and high-grade complications. Variables included as independent predictors were: sequential case number, surgeon, clinical stage, chemotherapy status, RPLND template, and body mass index. Univariate and multivariate analyses were conducted. Statistical significance was established at α = 0.05. Results: There was no change in setup time with case number (p = 0.317), but differences were noted between surgeons. Operative times decreased with increasing case number (p < 0.001) but were negatively affected by clinical stage III testis cancer (p = 0.029) and history of chemotherapy exposure (p = 0.050). Surgical times are predicted to decrease by 1 hour after 44 cases. Lymph node counts were dependent only on the surgeon. No factors were predictive of open conversions. Fewer overall complications occurred as experience was gained (p = 0.001), but high-grade complications could not be predicted. Conclusions: Consistent with the learning curves shown for other technologically advanced surgical techniques, experience appears to improve surgical times and lower complication rates for R-RPLND.

Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer.

BACKGROUND: Despite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis. RESULTS: To address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as 'low risk' by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0-3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score. CONCLUSIONS: This study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0-3).

Use of treatment pathway improves neoadjuvant chemotherapy use in muscle-invasive bladder cancer.

PURPOSE: To assess the trends of neoadjuvant chemotherapy (NAC) use since its introduction in our practice pathway in patients with cT2 + bladder cancer over a 20-year period. METHODS: This is a retrospective review of patients with cT2 + bladder cancer who underwent RC between 01/01/1998 and 01/01/2018 that aimed to evaluate the trends of NAC use and associated after implementation of a multidisciplinary treatment pathway. Cohorts were stratified into eras: pre-NAC (1998-2007) to NAC eras (2008-2018). Univariate analysis was conducted using Chi-squared test and Kaplan-Meier estimates were used to evaluate survival. RESULTS: In 904 total patients who underwent RC, there were 493 with cT2 + UCC disease. The rate of NAC peaked at 84.2% in the most recent year of analysis in all patients and was 100% in cT2 + patients eligible for NAC. There was an increased rate of complete response (downstage to pT0) from 8.7% to 15.8% (p = 0.018) between the two eras. Unadjusted survival analysis revealed improved overall survival (OS) between eras with 5-year OS 53.2% vs. 42.7% and 10-year OS 42.7% vs. 26.4% in the NAC vs. pre-NAC cohorts, respectively (p = 0.016). CONCLUSIONS: In this review of 20 years of experience, we report a dramatic rise in the use of NAC after adoption of a multidisciplinary pathway that is associated with expected survival benefits.

Robot Assisted Renal Allograft Nephrectomy: Initial Case Series and Description of Technique.

OBJECTIVE: To evaluate the outcomes and perioperative complication rates following robot- assisted transplant nephrectomy ((RATN). METHODS: All patients who underwent RATN at our institution were included. No exclusion criteria were applied. Clinical records were retrospectively reviewed and reported. This included preoperative, intraoperative, and postoperative outcomes. Complications were reported utilizing the Clavien-Dindo classification system. Descriptive statistics were reported using frequencies and percentages for categorical variables, means and standard deviation for continuous variables. RESULTS: Between July 2014 and April 2018, 15 patients underwent RATN. Most patients had the transplant in the right iliac fossa (13/15). Ten patients underwent a concomitant procedure. The total operative time for the entire cohort was 336 (±102) minutes (including cases who had concomitant procedures) and 259 (±46 minutes) when cases with concomitant procedures were excluded. Mean estimated blood loss was 383 (±444) mL. Postoperatively, 3 patients required blood transfusion. Average hospital stay was 4 (±2.7) days. Most patients had finding consistent with graft rejection on final pathology. There were 5 complications; 3 of which were minor (grade 2 = 2 and grade 3 = 1); one patient had a wound infection requiring dressing (3A) and one patient died due to pulmonary embolism following discharge. Limitations include small series and retrospective nature of the study. CONCLUSION: This case series demonstrate that RATN is technically feasible. With continued experience and larger case series, the robotic approach may provide a minimally invasive alternative to open allograft nephrectomy.

The effect of urinary diversion on long-term kidney function after cystectomy.

