Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients-A Tale of Two Cities: Sequencing Analysis Reveals Dual Lineage Markers Capturing the 2 Cellular Populations of HOT.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.

Characterization of Intercalated Cell Markers KIT and LINC01187 in Chromophobe Renal Cell Carcinoma and Other Renal Neoplasms.

Introduction. Chromophobe renal cell carcinoma (chromophobe RCC) is the third major subcategory of renal tumors after clear cell RCC and papillary RCC, accounting for approximately 5% of all RCC subtypes. Other oncocytic neoplasms seen commonly in surgical pathology practice include the eosinophilic variant of chromophobe RCC, renal oncocytoma, and low-grade oncocytic unclassified RCC. Methods. In our recent next-generation sequencing based study, we nominated a lineage-specific novel biomarker LINC01187 (long intergenic non-protein coding RNA 1187) which was found to be enriched in chromophobe RCC. Like KIT (cluster of differentiation 117; CD117), a clinically utilized chromophobe RCC related biomarker, LINC01187 is expressed in intercalated cells of the nephron. In this follow-up study, we performed KIT immunohistochemistry and LINC01187 RNA in situ hybridization (RNA-ISH) on a cohort of chromophobe RCC and other renal neoplasms, characterized the expression patterns, and quantified the expression signals of the two biomarkers in both primary and metastatic settings. Results. LINC01187, in comparison to KIT, exhibits stronger and more uniform expression within tumors while maintaining temporal and spatial consistency. LINC01187 also is devoid of intra-tumoral heterogeneous expression pattern, a phenomenon commonly noted with KIT. Conclusions. LINC01187 expression can augment the currently utilized KIT assay and help facilitate easy microscopic analyses in routine surgical pathology practice.

TERT Promoter Mutations in Keratinizing and Nonkeratinizing Squamous Metaplasia of the Urinary Tract.

We identified urothelial tract biopsy and resection specimens with keratinizing squamous metaplasia (KSM), nonkeratinizing squamous metaplasia (NKSM), and urothelial and squamous carcinomas over a 20-yr period, focusing on cases with neurogenic lower urinary tract dysfunction (NLUTD) and/or those with spatial or temporal variation in sampling. TERT promoter mutations as assessed via allele-specific polymerase chain reaction were surprisingly common in our testing cohort, identified not only in 15 (94%) invasive cancer foci but also in 13 (68%) examples of KSM and seven (70%) examples of NKSM. TERT promoter mutations were present in 23 foci from NLUTD specimens and 11 foci from bladder diverticula, including in foci of KSM, NKSM, and unremarkable urothelium from cases with no clinical association with previous, concurrent, or subsequent cancer. Our demonstration of temporally and spatially persistent TERT promoter mutation in examples of KSM and NKSM in cases of bladder cancer and in morphologically benign cases with neurogenic dysfunction suggests a molecular mechanism by which such pre-neoplastic lesions can potentially progress and develop into overt carcinoma. Given the interest in TERT promoter mutations as a potential biomarker for the development of bladder cancer, these findings possibly explain the association between conditions with chronic urinary bladder injury (such as the natural history of NLUTD) and higher risk of bladder cancer. TERT promoter mutations may represent an early event in bladder cancer tumorogenesis, and our findings expand on the clinical ramifications and predictive value of TERT promoter mutations in this context. PATIENT SUMMARY: Mutations in the TERT gene are the most common genetic changes in bladder cancer. We found that these mutations are also sometimes present in patients with chronic bladder irritation such as neurogenic bladder dysfunction and changes to the lining of the bladder that pathologists would consider "benign." This finding might explain why such conditions are associated with the development of bladder cancer.

The Feasibility and Impact of a Presurgical Exercise Intervention Program (Prehabilitation) for Patients Undergoing Cystectomy for Bladder Cancer.

