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Background: Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance., Results: Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease., Conclusions: Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Consent to participate was acquired through the Institutional Review Board under the Total Cancer care protocol (MCC #20148, Advarra [Pro00038234]). All experimental methods comply with the Declaration of Helsinki for Medical Research involving Human Subjects. Consent for publication: Not applicable. Competing interests: The corresponding author certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (i.e., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: ACS, MTH, TCP, OEO, NHC, AEB, PAS, JN, CMS, NLF, PMRE, KYT, JAB, YCP, JD, LAM, WEG, and BLF have no relevant disclosures; BJM is an NCCN Kidney Cancer Panel Member and an advisor for Merck; RL received research support from Predicine, Veracyte, CG Oncology, Valar Labs, and Merck, is on the clinical trials committee for CG Oncology, is scientific advisor for Bristol Myers Squibb, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, and Janssen, and has received honoraria from SAI MedPartners, Solstice Health Communications, Putnam Associates, and UroToday; JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics; NS, SK, and MG are or formerly were employees of NanoString., (© 2024. The Author(s).)

Introduction: It is unclear whether laterality has prognostic implications for patients with renal cell carcinoma (RCC). Some suggest that left sided tumors may have worse survival outcomes. The purpose of this study is to associate tumor characteristics and clinical outcomes with laterality in patients with RCC., Materials and Methods: Patients with RCC were identified in the National Cancer Database between 2004-2020. Patients were categorized as having either localized, regional or metastatic disease. Time-series charts were generated to demonstrate laterality differences and variance over time. Multivariable Cox proportional hazards regression was utilized to associate laterality with overall survival, stratified by clinical stage. Kaplan-Meier estimates were utilized to visualize survival functions., Results: A total of 306,196 patients were included, 156,450 (51.1%) had right sided tumors and 283,282 (92.5%) had localized RCC. Localized tumors were more likely to be right sided (0.51 [95% CI 0.50-0.52], p < 0.001). Metastatic and regional tumors (cN+M0) were more likely to be left sided (0.48 [0.47-0.49], p < 0.001; and 0.43 [0.41-0.45], p < 0.001; respectively). For localized disease, smaller tumors were more likely to be right sided (< 2 cm: 0.52 [0.51-0.52], p < 0.001), while tumors > 7cm showed no significant site association (0.49 [0.49-0.50], p = 0.07). When stratified by staging, there were no significant associations between laterality and OS (localized RCC: HR 1.01 [0.99-1.02], p = 0.50; metastatic RCC: 1.03 [1.00-1.07], p = 0.7; cN+M0 RCC: 0.96 [0.86-1.07], p = 0.50)., Conclusions: Left-sided RCC tumors are associated with larger tumor size and a higher propensity for regional nodal involvement and distant metastases. However, they do not demonstrate more aggressive behavior leading to meaningful survival differences.

Purpose: Urologic surgery involving placement of an indwelling ureteral and/or urethral drain can be associated with significant catheter-related bladder discomfort causing increased postoperative morbidity and opioid medication use. We sought to assess if a single dose of oxybutynin given preoperatively reduces immediate postoperative opioid use in common pediatric urology surgeries., Materials and Methods: This single-institution retrospective study identified pediatric patients who underwent surgery on the urinary tract with concomitant placement of a urethral and/or ureteral drain. Patients were given a single weight-based dose of oral oxybutynin in the preoperative area prior to surgery. The primary outcome was receipt of postoperative opioid medication. Multivariable regression analyses were used to assess variables associated with postoperative opioid use., Results: A total of 134 patients were included in our final study population with 42 receiving oxybutynin and 92 who did not. There was no statistical difference between the groups in terms of age, procedure type, anesthesia block, postoperative drain, or intraoperative morphine milligram equivalents per kilogram. Patients who received oxybutynin preoperatively had a decrease in postoperative opioid use (19%) compared to those who did not receive oxybutynin (47%). On multivariable logistic regression analysis, preoperative oxybutynin was associated with a 77% reduced risk of receiving postoperative opioid (odds ratio 0.23, [95% CI 0.09-0.56], P < .001)., Conclusions: For pediatric patients with an indwelling urinary drain after urologic surgery, a single preoperative dose of oxybutynin was significantly associated with lower postoperative utilization of opioids. This relatively low-risk intervention can be easily implemented.

Background and Objective: It is unclear whether cytoreductive nephrectomy (CN) practices have changed in the USA after the publication of the Cancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) trial in 2018. Our primary objective is to determine the effect of the CARMENA trial on CN rates in the USA., Methods: Patients were identified in the National Cancer Database from 2004 to 2020. A quasiexperimental difference-in-differences analysis was used to test the primary outcome, as follows: the change in CN rate was assessed among metastatic clear cell renal cell carcinoma (ccRCC) patients diagnosed before versus after 2018, while using the localized nephrectomy (LN) rate performed in the setting of nonmetastatic ccRCC as a control group., Key Findings and Limitations: The difference-in-differences analysis identified a statistically significant decrease in CN rate after CARMENA (β-coefficient [standard error]: -0.06 [0.025], p = 0.028), with a 10.2% absolute and a 31.8% relative rate reduction when compared with the counterfactual (expected) value (34.7% → 21.9% [actual] vs 32.1% [expected]). Primarily, relative differences in CN and LN rates before and after 2018 may be attributable to additional factors, aside from CARMENA publication, not tested in this quasiexperimental model., Conclusions and Clinical Implications: CN rates decreased significantly after the publication of the CARMENA trial in 2018, with a minimal difference in regional or demographic practice patterns. Overall, the publication of the CARMENA trial results is seemingly associated with substantial alteration of clinical practice in the USA, with relatively broad and nonspecific adoption across facilities, regions, and demographics., Patient Summary: For decades, the immediate surgical removal of the kidney tumor (cytoreductive nephrectomy) was a mainstay of metastatic kidney cancer treatment. In 2018, the CARMENA study showed that patients treated with systemic therapy alone had similar outcomes to patients who underwent cytoreductive nephrectomy first. In this study, we show that fewer cytoreductive nephrectomies were performed after the CARMENA trial results were published., (Copyright © 2024 European Association of Urology. All rights reserved.)