OBJECTIVES: Cystectomy with urinary diversion is associated with decreased long-term kidney function due to several factors. One factor that has been debated is the type of urinary diversion used: ileal conduit (IC) vs. neobladder (NB). We tested the hypothesis that long-term kidney function will not vary by type of urinary diversion. METHODS AND MATERIALS: We retrospectively identified all patients who underwent cystectomy with urinary diversion at our institution from January 1, 2007, to January 1, 2018. Data were collected on patient demographics, comorbid conditions, perioperative radiotherapy, and complications. Creatinine values were measured at several time points up to 120 months after surgery. Glomerular filtration rate (GFR) (ml/min per 1.73 m2) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. A linear mixed model with inverse probability of treatment weighting (IPTW) was used to compare GFR between the IC and NB cohorts over time. Multiple sensitivity analyses were performed based on 2 different calculations of GFR (Chronic Kidney Disease Epidemiology Collaboration equation vs. Modification of Diet in Renal Disease), with and without excluding patients with preoperative GFR less than 40 ml/min per 1.73 m2. RESULTS: Among 563 patients who underwent cystectomy with urinary diversion, a NB was used for 72 (12.8%) individuals. Patients who had a NB were significantly younger, had a lower American Society of Anesthesiologists score, greater baseline GFR, better Eastern Cooperative Oncology Group performance status, lower median Charlson comorbidity index, and were less likely to have received preoperative abdominal radiation (all P < 0.05). Both NB and IC patients had decreased kidney function over time, with mean GFR losses at 5 years of 17% and 14% of baseline values, respectively. The IPTW-adjusted linear mixed model revealed that IC patients had slightly more deterioration in kidney function over time, but this was not statistically significant (estimate, 0.12; P = 0.06). The sensitivity analyses yielded a similar trend, in that GFR decrease appeared to be greater in the IC cohort. This trend was statistically significant when using Modification of Diet in Renal Disease (P = 0.04). CONCLUSIONS: Among highly selected patients with an NB, deterioration of kidney function may potentially be lower over time than among IC patients. However, the statistical significance varied between analyses and we cautiously attribute these observed differences to patient selection.

Health Related Quality of Life of Patients with Bladder Cancer in the RAZOR Trial: A Multi-Institutional Randomized Trial Comparing Robot versus Open Radical Cystectomy.

PURPOSE: We evaluated health related quality of life following robotic and open radical cystectomy as a treatment for bladder cancer. MATERIALS AND METHODS: Using the Randomized Open versus Robotic Cystectomy (RAZOR) trial population we assessed health related quality of life by using the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index and the Short Form 8 Health Survey (SF-8) at baseline, 3 and 6 months postoperatively. The primary objective was to assess the impact of surgical approach on health related quality of life. As an exploratory analysis we assessed the impact of urinary diversion type on health related quality of life. RESULTS: Analyses were performed in subsets of the per-protocol population of 302 patients. There was no statistically significant difference between the mean scores by surgical approach at any time point for any FACT-Vanderbilt Cystectomy Index subscale or composite score (p >0.05). The emotional well-being score increased over time in both surgical arms. Patients in the open arm showed significantly better SF-8 sores in the physical and mental summary scores at 6 months compared to baseline (p <0.05). Continent diversion (versus noncontinent) was associated with worse FACT-bladder-cystectomy score at 3 (p <0.01) but not at 6 months, and the SF-8 physical component was better in continent-diversion patients at 6 months (p=0.019). CONCLUSIONS: Our data suggests lack of significant differences in the health related quality of life in robotic and open cystectomies. As robotic procedures become more widespread it is important to discuss this finding during counseling.

How the Beneficial Effects of Alvimopan Differ With Surgical Approach for Radical Cystectomy.