OBJECTIVE: To assess the feasibility of a prehabilitation program for cystectomy patients and to determine the effectiveness of the program in improving strength and functional capacity in the peri-operative period. MATERIALS AND METHODS: This phase I/II study accrued patients ≥60 years old from January 2013 to October 2017 with biopsy-proven bladder cancer, Karnofsky performance score ≥70 and a sedentary baseline lifestyle to participate in a 4-week supervised preoperative exercise training program. Primary outcomes were feasibility and safety; secondary outcomes included changes in fitness, patient-reported QOL, peri-operative complications and readmissions. Student's ttests and Wilcoxon signed-rank test were performed. RESULTS: Fifty-four patients enrolled in the program. Successful completion, defined as patients who began the program and adhered to >70% of the sessions, was attained by 41 of 51 patients (80.4%, 90% CI [71%-90%]). There were no adverse events. Fitness and patient-reported QOL improved postintervention, with sustained improvements in general and mental health 90-days postsurgery. The primary limitation is no control group. CONCLUSION: Prehabilitation prior to cystectomy is feasible, safe, and results in improvements in patient strength, endurance and sustained improvements in patient-reported QOL from baseline. Efforts to further evaluate the impact of prehabilitation in this population in an expanded and randomized fashion are warranted.

Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial.

Importance: Low-grade non-muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). Objective: To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non-muscle-invasive urothelial cancer compared with saline. Design, Setting, and Participants: Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non-muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. Interventions: Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. Main Outcomes and Measures: The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. Results: Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non-muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower. Conclusions and Relevance: Among patients with suspected low-grade non-muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. Trial Registration: clinicaltrials.gov Identifier: NCT00445601.

Multi-institutional Survival Analysis of Incidental Pathologic T3a Upstaging in Clinical T1 Renal Cell Carcinoma Following Partial Nephrectomy.

OBJECTIVE: To evaluate whether incidental pathologic T3a (pT3a) upstaging after partial nephrectomy (PN) for clinical T1 disease results in inferior oncologic outcomes compared to pT1a-b disease. MATERIALS AND METHODS: Retrospective chart review was completed at the University of Michigan and Moffitt Cancer Center to identify patients undergoing PN for clinical T1 masses between 1995 and 2015. A total of 1955 patients were identified, of which 95 had pT3a upstaging. Median follow-up was 38.2 months. Patients with pT3a disease were individually matched by clinicopathologic features with patients undergoing PN with pT1a-b disease in a 1:2 ratio. Kaplan-Meier analysis and univariate and multivariable Cox proportional hazards regression analysis were performed. Primary endpoint was recurrence-free survival (RFS). Secondary endpoints were all-cause mortality, cancer-specific survival (CSS), and rates of local and distant recurrence. RESULTS: Recurrence rates were significantly higher in pT3a disease compared to pT1a-b controls (P <.01). In those patients with pT3a upstaging, 3- and 5-year RFS were 81% and 58%, compared to 86% and 75% in pT1a-b controls (P = .01). CSS at 3 and 5 years were 91% and 90% in pT3a disease and 100% and 97% in pT1a-b controls (P <.01). All-cause mortality at 3 and 5 years were 82% and 71% in pT3a disease and 93% and 80% in pT1a-b controls (P = .04). Univariate and multivariable analysis of pT3a disease demonstrated no association between demographic or pathologic characteristics and RCC recurrence. CONCLUSION: Patients with pT3a upstaging following PN experience a significantly reduced RFS and CSS when compared to pT1 disease.

Utility of Pelvic CT for Surveillance of T2-T4 Renal Cell Carcinoma After Nephrectomy With Curative Intent.

OBJECTIVE: The purpose of this study was to determine whether routine pelvic imaging is necessary during postoperative surveillance of pathologic T2-T4 renal cell carcinoma after nephrectomy for curative intent. MATERIALS AND METHODS: A retrospective single-institution cohort study with 603 subjects undergoing partial or radical nephrectomy of T2-T4 renal cell carcinoma with curative intent was conducted from January 1, 2000, through December 31, 2015. Clinical and imaging (CT or MRI) follow-up findings were evaluated in a prospectively maintained registry to determine the timing and location of recurrent and metastatic disease. The primary outcome was the proportion of subjects with positive or equivocal findings in the pelvis and negative findings in the chest and abdomen. Binomial CIs were calculated and compared with a prespecified minimum detection threshold of 5%. RESULTS: The T category distribution was as follows: T2 (28.9% [174/603]), T3 (70.3% [424/603]), and T4 (0.8% [5/603]). Most (81.8% [493/603]) of the patients underwent radical nephrectomy, and 27.0% (163/603) had recurrence or metastasis (mean time to first recurrence, 600 ± 695 days). Pelvic imaging findings were negative in 97.0% (585/603) of cases. Four subjects (0.7% [95% CI, 0.2-1.7%]) had isolated positive findings in the pelvis (p < 0.0001 vs the 5% threshold). Two (0.3% overall [95% CI, 0.04-1.1%]) of these positive findings were in subjects who did not have symptoms. CONCLUSION: Routine pelvic imaging of patients undergoing surveillance for asymptomatic T2-T4 renal cell carcinoma after nephrectomy performed with curative intent has minimal value and probably should not be performed.