The diagnosis of occult inguinal lymph node metastasis in clinically node-negative invasive penile squamous cell carcinoma (PSCC) has remained a challenge, with substantial perioperative complications. The recent refinements in the technique of dynamic sentinel lymph node biopsy (DSLNB) demonstrated high diagnostic accuracy with considerably lower morbidity compared to conventional open modified/superficial inguinal lymph node dissection (ILND). Although DSLNB, if available, has been endorsed as the preferred method for nodal staging in patients with invasive PSCC and no palpable inguinal lymphadenopathy in the recent penile cancer guidelines, its utilization has been quite limited so far. Laparoscopic and robotic-assisted ILND have emerged as alternatives for nodal staging in this patient population and are shown to improve the rate of wound infections and postoperative pain. For management of nodal metastasis in patients with clinically palpable inguinal lymph nodes, minimally invasive ILND has shown promising results as well. Nonetheless, given the rarity of PSCC and the absence of prospective studies and clinical trials, nodal staging and treatment of nodal metastasis in clinical practice will likely continue to vary across the medical centers in the following years. In this review, we first summarize the evolution of DSLNB and minimally invasive ILND and discuss the advantages and drawbacks of each management strategy. We further discuss the remaining challenges and future perspectives in the management of inguinal lymph nodes in patients with PSCC.

Background: Neoadjuvant cisplatin-containing chemotherapy before radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer (MIBC). However, a large proportion of patients are ineligible for cisplatin. Single-arm phase 2 neoadjuvant immunotherapy trials have reported promising tumor response rates, but interpretation is limited owing to lack of a comparator arm., Objective: To compare rates of pathologic downstaging and overall survival between patients receiving neoadjuvant immunotherapy (NAI), neoadjuvant chemotherapy (NAC), or no neoadjuvant therapy (NNAT)., Design, Setting, and Participants: We identified 18 483 patients in the National Cancer Data Base who were diagnosed with clinically localized MIBC and underwent radical cystectomy from 2014 to 2019., Outcome Measurements and Statistical Analysis: Nearest-neighbor propensity-score caliper matching was used to create three demographically similar and equally sized cohorts stratified by NAT receipt. Logistic regression was used to examine the association of treatment received with pathologic downstaging to pT0N0 and pT < 2N0. Cox proportional-hazards regression was used to assess the association of treatment received with overall survival (OS)., Results and Limitations: Propensity score matching yielded three equally sized cohorts without significant differences in baseline characteristics (n = 840). The NAI group had a higher rate of pathologic downstaging to pT0N0 than the NNAT group and a similar rate to the NAC group (NNAT 6.7% vs NAC 26.4%, odds ratio 5.0, 95% confidence interval [CI] 2.9-8.3; NAI 22.5%, odds ratio 4.0, 95% CI 2.4-7.1). The NAI group had better OS than the NNAT group and similar OS to the NAC group (NAC: hazard ratio 0.62, 95% CI 0.42-0.92; NAI: hazard ratio 0.68, 95% CI 0.46-0.97, with NNAT as the reference). The primary limitation is selection bias from confounding by clinical indication., Conclusions: NAI is a promising alternative to NAC for patients with clinically localized MIBC, as evidenced by similar pathologic downstaging rates and OS benefits in comparison to no NAT. Phase 3 trials should be conducted to test the noninferiority of NAI to NAC., Patient Summary: We compared outcomes for patients with muscle-invasive bladder cancer according to whether they received chemotherapy, immunotherapy, or no medical therapy before surgical removal of their bladder. We found that preoperative immunotherapy improved patient survival and regression of the cancer stage in comparison to no medical therapy, similar to the outcomes seen with preoperative chemotherapy. Randomized clinical trials are needed to confirm these findings., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates., Results: 21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV . In CPTAC, collagen IV protein was more abundant in advanced stages of disease., Conclusions: On spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC., Competing Interests: Competing interests: The corresponding author certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (ie. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: ACS, MTH, TCP, OEO, NHC, AEB, PAS, JN, CMS, NLF, PMRE, KYT, JAB, YCP, JD, LAM, WEG, and BLF have no relevant disclosures; BJM is an NCCN Kidney Cancer Panel Member and an advisor for Merck; RL received research support from Predicine, Veracyte, CG Oncology, Valar Labs, and Merck, is on the clinical trials committee for CG Oncology, is scientific advisor for Bristol Myers Squibb, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, and Janssen, and has received honoraria from SAI MedPartners, Solstice Health Communications, Putnam Associates, and UroToday; JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics; NS, SK, and MG are or formerly were employees of Nanostring.