OBJECTIVE: To assess whether the beneficial perioperative effects of alvimopan differ with surgical approach for patients who undergo open radical cystectomy (ORC) vs robot-assisted radical cystectomy (RARC). METHODS: This retrospective study reviewed all patients who underwent cystectomy with urinary diversion at our institution between January 1, 2007, and January 1, 2018. Data were collected on demographic characteristics, comorbidities, surgical approach, alvimopan therapy, hospital length of stay (LOS), days until return of bowel function (ROBF), and complications. Outcomes and interactions were evaluated through regression analysis. RESULTS: Among 573 patients, 236 (41.2%) underwent RARC, 337 (58.8%) underwent ORC, and 205 (35.8%) received alvimopan. Comparison of 4 cohorts (ORC with alvimopan, ORC without alvimopan, RARC with alvimopan, and RARC without alvimopan) showed that patients who underwent ORC without alvimopan had the highest rate of postoperative ileus (25.6%, P = .02), longest median hospital LOS (7 days, P < .001), and longest time until ROBF (4 days, P < .001). On multivariable analysis, the interaction between surgical approach and alvimopan use was significant for the outcome of ROBF (estimate, 1.109; 95% confidence interval, 0.418-1.800; P = .002). In the RARC cohort, multivariable analysis showed no benefit of alvimopan with respect to ileus (P = .27), LOS (P = .09), or ROBF (P = .36). Regarding joint effects of robotic approach and alvimopan, RARC had no effect on gastrointestinal tract outcomes. CONCLUSION: We observed a diminished beneficial effect of alvimopan among patients undergoing RARC and a statistically significant benefit of alvimopan among patients undergoing ORC. The implications of these findings may permit more selective medication use for patients who would benefit the most from this drug.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Primary robotic RLPND for nonseminomatous germ cell testicular cancer: a two-center analysis of intermediate oncologic and safety outcomes.

OBJECTIVE: To evaluate the intermediate-term oncologic outcomes and safety profile of the largest case series of primary robotic retroperitoneal lymphadenectomy for low-clinical-stage non-seminomatous germ cell testicular cancer. METHODS: This was a two-center retrospective analysis of robotic RPLND cases for low-clinical-stage (stage I-IIB) non-seminomatous germ cell testicular cancer in the primary setting. Demographic, perioperative, operative and oncologic variables were collected between March 2008 and May 2019. Descriptive analyses were performed and presented as medians with interquartile ranges for continuous variables and frequency and proportions for categorical variables. A survival analysis of time to recurrence was performed using Cox proportional hazards model. Using logistic regression, risk factors for complications were analyzed. Both univariate and multivariate analyses were performed. RESULTS: A total of 58 patients (CS 1 = 56, CS IIA = 2, CS IIB = 0) were identified. The median follow-up was 47 months and the 2-year recurrence-free survival rate was 91%. The five recurrences were all out of the performed dissection template (pelvis = 1 and lung = 4). Only five patients (29%) with occult metastasis underwent adjuvant chemotherapy. The median operative time was 319 min [interquartile range (IQR) 276-355 min], estimated blood loss was 100 ml (IQR 75-200 ml), node count was 26 (IQR 20-31), and length of stay 2 d (IQR 1-3 days). There were 2 (3.3%) intraoperative complications, 19 (32.7%) 30-day postoperative complications to include 14 (24.1%) Clavien grade I, 4 (6.9%) Clavien grade II, 1 (1.7%) Clavien grade III and 0 Clavien grade IV complications. No statistical significance was found on multivariate or univariate analysis for survival analysis of time to recurrence and risk factors for complications. CONCLUSIONS: This study represents the largest case series of primary R-RPLND for the treatment of low-stage non-seminomatous germ cell tumors (NSGCT). With 47 months of follow-up and a low rate of adjuvant chemotherapy, intermediate oncologic efficacy appears to be comparable to the gold standard open approach.

Molecular Inhibitor of QSOX1 Suppresses Tumor Growth In Vivo.

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion in vitro and in vivo, we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as "SBI-183," suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1.

Comparison of Open and Robot Assisted Radical Nephrectomy With Level I and II Inferior Vena Cava Tumor Thrombus: The Mayo Clinic Experience.