Detailed pathologic analysis on the co-occurrence of non-seminomatous germ cell tumor subtypes in matched orchiectomy and retroperitoneal lymph node dissections.

The frequency of co-occurrence between germ cell tumor (GCT) components in non-seminomatous germ cell tumor (NSGCT) orchiectomy specimens and their correlation with histologic findings in subsequent retroperitoneal lymph node dissection (RPLND) specimens have not been well characterized. The objective of the study was to report the first detailed clinicopathologic analysis of NSGCT orchiectomy and RPLND samples to determine the likelihood and agreement of the co-occurrence of GCT components. A total of 118 consecutive patients with NSGCT treated between 1988 and 2012 who underwent both orchiectomy and RPLND at a single academic tertiary care center were analyzed. Statistical analysis of co-occurrence likelihood and agreement of GCT components was performed, both within and between orchiectomy and RPLND specimens. Embryonal carcinoma was the most frequent component present in orchiectomy specimens, and there were multiple significant associations between orchiectomy GCT components; seminoma occurred less frequently with embryonal carcinoma (OR 0.29 [95% confidence interval (CI) 0.11-0.75]; p < 0.01), and teratoma more frequently occurred with choriocarcinoma (OR 9.64 [95% CI 1.22-76.12]; p = 0.01). Presence of teratoma in the orchiectomy specimen predicted for a fourfold increase in distant metastasis on multivariate analysis (HR 4.92 [1.14-18.9]; p = 0.02). The only significant association of co-occurrence in the RPLND specimen was between embryonal carcinoma and teratoma (OR 0.01 [95% CI 0-0.07]; p < 0.001), where it was significantly less likely for them to occur together. Our findings are limited by their retrospective nature. The co-occurrence of GCT components within orchiectomy specimens does not appear to be a completely random process. However, there is less agreement and more randomness between the occurrence of the GCT components in matched orchiectomy and RPLND samples. In this report, we look at the co-occurrence of different GCT components within matched orchiectomy and RPLND pathology specimens and show that co-occurrence is not a completely random process.

The Urology Applicant: An Analysis of Contemporary Urology Residency Candidates.

OBJECTIVE: To better understand today's urology applicant. METHODS: All 2016 Urology Residency Match applicants to the study-participating institutions were provided a survey via email inquiring about their paths to urology, their career aspirations, how they evaluate a training program, and how they perceive residency programs evaluate them. RESULTS: Of a possible 468 applicants registered for the match, 346 applicants completed the survey. Only 8.7% had a mandatory urology rotation, yet 58.4% believed that a mandatory urology rotation would influence their career decision. Most applicants (62.1%) spent more than 8 weeks on urology rotations, and 79.2% completed 2 or more away rotations. Applicants were attracted to urology by the diversity of procedures, prior exposure to the field, and the mix of medicine and surgery, with mean importance scores of 4.70, 4.52, and 4.45 of 5, respectively. Female applicants were more likely to be interested in pediatric urology, trauma or reconstructive urology, and female pelvic medicine and reconstructive surgery. Significant differences in survey results were noted when applicants were separated by gender. Three-fourths of respondents (75.7%) applied to more than 50 residency programs. Applicants ranked operative experience, interactions with current residents, and relationships between faculty and residents as the most important criteria when evaluating training programs. Of the subspecialties, 62.1% of applicants expressed most interest in urologic oncology. At this stage in their career, a significant majority (83.5%) expressed interest in becoming academic faculty. CONCLUSION: This study provides new information that facilitates a more comprehensive understanding of today's urology applicants.

The Fate of Radical Cystectomy Patients after Hospital Discharge: Understanding the Black Box of the Pre-readmission Interval.