Objective: Patients with advanced penile squamous cell cancer have a poor prognosis and can benefit from early palliative care consultation. We built a model to identify those patients most likely to benefit., Methods: Patients with penile squamous cell cancer undergoing inguinal lymph node dissection were identified from the National Cancer Database (NCDB) and a multi-institutional international dataset (INT). A multivariable Cox proportional hazards model for overall survival (OS) was developed using the NCDB and applied to the INT dataset. Parameters were used to make receiver operating characteristic (ROC) curves. ROC-related criteria were optimized to identify a predictive probability cut point and dichotomize patients from INT into risk groups for limited OS of <6 and <12 months., Results: NCDB had 860 deaths; 105 (5%) at 6 months and 296 (15%) at 12 months. INT had 257 deaths; 56 (8%) at 6 months and 124 (18%) at 12 months. Limited OS was associated with older age, greater T and N stage, and fewer lymph nodes removed. Optimized ROC criteria using the OS <6 months curve best dichotomized INT patients into high-risk group with median OS of 24 months (95% CI 18-34) and low-risk group with median OS of 174 months (95% CI 120-NE)., Conclusion: We developed a simple model that could be used as a screening tool for early palliative care referral., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary., Methods: Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley's K analysis, a methodology adapted from ecology., Results: Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor-stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR -0.5 to 5.1); stage III: 1.4 (IQR -0.3 to 3.5); stage IV: 0.6 (IQR -2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS-hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p<0.001; median CSS-hi=174 months, lo=85 months; FDR-adj. Cox p<0.001). An RNA-seq differential gene expression score was developed using this geospatial metric, and was externally validated in multiple independent cohorts of patients with ccRCC including: TCGA KIRC, and the IMmotion151, IMmotion150, and JAVELIN Renal 101 clinical trials. In addition, this CD163+ geospatial pattern was found to be associated with a higher TIM-3+ proportion of CD8+T cells, indicative of terminal exhaustion (tumor-core: 0.07 (IQR 0.04-0.14) vs 0.40 (IQR 0.15-0.66), p=0.05)., Conclusions: Geospatial clustering of CD163+M2 like TAMs into the stromal compartment at the tumor-stromal interface was associated with poor clinical outcomes and CD8+T cell terminal exhaustion., Competing Interests: Competing interests: The corresponding author certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (ie. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: NC, YK, AB, AC, GJK, AH, JN, CM-S, DS-V, ENK, NL-B, PR, MF, DJ, LW, JD, JKT, JD, PMA, and AAH have no disclosures; BJM is an NCCN Kidney Cancer Panel Member and an advisor for Merck; PES is an NCCN Bladder and Penile Cancer Panel Member and Vice-Chair; JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Mersana Therapeutics, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC., Significance: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221., (©2022 American Association for Cancer Research.)