OBJECTIVE: To compare the perioperative and oncologic outcomes associated with open radical nephrectomy with tumor thrombus (O-RNTT) vs robot assisted radical nephrectomy with tumor thrombus (RA-RNTT). Renal cell carcinoma with venous tumor thrombus has traditionally been managed through an open surgical approach. The robot assisted approach may offers improved perioperative outcomes compared to open, but there are few studies comparing these 2. METHODS: We analyzed patients with renal cell carcinoma and inferior vena cava tumor thrombus between 1998 and 2018, comparing perioperative and oncologic outcomes of these patients with Level I and Level II thrombus. Cohorts were stratified by surgical approach: O-RNTT vs RA-RNTT. Univariate analysis was conducted using chi-squared test and t tests when appropriate. Kaplan-Meier estimates were used to evaluate survival. RESULTS AND LIMITATION: Twenty-seven patients were in the O-RNTT group, and 24 in the RA-RNTT group. Patients in the RA-RNTT group, compared to the O-RNTT group, demonstrated shorter length of stay (3 vs 7 nights, P = .03), lower estimate blood loss (450 vs 1800 mL, P <.01), and lower transfusion rate (21% vs 82%, P <.01). The RA-RNTT group had 26% fever complications compared to the open (17% vs 43%, P <.01). There was no significant difference in estimated overall survival or recurrence-free survival between the O-RNTT and RA-RNTT groups. CONCLUSION: RA-RNTT produced a shorter length of stay, less transfusions, and a lower rate of complications with no significant difference in overall survival.

Single-dose perioperative mitomycin-C versus thiotepa for low-grade noninvasive bladder cancer.

INTRODUCTION: Mitomycin-C (MMC) and thiotepa are intravesical agents effective in reducing the recurrence of low-grade noninvasive bladder cancer when instilled perioperatively. No studies have compared these agents as a single-dose perioperative instillation. This study tests whether there is a difference in recurrence-free survival in patients with low-grade noninvasive bladder cancer who received intravesical MMC versus thiotepa. MATERIALS AND METHODS: A retrospective review was performed of patients who underwent cystoscopic excision of a bladder mass identified as a small, low-grade, treatment-naïve, noninvasive, wild-type urothelial carcinoma of the bladder and who received either intravesical thiotepa (30 mg/15 cc) or MMC (40 mg/20 cc) between January 1, 2002, and January 1, 2016. Data were collected for demographic characteristics, comorbid conditions, operative information, surveillance, and recurrence. The primary outcome was disease-free survival. Cohorts were compared via the doubly robust estimation approach, which used logistic regression to model the probability of recurrence. RESULTS: Of 154 total patients, 84 received intravesical MMC; 70, thiotepa. No statistical differences were shown between groups for age, sex, race, body mass index, smoking status, or baseline comorbid conditions; mass size, tumor multifocality, or tumor grade; and unadjusted recurrence rates (MMC, 36.0%; thiotepa, 46.0%; p = .33) at similar median follow up (MMC, 20.4; thiotepa, 22.8 months; p = .46). The robust logistic regression analysis yielded no differences in recurrence rates between MMC and thiotepa (OR, 0.65 [95% CI, 0.33-1.31]; p = .23). No episodes of myelosuppression or frozen pelvis were identified. CONCLUSIONS: As single-dose perioperative agents, both thiotepa and MMC were associated with similar recurrence-free survival rates.

Robot Assisted Surgery of the Vena Cava: Perioperative Outcomes, Technique, and Lessons Learned at The Mayo Clinic.

Introduction: This study aims to describe robot assisted surgery of the inferior vena cava (IVC) by assessing techniques utilized, perioperative outcomes, complications, and long-term patency of the IVC. Methods: A retrospective review was performed on all robotic surgeries involving dissection and repair of the IVC at our institution. Patient characteristics, operative reports, and follow-up visits were analyzed. Preoperative and postoperative imaging was independently reviewed by a single radiologist to determine changes in IVC diameter. Complications were analyzed according to early (<30 days) vs late (>30 days). Results: Thirty-four patients underwent robot assisted surgery of the vena cava from 2008 to 2018. Twenty-six cases were performed for urologic malignancy, four were performed for IVC filter explantation, and four renal vein transpositions were performed for nutcracker syndrome. Twenty-four of the 26 patients with urologic malignancy underwent radical nephrectomy with IVC tumor thrombectomy. Three cases were converted to open. Median length of stay was two nights, and mean estimated blood loss (EBL) was 375 mL. There were five complications, ranging from Clavien-Dindo grade II-IIIa, four of which were early complications. No patients required return to the operating room, and there were no perioperative mortalities. IVC diameter was reduced by 41% on axial diameter, with no patients experiencing compromised venous return. Conclusion: Robot assisted surgery offers the advantage of minimally invasive surgery with the ability to apply open surgical principles. In our series, an experienced multidisciplinary team approach yielded low EBL, short length of stay, and low complication rates.