BACKGROUND: Radical cystectomy has one of the highest 30-d hospital readmission rates but circumstances leading to readmission remain poorly understood. OBJECTIVE: To examine the postdischarge period and better understand hospital readmission after radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort study of patients treated with radical cystectomy for bladder cancer from 2005 to 2012 using our institutional database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed patient communication with any healthcare system after hospital discharge based on timing, methods, and concern types. Logistic regression and Cox proportional-hazards analyses were used to compare postdischarge concerns among readmitted and nonreadmitted patients. We internally validated the logistic model using a bootstrap resampling technique. RESULTS AND LIMITATIONS: One-hundred patients (23%) were readmitted within 30 d of index discharge. Readmitted patients were more likely to use the emergency department with initial concerns compared with nonreadmitted patients (27% vs 1.0%, p<0.001). Patients who took longer to first communicate their concerns and who were able to tolerate their symptoms longer had lower odds of readmission. Patients who reported infection (adjusted hazard ratio: 2.8, 95% confidence interval: 1.4-5.8) and failure to thrive concerns (adjusted hazard ratio: 4.4, 95% confidence interval: 2.0-9.3) were more likely to be readmitted compared with those who communicated noninfectious wounds and/or urinary concerns. CONCLUSIONS: Radical cystectomy patients who contact the health system soon after discharge or communicated infectious or failure to thrive symptoms (fever, poor oral intake, or vomiting) are more likely to experience readmission as opposed to those that endorse pain, constipation, or ostomy issues. Better understanding of this pre-readmission interval can optimize postdischarge practices. PATIENT SUMMARY: We looked at bladder cancer patients who had surgery and the reasons why they were readmitted to hospital. We found patients who had a fever or difficulty with eating and maintaining their weight had the highest chance of being readmitted.

Robotic-assisted Thoracoscopic Transdiaphragmatic Adrenalectomy (RATTA) for Metastatic Renal Cell Carcinoma.

OBJECTIVE: Robotic-assisted thoracoscopic transdiaphragmatic adrenalectomy (RATTA) represents a novel surgical approach for the management of adrenal pathology in patients with a history of extensive transperitoneal or retroperitoneal procedures. METHODS: Here we report the first described case of RATTA in a 56-year-old woman with metastatic renal cell carcinoma to the left adrenal gland and right lung. With the assistance of cardiothoracic surgery, this patient underwent robotic-assisted thoracoscopic pulmonary wedge resection and RATTA. In brief, after completion of the pulmonary wedge resection by thoracic surgery the diaphragm was incised starting at the left crus and extending laterally through the diaphragmatic muscle, exposing the retroperitoneal space and fat. The adrenal gland with mass was identified, dissected from surrounding structures, and extracted. The diaphragm was then closed using Ethibond suture with polytetrafluoroethylene felt pledgets. A 22-Fr chest tube was placed in the thoracic cavity. RESULTS: Operative and postoperative courses were uncomplicated. The patient was discharged on postoperative day 4. Pathology confirmed metastatic clear cell renal cell carcinoma in both the left adrenal and the right lung nodules with negative surgical margins. CONCLUSION: The case described here highlights the surgical technique and ideal patient population in which RATTA serves as a feasible and safe alternative to conventional laparoscopic approaches in the treatment of adrenal pathologies.

Programmed Death-ligand 1 Expression in Upper Tract Urothelial Carcinoma.

BACKGROUND: Urothelial carcinoma (UC) is the most common malignancy of the urinary tract. Upper tract (renal pelvis and ureter) urothelial carcinomas (UTUC) account for approximately 5% of UCs but a significant subset are invasive and associated with poor clinical outcomes. OBJECTIVE: To evaluate programmed death-ligand 1 (PD-L1) expression in UTUC. DESIGN, SETTING, AND PARTICIPANTS: UTUC cases from 1997-2016 were retrospectively identified from the surgical pathology database at a single large academic institution. The cohort included 149 cases: 27 low-grade and 24 high-grade pathologic T (pT)a, 29 pT1, 23 pT2, 38 pT3, and eight pT4. PD-L1 immunohistochemistry (IHC) was performed on representative whole tumor sections using anti-PD-L1 primary antibody clone 5H1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PD-L1 expression was evaluated using a previously established cut-off for positivity (≥ 5% membranous staining). Association between PD-L1 IHC expression and clinicopathologic parameters was examined with Fisher's exact test; the effect of PD-L1 expression on cancer-specific mortality was assessed using the Cox proportional hazard model. RESULTS AND LIMITATIONS: Approximately one-third (32.7%) of invasive primary UTUC and 23.5% of all primary UTUC (invasive and noninvasive tumors) demonstrated positive PD-L1 expression. Positive PD-L1 expression was associated with high histologic grade, high pathologic stage, and angiolymphatic invasion. Cancer-specific survival was not significantly associated with positive PD-L1 expression using a 5% cut-off. Study limitations include the retrospective nature and the fact that PD-L1 expression by IHC is an imperfect surrogate for response to therapy. CONCLUSIONS: Positive PD-L1 expression in approximately one-third of primary invasive UTUC and association with high-risk clinicopathologic features provide a rational basis for further investigation of PD-L1-based immunotherapeutics in these patients. PATIENT SUMMARY: Upper tract urothelial carcinoma is often associated with poor clinical outcome. While current treatment options for advanced upper tract urothelial carcinoma are limited, programmed death-ligand 1 positivity in approximately one-third of invasive tumors provides a rational basis for further investigation of programmed death-ligand 1-based immunotherapeutics in these patients.