Background: Alternative mRNA splicing can be dysregulated in cancer, resulting in the generation of aberrant splice variants (SVs). Given the paucity of actionable genomic mutations in clear cell renal cell carcinoma (ccRCC), aberrant SVs may be an avenue to novel mechanisms of pathogenesis., Objective: To identify and characterize aberrant SVs enriched in ccRCC., Design, Setting, and Participants: Using RNA-seq data from the Cancer Cell Line Encyclopedia, we identified neojunctions uniquely expressed in ccRCC. Candidate SVs were then checked for expression across normal tissue in the Genotype-Tissue Expression Project and primary tumor tissue from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and our institutional Total Cancer Care database., Outcome Measurements and Statistical Analysis: Clinicopathologic, genomic, and survival data were available for all cohorts. Epigenetic data were available for the TCGA and CPTAC cohorts. Proteomic data were available for the CPTAC cohort. The association of aberrant SV expression with these variables was examined using the Kruskal-Wallis test, pairwise t test, Spearman correlation test, and Cox regression analysis., Results and Limitations: Our pipeline identified 16 ccRCC-enriched SVs. EGFR, HPCAL1-SV and RNASET2-SV expression was negatively correlated with gene-specific CpG methylation. We derived a survival risk score based primarily on the expression of five SVs (RNASET2, FGD1, PDZD2, COBLL1, and PTPN14), which was consistent and applicable across multiple cohorts on multivariate analysis. The splicing factor RBM4, which modulates splicing of HIF-1α, exhibited significantly lower expression at the protein level in the high-risk group, as defined by our SV-based score., Conclusions: We describe 16 aberrant SVs enriched in ccRCC, many of which are associated with disease biology and/or clinical outcomes. This study provides a novel strategy for identifying and characterizing disease-specific aberrant SVs., Patient Summary: We describe a method to identify disease targets and biomarkers using transcriptomic analysis beyond somatic mutations or gene expression. Kidney tumors express unique splice variants that may provide additional prognostic information following surgery., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To compare overall agreement between magnetic resonance imaging (MRI)-ultrasound (US) fusion biopsy (FB) and MRI cognitive fusion biopsy (CB) of the prostate and determine which factors affect agreement for prostate cancer (PCa) who underwent both modalities in a prospective within-patient protocol., Patients and Methods: From August 2017 to January 2021, patients with at least one Prostate Imaging Reporting & Data System (PI-RADS) 3 or higher lesion on multiparametric MRI underwent transrectal FB and CB in a prospective within-patient protocol. CB was performed for each region of interest (ROI), followed by FB, followed by standard 12 core biopsy. Patients who were not on active surveillance were analysed. The primary endpoint was agreement for any PCa detection. McNemar's test and kappa statistic were used to analyse agreement. Chi-square test, Fisher's exact test and Wilcoxon rank sum test were used to analyse disagreement across clinical and MRI spatial variables. A multivariable generalized mixed-effect model was used to compare the interaction between select variables and fusion modality. Statistics were performed using SAS and R., Results: Ninety patients and 98 lesions were included in the analysis. There was moderate agreement between FB and CB ( k  = 0.715). McNemar's test was insignificant ( p  = 0.285). Anterior location was the only variable associated with a significant variation in agreement, which was 70% for anterior lesions versus 89.7% for non-anterior lesions ( p  = 0.035). Discordance did not vary significantly across other variables. In a mixed-effect model, the interaction between anterior location and use of FB was insignificant ( p  = 0.411)., Conclusion: In a within-patient protocol of patients not on active surveillance, FB and CB performed similarly for PCa detection and with moderate agreement. Anterior location was associated with significantly higher disagreement, whereas other patient and lesion characteristics were not. Additional studies are needed to determine optimal biopsy technique for sampling anterior ROI., (© 2022 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Importance: Level I evidence has failed to demonstrate an overall survival (OS) advantage for cytoreductive nephrectomy in patients with metastatic clear cell renal cell carcinoma (ccRCC) in the modern era, which is at odds with observational studies reporting a marked OS benefit associated with these operations. These observational studies were not designed to adjust for unmeasured confounding., Objective: To assess whether cytoreductive nephrectomy is associated with improved OS in patients with metastatic ccRCC., Design, Setting, and Participants: This cohort study identified patients with metastatic ccRCC in the National Cancer Database from January 1, 2006, to December 31, 2016, who received systemic targeted therapy. The analysis was finalized on July 23, 2021., Exposures: Receipt of cytoreductive nephrectomy., Main Outcomes and Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. Distance from the patients' zip code of residence to the treating facility was identified as a valid instrument and was used in a 2-stage residual inclusion instrumental variable analysis. Conventional adjustments for selection bias, multivariable Cox proportional hazards regression, and propensity score matching were performed for comparison. Measured covariates adjusted for in all analyses included age, sex, race, Charlson-Deyo score, facility type, year of diagnosis, clinical T stage, and clinical N stage., Results: The final study population included 12 766 patients (median age, 63 years; IQR, 56-70 years; 8744 [68%] male; 11 206 [88%] White). Cytoreductive nephrectomy was performed in 5005 patients (39%). Conventional adjustments for selection bias demonstrated a significant OS benefit associated with cytoreductive nephrectomy (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% CI, 0.47-0.51; propensity score matching: HR, 0.48; 95% CI, 0.46-0.50). Instrumental variable estimates did not demonstrate an association between cytoreductive nephrectomy and OS (HR, 0.92; 95% CI, 0.78-1.09)., Conclusions and Relevance: Instrumental variable analysis did not demonstrate a survival advantage associated with cytoreductive nephrectomy for patients with metastatic ccRCC. This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets.