Robot Assisted Radical Cystectomy vs Open Radical Cystectomy: Over 10 years of the Mayo Clinic Experience.

OBJECTIVES: There is scant information about intermediate / long-term comparative outcomes between robot assisted radical cystectomy (RARC) and open radical cystectomy (ORC). The purpose of this study is to present survival and oncological outcomes between bladder cancer patients who undergo RARC vs. ORC with an overall median follow-up of over 5 years. MATERIALS AND METHODS: A query of all patients who underwent radical cystectomy between January, 2007 and January, 2018 at Mayo Clinic Arizona yielded 595 patients. After excluding cystectomy performed for nonmalignant indication, cancer secondary to nonbladder primary, and cancers with grossly metastatic disease at the time of surgery, 481 patients remained. Data was collected on patient demographics, preoperative information, operative details, complications, and follow-up. Statistical analyses were generated using SPSS 22.0. RESULTS: In 481 total patients, 203 (42.2%) underwent RARC and 278 (57.8%) underwent ORC. The median follow-up for the entire cohort was 66 months. The 5-year recurrence-free survival (RFS) was 70.8% vs. 64.7% and the 10-year RFS was 69.6% vs. 62.7% for the RARC vs. ORC, respectively (P = 0.135). The 5-year overall survival (OS) was 58.9% vs. 57.7% and the 10-year OS was 39.9% vs. 45.6% for RARC vs. ORC patients, respectively (P = 0.466). There were no differences in any recurrence patterns, including the incidence of atypical recurrences (1.5% vs. 1.8% [P = 0.786], respectively). A Cox-proportional hazards model was fitted that included independent predictors of RFS and OS. The results revealed no difference in RFS (HR 1.235, 95% CI: 0.832-1.833, P = 0.295) or OS (HR 0.790, 95% CI: 0.550-1.135, P = 0.202) between the respectively. CONCLUSIONS: Recurrence free survival, OS, and recurrence patterns are similar in bladder cancer patients who undergo either RARC or ORC.

Robot Assisted Cystectomy With Holmium Laser Debridement for Osteomyelitis of the Pubic Symphysis With Urinary Fistula.

OBJECTIVE: To assess the success of robot-assisted holmium laser debridement of the pubic symphysis for osteomyelitis of the pubic symphysis with associated urosymphyseal fistula. Traditionally, excision of the fistulous tract and concomitant cystectomy with urinary diversion and pubic symphyseal debridement has been done using an open approach. This paper presents patients who were successfully managed with this approach. METHODS AND MATERIALS: Between January 2007 and January 2018, all patients who underwent pubic symphyseal debridement with or without cystectomy were identified. We reviewed patients who underwent planned robot-assisted cystectomy with holmium laser debridement for osteomyelitis of the pubic symphysis as a result of urinary fistula. Data on clinical presentation, perioperative outcomes, and recurrence of urinary tract fistula and symptoms were collected. RESULTS: Twelve patients underwent holmium laser debridement of the pubic symphysis during robot-assisted cystectomy for urinary fistula. Eleven patients had prior radiation treatments for prostate cancer with all having failed prior conservative management. Median operative time was 270 minutes with median length of stay of 5 days. At last follow-up, 11 (91.7%) of patients had complete resolution of their urinary fistula at median follow-up of 29 months. No patients developed osteonecrosis of the bone or complications from their urinary diversion at last follow-up. CONCLUSION: Definitive surgical treatment with holmium laser debridement of the pubic symphysis with concomitant robot-assisted cystectomy and urinary diversion is a safe and durable approach to the complex problem of urinary fistula with pubic symphysis osteomyelitis.

Role of robot-assisted retroperitoneal lymph node dissection in malignant mesothelioma of the tunica vaginalis: case series and review of the literature.