No Differences in Population-based Readmissions After Open and Robotic-assisted Radical Cystectomy: Implications for Post-discharge Care.

OBJECTIVE: To inform whether readmission reduction strategies should consider surgical approach, we examined readmission differences between open and robotic-assisted radical cystectomy (RARC) using population-based data. METHODS: We identified patients who underwent cystectomy between January 2010 and September 2013 based on International Classification of Diseases-9th edition codes and administrative claims from a large, national US health insurer (Clinformatics Data Mart Database, OptumInsight, Eden Prairie, MN). We assessed post-discharge health system utilization and tested for differences in readmissions after the 2 surgical approaches. RESULTS: We identified 935 patients treated with cystectomy: open = 785 (84%) and RARC = 150 (16%). Patients undergoing RARC were slightly older, male, had more ileal conduit urinary reconstruction, and less need for intensive care. Index length of stay was shorter for RARC than for open surgery (7 days vs 8 days, P < .001). However, we found no differences in 30-day readmission rates (24% open vs 29% RARC, P = .26) or other readmission parameters, including readmission length of stay (5 days open vs 4 days RARC, P = .32), emergency department use (22% open vs 24% RARC, P = .86), reasons for readmission, or timing of first outpatient visits (11.5 days open vs 9 days RARC, P = .41). For both approaches, the majority of patients were readmitted within 2 weeks. CONCLUSION: The surgical approach to cystectomy does not appear to impact readmissions. Strategies to reduce the readmission burden after cystectomy do not need to consider surgical approach but should focus on timing of medical contacts.

Safety and Early Oncologic Effectiveness of Primary Robotic Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Testicular Cancer.

BACKGROUND: Primary robot-assisted retroperitoneal lymph node dissection (R-RPLND) has been studied as an alternative to open RPLND in single-institution series for patients with low-stage nonseminomatous germ cell tumors (NSGCT). OBJECTIVE: To evaluate a multicenter series of primary R-RPLND for low-stage NSGCT. DESIGN, SETTING, AND PARTICIPANTS: Between 2011 and 2015, 47 patients underwent primary R-RPLND at four centers for Clinical Stage (CS) I-IIA NSGCT. SURGICAL PROCEDURE: R-RPLND was performed using the da Vinci surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data were collected regarding patient demographics, primary tumor characteristics, pathologic findings, and clinical outcomes. RESULTS AND LIMITATIONS: Forty-two patients (89%) were CS I and five (11%) were CS IIA. The median operative time was 235min (interquartile range [IQR]: 214-258min), estimated blood loss was 50ml (IQR: 50-100ml), node count was 26 (IQR: 18-32), and length of stay was 1 d. There were two intraoperative complications (4%), four early postoperative complications (9%), no late complications, and the rate of antegrade ejaculation was 100%. Of the eight patients (17%) with positive nodes (seven pN1and one pN2), five (62%) received adjuvant chemotherapy. The one recurrence was out of template in the pelvis after adjuvant chemotherapy (resected teratoma). The median follow-up was 16 mo and the 2-yr recurrence-free survival rate was 97% (95% confidence interval: 82-100%). Limitations include retrospective design and limited follow-up. CONCLUSIONS: Our multicenter experience supports R-RPLND as a potential option at experienced centers in select patients with low-stage NSGCT. Informal comparison to open and laparoscopic series suggests R-RPLND has an acceptably low morbidity profile, but oncologic efficacy evaluation requires further evaluation. PATIENT SUMMARY: We examined outcomes after robot-assisted retroperitoneal lymph node dissection for patients with low-stage nonseminomatous testicular cancer with our data suggesting the robotic approach has acceptable morbidity and early oncologic outcomes.