Background: Clear cell renal cell carcinoma (ccRCC) tumors have low frequencies of genetic alterations compared with other malignancies, but very high levels of immune cell infiltration and favorable response rates to immunotherapy. Currently, the interplay between specific ccRCC somatic mutations and immune infiltration pattern is unclear., Objective: To analyze the associations between common ccRCC somatic mutations and immune cell infiltration patterns within the tumor immune microenvironment (TIME)., Design, Setting, and Participants: The study included tumor samples (24 primary and 24 metastatic) from 48 patients with stage IV ccRCC. Targeted sequencing was performed for well-characterized recurrent somatic mutations in ccRCC, with the analysis focusing on the six most common ones: VHL, BAP1, PBRM1, SETD2, TP53, and KDM5C. For each sample, multiplex immunofluorescence (IF) was performed in lymphoid and myeloid panels, for seven regions of interest in three zones (tumor core, stroma, and tumor-stroma interface). IF-derived cellular densities were compared across patients, stratified by their somatic mutation status, using a linear mixed-model analysis. External validation was pursued using RNA-seq enrichment scoring from three large external data sources., Results and Limitations: Tumors with SETD2 mutations demonstrated significantly decreased levels of FOXP3+ T cells in the tumor core, stroma, and tumor-stroma interface. PBRM1 mutations were associated with decreased FOXP3+ T cells in the tumor core. Primary KDM5C mutations were associated with significantly increased CD206+ macrophage tumor infiltration in the tumor core. A computational method estimating immune cell types in the TIME using bulk RNA-seq data, xCell scoring, failed to validate associations from the IF analysis in large external data sets. A major limitation of the study is the relatively small patient population studied., Conclusions: This study provides evidence that common somatic mutations in ccRCC, such as SETD2, PBRM1, and KDM5C, are associated with distinct immune infiltration patterns within the TIME., Patient Summary: In this study, we analyzed tumor samples from patients with metastatic kidney cancer to determine whether common genetic mutations that arise from the cancer cells are associated with the density of immune cells found within those tumors. We found several distinct immune cell patterns that were associated with specific genetic mutations. These findings provide insight into the interaction between cancer genetics and the immune system in kidney cancer., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Immune checkpoint blockade (ICB) is a rapidly emerging field of oncology that has revolutionized the metastatic renal cell carcinoma (mRCC) treatment. Four recent treatment regimens Nivolumab-Ipilimumab, Pembrolizumab-Axitinib, Nivolumab-Cabozantinib, and Pembrolizumab-Lenvatinib-have demonstrated improved clinical endpoints compared to standard of care and are endorsed by NCCN (2021). However, data on patient-reported outcomes (PROs) for patients receiving these regimens are limited. We conducted a comparative assessment of the quality and standardization of PROs endpoints and data reported for these randomized controlled trials (RCTs)., Patients and Methods: We systematically identified all RCTs evaluating combination ICB for ccRCC. PROs-specific data were abstracted from the final version of 4 RCT protocols, as well as clinical and PROs specific manuscripts published between April 2018 and April 2021. We used 3 previously published guides standardizing PROs research to objectively score the data: (i) 24-point PROEAS; (ii) 12-point SPIRIT-PRO; and (iii) 14-point CONSORT-PRO., Results: The CheckMate 214, KEYNOTE 426, CheckMate 9ER, and CLEAR studies had PROEAS scores of 88% (21/24), 37% (9/24), 83% (20/24), and 16% (4/24), respectively, and SPIRIT-PRO scores of 50% (6/12), 75% (9/12), 66% (8/12), and 41% (5/12) respectively. The CONSORT-PRO scores were 86% (12/14) for CheckMate 214 and 43% (6/14) for CheckMate 9ER, but scores were not available for the CLEAR and KEYNOTE 426 studies because of a lack of sufficient data. The average SPIRIT-PRO score across the 4 RCTs was 58%, indicating a reasonable adoption of PROs research in data management and analysis. The CheckMate 214 trial had the longest follow-up and most comprehensive published PROs data., Conclusion: Our analysis identified the limitations of current PROs data in combination ICB approved for mRCC. This analysis will enable clinicians to better interpret the current PROs results and emphasize the importance of better incorporation of PROs endpoints in future mRCC trial design., (Copyright © 2021. Published by Elsevier Inc.)

Background: Clinical trials have not shown a significant overall survival (OS) difference between chemotherapy and immunotherapy as first-line agents in metastatic urothelial carcinoma (UC). However, the generalizability of these findings in a real-world setting has not yet been evaluated in comparative effectiveness studies., Objective: To assess the effectiveness of first-line immunotherapy compared with chemotherapy regimens on OS in patients with metastatic UC of the bladder., Design, Setting, and Participants: This retrospective propensity-matched study identified metastatic bladder UC patients in the National Cancer Database from 2014 to 2017 who received either first-line immunotherapy-monotherapy or multi-agent chemotherapy, and who were not treated on a clinical trial protocol., Outcome Measures and Analysis: The primary outcome was OS from the date of diagnosis to date of death or censoring at last follow-up. Patients were stratified into first-line immunotherapy and chemotherapy treatment groups. After 1:1 nearest-neighbor caliper-matching of propensity scores, the survival analysis was conducted using Cox regression modeling and Kaplan-Meier estimates., Results and Limitations: A total of 2,796 patients were included in the final study population, and 960 in the matched cohort (480 per treatment group). Utilization of immunotherapy increased over the time period studied as chemotherapy decreased (Immunotherapy: 3%-37%; Chemotherapy: 97%-63%; P < 0.001). In the overall cohort, patients who received first-line immunotherapy were older and more comorbid than those who received first-line chemotherapy (Age: 73 v. 67, respectively, P < 0.001; Charlson-Deyo score ≥2: 17% v. 11.5%, respectively, P < 0.001). In the matched cohort, patients who were treated with first-line immunotherapy had similar OS to those who were treated with first-line chemotherapy (HR: 0.91, 95CI 0.72-1.15). Due to the retrospective nature of the study, interpretation is limited by potential selection bias from unmeasured confounding., Conclusions and Relevance: Metastatic bladder UC patients who received first-line immunotherapy had similar OS to those who received first-line chemotherapy., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immune-modulating systemic therapies are often used to treat advanced cancer such as metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor immune microenvironment. To better understand the tumor ecology of this immune microenvironment, we quantified tumor infiltration across three distinct ccRCC patient tumor cohorts using complementarity determining region-3 (CDR3) sequence recovery counts in tumor-infiltrating lymphocytes and a generalized diversity index (GDI) for CDR3 sequence distributions. GDI can be understood as a curve over a continuum of diversity scales that allows sensitive characterization of distributions to capture sample richness, evenness, and subsampling uncertainty, along with other important metrics that characterize tumor heterogeneity. For example, richness quantified the total unique sequence count, while evenness quantified similarities across sequence frequencies. Significant differences in receptor sequence diversity across gender and race revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. The GDI inflection point (IP) allowed for a novel and robust measure of distribution evenness. High IP values were associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. These results propose a new quantitative tool that can be used to better characterize patient-specific differences related to immune cell infiltration, and to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies., Significance: Assessment of tumor-infiltrating T-cell and B-cell diversity in renal cell carcinoma advances the understanding of tumor-immune system interactions, linking tumor immune ecology with tumor burden, aggressiveness, and patient survival. See related commentary by Krishna and Hakimi, p. 764., (©2022 The Authors; Published by the American Association for Cancer Research.)