INTRODUCTION: The management of malignant mesothelioma of the tunica vaginalis (MMTVT) is not clearly defined. Retroperitoneal lymph node dissection has been reported as a potential management option. Herein we present our experience with robot-assisted retroperitoneal lymph node dissection (RARPLND) in our series of patients with MMTVT. MATERIALS AND METHODS: The Mayo Clinic cancer registry was queried from 1972-present for all patients who had a diagnosis of MMTVT. Six patients were identified, five of whom were treated with RPLND, where four underwent RARPLND. RESULTS: In five patients who underwent RPLND, the median age was 50 years (IQR 34-51). Four patients originally presented with right sided symptomatic hydroceles, while one presented with right sided chronic epididymitis. Orchiectomy (one simple, two inguinal radical) was performed in three patients prior to presentation. Preoperative cross-sectional imaging, including PET-CT scan in three patients, was negative for lymphadenopathy or metastasis. RARPLND was performed in 4/5 (80%) cases and concomitant hemiscrotectomy in 4/5 (80%) cases. Full bilateral template was performed in three patients and right modified template was performed in the remaining two. Median lymph node yield was 29 (IQR 22-32) and median blood loss was 275 cc (IQR 200-300). Positive retroperitoneal lymph nodes were found in 3/5 (60%) cases. All patients who underwent RARPLND were discharged home on postoperative day one. Mean follow up was 27 months (range 3-47). No patients recurred. CONCLUSIONS: Regardless of the approach, RPLND may provide a diagnostic benefit in patients who present with MMTVT, with the robotic approach affording a potentially expedited recovery.

Intracorporeal orthotopic neobladder formation: Why not to do it?

OBJECTIVES: There has been growing  interest in intracorporeal techniques to urinary diversion during cystectomy in the modern area. There is little high-quality evidence that this technique is superior to  extracorporeal diversion in patients who are obtaining  an orthotopic intracorporeal neobladder urinary diversion. This study describes the proposed advantages and  disadvantages of intracorporeal orthotopic neobladder urinary diversion and expert opinion on preference.  METHODS: We reviewed the literature for all studies  discussing the outcomes and advantages of intracorporeal orthotopic neobladder urinary diversion, including those comparing the intracorporeal and extracorporeal approach. The studies were reviewed and these findings were summarized based on categories of the proposed advantages and disadvantages of the intracorporeal approach. We provided an assessment of the claims made in favor of the intracorporeal approach and discussed advantages of the extracorporeal approach that may persuade even the most experienced robotic surgeons to lean away from the former.  RESULTS AND CONCLUSIONS: Herein we review the studies that propose advantages of the intracorporeal diversion, as well as the studies that do not demonstrate any advantage to this approach. Some of the proposedadvantages addressed include decreased stricture rate, lower complications and shorter hospitalization. Furthermore, we address the issues of the steep learningcurve and the impact on resident education. We conclude that the proposed benefits of an intracorporeal approach to urinary diversion are not substantiated and it is the preference of the authors to primarily perform extracorporeal urinary diversions.

ARTICULO SOLO EN INGLES.OBJETIVOS: Ha habido un interés creciente  en la era moderna por las técnicas intracorpóreas dederivación urinaria durante la cistectomía. Hay pocaevidencia de alta calidad que muestre que esta técnicaes superior a la derivación extracorpórea en pacientesa los que se les hace una derivación con neovejigaortotópica intracorpórea. Este estudio describe las ventajasy desventajas propuestas de la derivación urinariacon neovejiga ortotópica intracorpórea y la opinión deexpertos sobre preferencias.MÉTODOS: Revisamos todos los estudios de la literaturaque discuten los resultados y ventajas de la derivaciónurinaria con neovejiga ortotópica intracorpórea, incluyendolos que comparan los abordajes intra y extracorpóreo.Se revisaron los estudios y estos hallazgos fueron resumidos en base a las categorías de las ventajas einconvenientes propuestos del abordaje intracorpóreo.Hicimos una evaluación de las reivindicaciones a favor del abordaje intracorpóreo y discutimos las ventajas del abordaje extracorporeo que pueden persuadir incluso a los cirujanos robóticos más experimentados para noinclinarse por el primero.RESULTADOS Y CONCLUSIONES: Revisamos los estudios que proponen ventajas de la derivación intracorpórea, así como los estudios que no demuestran ninguna ventaja de este abordaje. Entre las ventajas tratadas se incluyen: disminución de la tasa de estenosis, menores complicaciones y estancias hospitalarias menores. Además, tratamos los aspectos de dificultad de la curvade aprendizaje e impacto sobre la educación del residente.Concluimos que los beneficios propuestos de un abordaje intracorpóreo de la derivación urinaria no están probados y que la preferencia de los autores esrealizar las derivaciones urinarias extracorpóreas.