Potential Implications of Shortening Length of Stay Following Radical Cystectomy in a Pre-ERAS Population.

OBJECTIVE: To investigate whether shortened inpatient length of stay (LOS) after radical cystectomy (RC) is associated with increased complication rates after hospital discharge. MATERIALS AND METHODS: The analytic cohort comprised 484 consecutive patients with 90-day follow-up who underwent RC at our institution from 2005 to 2012 and with LOS ≤9 days. Patients were categorized according to LOS as short (s-LOS; ≤5 days) or routine (r-LOS; 6-9 days). The primary outcome was major complications (Clavien-Dindo grades 3-5) occurring within 90 days after discharge. A Cox proportional hazards model was used to determine the association between LOS and post-discharge major complications. Hospital readmission was a secondary outcome. RESULTS: Patients in the s-LOS cohort had fewer comorbidities (P < .01), less frequently received neoadjuvant chemotherapy (P = .02), and more often underwent robotic RC (P < .01). Major outpatient complications occurred in 18.1% of s-LOS patients vs 11.2% of r-LOS patients, and s-LOS was associated with a significant independent increase in the risk of major outpatient complications (hazard ratio 1.91, 95% confidence interval 1.03-3.56, P = .04). There was also a statistically significant association between s-LOS and readmission (hazard ratio 1.60, 95% confidence interval 1.01-2.44, P = .048). CONCLUSION: Early discharge post RC appears to be associated with an increased risk of major outpatient complications, suggesting that attempts to reduce LOS may need to be supplemented by additional outpatient services to diminish this effect. Further attention should be given to understanding how to better support patients discharged after a short LOS.

Effect of delayed resection after initial surveillance and tumor growth rate on final surgical pathology in patients with small renal masses (SRMs).

OBJECTIVE: To understand potential harms associated with delaying resection of small renal masses (SRMs) in patients ultimately treated, and whether these patients have factors associated with adverse pathology. METHODS: Patients with SRMs (≤4cm) who underwent surgical resection at our institution (2009-2015) were classified as undergoing early resection or initial surveillance with delayed resection (defined by a time from presentation to intervention of at least 6mo). Demographic and clinical variables were compared among groups. Using multivariable logistic regression, we examined the association between delayed resection and adverse pathology (Fuhrman grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage≥pT3). For patients who underwent delayed intervention, we used similar methods to examine the association between SRM growth rate and adverse pathology. RESULTS: Overall, 401 (81%) and 94 (19%) patients underwent early and delayed resection, respectively. Median time to resection was 84 days (interquartile range: 59-121) and 386 days (interquartile range: 272-702) (P<0.001). Patients undergoing delayed resection were older (62 vs. 58y, P = 0.01) and had smaller masses (2.3 vs. 2.7cm, P<0.001) at initial presentation. Utilization of partial vs. radical nephrectomy was similar regardless of resection timing (P = 0.5). Delayed resection was not associated with adverse pathology (P = 0.8); however, male sex was independently associated with adverse pathology (odds ratio: 1.7, 95% CI: 1.1-2.4, P = 0.009). In patients on surveillance, increasing annual SRM growth rate was associated with adverse pathology (odds ratio: 1.2, 95% CI: 1.03-1.3mm/y, P = 0.02). CONCLUSIONS: Delayed resection was not associated with adverse pathology. Patients on surveillance with increased SRM growth rates had a modest but significant increase in the risk of adverse pathology.

Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation. SIGNIFICANCE: MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258-66. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1197.

A Multi-Center International Study Assessing the Impact of Differences in Baseline Characteristics and Perioperative Care Following Radical Cystectomy.