Summary: Multiplex immunofluorescence (mIF) staining combined with quantitative digital image analysis is a novel and increasingly used technique that allows for the characterization of the tumor immune microenvironment (TIME). Generally, mIF data is used to examine the abundance of immune cells in the TIME; however, this does not capture spatial patterns of immune cells throughout the TIME, a metric increasingly recognized as important for prognosis. To address this gap, we developed an R package spatialTIME that enables spatial analysis of mIF data, as well as the iTIME web application that provides a robust but simplified user interface for describing both abundance and spatial architecture of the TIME. The spatialTIME package calculates univariate and bivariate spatial statistics (e.g. Ripley's K, Besag's L, Macron's M and G or nearest neighbor distance) and creates publication quality plots for spatial organization of the cells in each tissue sample. The iTIME web application allows users to statistically compare the abundance measures with patient clinical features along with visualization of the TIME for one tissue sample at a time., Availability and Implementation: spatialTIME is implemented in R and can be downloaded from GitHub (https://github.com/FridleyLab/spatialTIME) or CRAN. An extensive vignette for using spatialTIME can also be found at https://cran.r-project.org/web/packages/spatialTIME/index.html. iTIME is implemented within a R Shiny application and can be accessed online (http://itime.moffitt.org/), with code available on GitHub (https://github.com/FridleyLab/iTIME)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

Objectives: To identify incidence and risk factors for upstaging from cN1 to pN2/N3 at inguinal lymphadenectomy (ILND) for penile cancer (pSCC). Our secondary objective is to assess survival outcomes and associations for cN1 patients undergoing ILND., Subjects/patients and Methods: Patients with pT≥1cN1cM0 pSCC who underwent bilateral ILND and had complete data were identified in a multi-institutional international cohort from 8 referral centers in 7 countries diagnosed from 1980 to 2017. Upstaging was defined as pN2/N3 at ILND. Multivariable logistic regression analysis was used to determine associations with upstaging, and Cox multivariable logistic regression analysis to determine associations with overall survival (OS)., Results: Of 144 patients were included in the final study population. 84 patients (58%) were upstaged from cN1 to pN2/N3, and 25 (17%) were down staged to pN0. Upstaging was associated with pT3/T4 (OR 4.1, 95%CI 1.5-11.7, P < 0.01) and pTX (OR 7.1, 95CI 1.6-51.1, P = 0.02). Age, smoking status, HPV status, and LVI were not associated with upstaging. Age (HR 1.03/y, 95%CI 1.01-1.06, P < 0.01) and upstaging (HR 2.8, 95%CI 1.3-5.9, P < 0.01) were associated with worse OS. Upstaged patients had a 5-year OS of 49%, compared with 86% for patients who were not upstaged., Conclusion: The majority of cN1 pSCC patients harbor a higher-risk disease state than their clinical staging suggests, especially those with higher pT stages. More intensive pre-operative workup may be warranted for these patients to identify upstaging prior to ILND and potentially qualify them for neoadjuvant chemotherapy or clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Our primary objective is to detail the incidence, site, and timing of penile squamous cell carcinoma (pSCC) recurrence after inguinal lymph node dissection (ILND)., Materials and Methods: We performed a retrospective analysis of 551 patients who underwent ILND for pSCC from 2000 to 2017. The primary outcome was pSCC recurrence after ILND. Recurrences were identified and stratified by site. Timing of recurrence was determined. Multivariable logistic regression analysis determined associations with recurrence. Multivariable Cox regression analysis determined associations with overall survival (OS). Sub-group analysis of the distant recurrences analyzed timing and OS by site of distant recurrence., Results: After ILND pSCC recurred in 176 (31.9%) patients. Median time to recurrence was 10 months for distant recurrences, 12 for inguinal, 10.5 for pelvic, and 44.5 for local. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months of ILND, versus 127 months for local recurrences. Post-ILND recurrence was associated with pN2 (OR 1.99, 95% CI 1.0-4.1), and pN3 (OR 7.2, 95% CI 4.0-13.7). Patients who had local recurrence had similar OS to those without (HR 1.5, 95% CI 0.6-3.8), and worse OS was identified in patients with inguinal (HR 4.5, 95% CI 2.8-7.1), pelvic (HR 2.6, 95% CI 1.5-4.5), or distant (HR 4.0, 95% CI 2.7-5.8) recurrences. Patients with lung recurrences had worse OS than other sites (HR 2.2, 95% CI 1.1-4.3)., Conclusions: Of the patients 31.9% had post-ILND recurrence associated with high pN staging. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months, suggesting surveillance beyond this is low yield. Local recurrences occurred over a longer timeline, emphasizing necessity of long-term surveillance of the primary site.

Purpose: Patients with muscle invasive bladder cancer (MIBC) of variant histology have a poor prognosis. It is unclear if neoadjuvant chemotherapy prior to radical cystectomy is associated with pathological downstaging or improved overall survival (OS) for patients with variant histology. Our objective was to assess for associations between receipt of neoadjuvant chemotherapy, pathological downstaging and OS for patients with variant histology MIBC., Materials and Methods: Patients were identified in the National Cancer Database from 2004 to 2017 with MIBC, without metastases, who underwent radical cystectomy. Patients were stratified by histological subgroup, and receipt or nonreceipt of neoadjuvant chemotherapy. Pathological downstaging was defined as pT0N0 or pT ≤1N0, and OS from the time of diagnosis to date of death or censoring at last followup. Multivariable logistic regression analysis determined associations between neoadjuvant chemotherapy and pathological downstaging. Multivariable Cox regression analysis determined associations between neoadjuvant chemotherapy and OS., Results: A total of 31,218 patients were included in the final study population (urothelial carcinoma [UC]: 27,779; sarcomatoid UC: 501; micropapillary UC: 418; squamous cell carcinoma: 1,141; neuroendocrine carcinoma: 629; adenocarcinoma: 750). Neoadjuvant chemotherapy was associated with pathological downstaging to pT0N0 in all histological subgroups (UC: OR 5.1 [4.6-5.6]; sarcomatoid UC: OR 13.8 [5.5-39.0]; micropapillary UC: OR 9.7 [2.8-46.8]; squamous cell carcinoma: OR 7.4 [2.1-24.5]; neuroendocrine: OR 4.7 [2.6-9.2]; adenocarcinoma: OR 23.3 [8.0-74.2]). Neoadjuvant chemotherapy was associated with improved OS for UC (HR 0.8 [0.77-0.84]), sarcomatoid UC (HR 0.64 [0.44-0.91]) and neuroendocrine carcinoma (HR 0.55 [0.43-0.70])., Conclusions: Neoadjuvant chemotherapy was associated with pathological downstaging for all MIBC histological variants, with improved OS for patients with UC, sarcomatoid variant UC and neuroendocrine carcinoma.

INTRODUCTION To evaluate the educational value of transplant rotation in urology residency. In the United States, exposure to kidney transplantation during urology residency has declined significantly over the past few decades. At our institution, transplantation has been a core component of urology residency since its inception in 1959., Materials and Methods: A 15-question anonymous survey was developed. The first 8 questions queried demographics and the last 7 were a set of questions with a Likert Scale response. The survey was electronic- mailed to past and current urology residents who had completed the transplant rotation, dating back to 1972., Results: A total of 61 out of 98 (62%) individuals responded. The majority (59%) were general urologists, and one (2%) had completed a transplant fellowship. In their practices, 17% performed kidney transplants and 28% performed donor nephrectomies. Overall, 100% responded that the skills learned on the transplant rotation were beneficial for urology training, 100% had learned valuable vascular surgical techniques, and 93% felt that urology residents should have clinical transplant experience during their training. There was no statistical difference between the younger and older graduates in Likert scale responses., Conclusion: The majority of graduates did not perform transplants in their practice, yet, all of responders agreed that the skills learned on the transplant rotation were beneficial and 93% expressed that urology residents should have clinical transplant experience during residency. Kidney transplantation should be an integral part of urology residency training.

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point patterns were generated, which were then used to perform spatial analyses using a normalized Ripley's K function at a radius of 25 μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups. Multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) <6 months, and therapy response was defined as PFS >9 months. CAFs exhibited higher cellular clustering with Ki-67 + cells than with caspase-3 + cells (nK(25): Ki-67 1.19; caspase-3 1.05; p = 0.04). The median nearest neighbor (NN) distance from CAFs to Ki-67 + cells was shorter compared to caspase-3 + cells (15 μm vs. 37 μm, respectively; p < 0.001). Multivariable Cox regression analyses demonstrated that both high Ki-67 + density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding αSMA+CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3 + , high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT responses. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.

Purpose: Following radical orchiectomy, surveillance and primary retroperitoneal lymph node dissection (RPLND) are acceptable options for the management of early stage pure testicular teratoma in adult patients; however, there is no uniform consensus. The aim of this study was to investigate survival outcomes of adults with early stage pure testicular teratoma based on management strategy., Methods: Data was extracted from the National Cancer Database (NCDB) from testicular cancer patients diagnosed with clinical stage (CS) I pure teratoma (pT1-4N0M0S0) between 2004 and 2014. Kaplan-Meier and Cox regression analyses were used to assess clinical outcomes based on management strategy., Results: Of the 61,167 patients diagnosed with testicular cancer, 692 (1.1%) had pure teratoma. Only individuals with CS I disease were considered (n = 237). The median age was 28 (23-35) years. Overall, 43 (18%) patients underwent RPLND and 194 (82%) patients were managed with surveillance. There was an increase in surveillance for CS I teratoma during the study period. Increasing distance from residence to treatment facility was an unadjusted predictor for undergoing primary RPLND (p < 0.001). Median follow-up was 54 months and there was no significant difference in overall survival between CS I teratoma patients managed with RPLND and those managed with surveillance (p = 0.13)., Conclusions: There has been a trend toward increasing adoption of surveillance for the management of early stage pure testicular teratoma in adults. Our findings suggest that surveillance provides comparable survival outcomes to primary retroperitoneal lymph node dissection in this setting.