Background: To identify potential avenues for quality improvement, we compared the variations in clinical practice and their association with perioperative morbidity and mortality following radical cystectomy (RC) for bladder cancer in the United States (US) and Japan. Methods: We reviewed our retrospectively collected database of 2240 patients who underwent RC for bladder cancer at the University of Michigan (n = 1427) and in 21 Japanese institutions (n = 813) between 1997 and 2014. We performed a systematic comparison of clinical and perioperative factors and assessed predictors of perioperative morbidity and mortality. Death within 90 days of surgery was the primary outcome. Results: There were apparent differences between the two study populations. Notably, US patients had a significantly greater BMI and higher ASA score. In Japanese institutions, median postoperative hospital stay was significantly higher (40 days vs. 7 days, p <  0.001) and 90-day readmission rates were significantly lower (0.6% vs. 26.8% , p <  0.001). There was a total of 1372/2240 (61.2%) patients with complications within 90 days and 66/2240 (2.9%) patient deaths. Significant predictors of 90-day mortality were older age (OR 1.04, CI 1.01-1.07), higher body mass index (OR 1.07, CI 1.02-1.12), node-positive disease (OR 3.14, CI 1.78-5.47), increased blood loss (OR 1.02, CI 1.01-1.03), and major (Clavien-grade 3 or greater) complication (OR 3.29, CI 1.88-5.71). Conclusion: Despite major differences in baseline characteristics and care of cystectomy patients between the two study populations, peri-operative mortality rates proved to be comparable. This data supports an exploration of non-traditional factors that may influence mortality after cystectomy.

Predictors of Delayed Intervention for Patients on Active Surveillance for Small Renal Masses: Does Renal Mass Biopsy Influence Our Decision?

OBJECTIVE: To review our clinical T1a renal mass active surveillance (AS) cohort to determine whether renal mass biopsy was associated with maintenance of AS. MATERIALS AND METHODS: From our prospectively maintained database we identified patients starting AS from June 2009 to December 2011 who had at least 5 months of radiologic follow-up, unless limited by unexpected death or delayed intervention. The primary outcome was delayed intervention. Clinical, radiologic, and pathologic variables were compared. We constructed Kaplan-Meier survival curves for maintenance of AS. Cox multivariable regression analysis was performed to assess predictors of delayed intervention. RESULTS: We identified 118 patients who met criteria for inclusion with a median radiologic follow-up of 29.5 months. The delayed intervention group had greater initial mass size and faster growth rate compared to those who continued AS. Rate of renal mass biopsy was similar between the 2 groups. In the multivariable analysis, size >2 cm (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.28-10.38, P = .015), growth rate (continuous by mm/year: HR 1.26, 95% CI 1.12-1.41, P < .001), but not renal biopsy (HR 1.52, 95% CI 0.70-3.30, P = .29), were associated with increased risk of delayed intervention. Time-to-event curves also showed that size was closely associated with delayed intervention whereas renal mass biopsy was not. CONCLUSION: At our institution, growth rate and initial tumor size appear to be more influential than renal mass biopsy results in determining delayed intervention after a period of AS. Further analysis is required to determine the role of renal biopsy in the management of patients being considered for AS.

Patient-Reported Convalescence and Quality of Life Recovery: A Comparison of Open and Robotic-Assisted Radical Cystectomy.

Background Robotic-assisted radical cystectomy (RARC) is gaining traction as a surgical approach, but there are limited data on patient-reported outcomes for this technique compared to open radical cystectomy (ORC). Objective To compare health-related quality of life (HRQoL) and short-term convalescence among bladder cancer patients who underwent ORC and RARC. Methods Review of a single-institution bladder cancer database was conducted. Baseline and postoperative HRQoL was evaluated using the Bladder Cancer Index (BCI) for 324 patients who had ORC (n = 267) or RARC (n = 57) between 2008 and 2012. The BCI assesses function and bother in urinary, bowel, and sexual domains. Among 87 distinct patients (ORC n = 67, RARC n = 20), we also evaluated short-term postoperative convalescence using the Convalescence and Recovery Evaluation (CARE) questionnaire. Our primary outcomes were HRQoL within 12 months and short-term convalescence within 6 weeks following cystectomy. We fit generalized estimating equation regression models to estimate longitudinal changes in BCI scores within domains, and CARE domain score differences were tested with Wilcoxon rank-sum tests. Results Clinical characteristics and baseline BCI/CARE scores were similar between the 2 groups (all P > .05). Within 1 year after surgery, recovery of HRQoL across all BCI domains was comparable, with scores nearly returning to baseline at 1 year for all patients. CARE scores at 4 weeks revealed that patients treated with ORC had better pain (29.1 vs 20.0, P = .02) domain scores compared to RARC. These differences abated by week 6. Conclusions HRQoL recovery and short-term convalescence were similar in this cohort following ORC and RARC.