INTRODUCTION Perioperative stroke and myocardial infarction are uncommon but devastating thromboembolic complications. There is no comprehensive study detailing these complications for urologic procedures. The primary aim of this study is to determine which urologic procedures and patients carry the highest risk of perioperative stroke and myocardial infarction., Materials and Methods: The National Surgical Quality Improvement Program data set was reviewed from 2008-2017. Procedures coded under the urology specialty were included and patients who had a perioperative stroke or myocardial infarction were identified. CPTs were stratified into clinically relevant procedure groups. Two multivariable logistic regression analyses were performed to determine preoperative and procedural risk factors for developing perioperative stroke or myocardial infarction. A multivariable logistic regression analysis was performed to determine the association between these complications and 30-day mortality., Results: A total of 281,744 cases were included, identifying 392 strokes (0.14%) and 1,016 myocardial infarctions (0.36%). Age ≥ 70, hypertension, and disseminated cancer were the strongest preoperative risk factors for perioperative stroke or myocardial infarction. Cystectomy was the highest risk urologic procedure (stroke: OR 3.3, 95%CI 2.3-4.8; MI: OR 7.2, 95%CI 5.6-9.1). Thirty-day mortality was dramatically worse for patients who had a perioperative stroke or myocardial infarction., Conclusions: Perioperative stroke and myocardial infarction were confirmed to be uncommon but devastating complications of urologic surgery, with incidence of 0.14% and 0.36%, respectively. Cystectomy was the highest risk urologic procedure. Perioperative stroke and myocardial infarction were strongly associated with age ≥ 70, hypertension, and disseminated cancer.

Purpose: Men with nonseminomatous germ cell tumors of the testicle without evidence of residual disease after radical orchiectomy (clinical stage I) are increasingly managed with active surveillance. The guideline-recommended cornerstones of surveillance are conventional serum tumor markers and computerized tomography. The reliability of serum tumor markers as a tool to diagnose early recurrence of clinical stage I nonseminomatous germ cell tumors is unclear. The study objective was to conduct a systematic review of the currently available evidence assessing the reliability of serum tumor markers as a test to diagnose recurrence in patients with clinical stage I nonseminomatous germ cell tumors under active surveillance., Materials and Methods: A systematic review was conducted in accordance with PRISMA guidelines, with no language or date restrictions. Studies were included that readily identified the tumor marker status of patients with clinical stage I nonseminomatous germ cell tumors who had a recurrence on active surveillance. The primary outcome was marker positivity at the time of recurrence. Risk of bias assessment was undertaken., Results: A total of 2,157 studies were identified and independently screened by 2 reviewers, with 37 studies ultimately being included. A relatively high risk of bias was identified among the studies, with the vast majority being retrospective series. The total population for the included studies was 8,545 patients with clinical stage I nonseminomatous germ cell tumors managed by active surveillance, and 2,254 ultimately relapsed. Serum tumor markers were elevated in 28% to 75% of patients at the time of recurrence and were the only indication of recurrence in 4% to 39%. The unavailability of patient-level data is the major limitation to the present findings., Conclusions: In patients with clinical stage I nonseminomatous germ cell tumors managed by active surveillance, the use of serum tumor markers cannot obviate the need for computerized tomography. More reliable serum markers are needed in order to limit radiation exposure for these patients.

Background: Relative value units (RVUs) are the measure of value used in US Medicare reimbursement. Medicare determines physician work RVUs (wRVUs) from the Relative Value Update Committee (RUC) for a procedure based on operative time, technical skill and effort, mental effort and judgment, and stress. In theory, work RVUs should account for the complexity and operative time involved in a procedure. The aim of this study was to assess whether major procedures for treatment of benign prostatic enlargement (BPE) are fairly compensated based on complexity and operative time in the RVU system and compare them with the intended reimbursement. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database and the Centers for Medicare and Medicaid Services (CMS) Medicare Physician Fee Schedule were queried from 2015 to 2017. Single, current, procedural terminology codes associated with BPE treatments were included: transurethral resection of the prostate (TURP), photovaporization of the prostate (PVP), holmium laser enucleation of the prostate (HoLEP), retropubic simple prostatectomy (RSP), and suprapubic simple prostatectomy (SSP). The CMS operative times and the NSQIP real data were used in turn to calculate separate values for wRVUs per hour (wRVUs/hr) of operative time. The wRVUs/hr derived from CMS operative times represent RUC-estimated wRVUs/hr and wRVUs/hr derived from NSQIP represent actual wRVUs/hr. Results: A total of 27,664 cases were included from the NSQIP dataset. Median wRVU was 15.3 (interquartile range [IQR] 12.2-15.3), median operative time 50 minutes (IQR 33-74), and median wRVUs/hr 17.0 (IQR 11.6-26.2). RUC-estimated wRVUs/hr were TURP 12.2, PVP 12.2, RSP 9, SSP 9.3, and HoLEP 7.3. The actual wRVUs/hr were TURP 19.1, PVP 15.5, RSP 10.2, HoLEP 9.4, and SSP 7.6. Conclusions: Laser enucleation and simple prostatectomy are highly complex and efficacious procedures for treating BPE, yet the current payment schedule assigns these procedures the least amount of wRVUs/hr. Financial incentives for performing BPE surgeries are clearly misaligned.

Importance: Clinical trials have shown an overall survival (OS) benefit associated with first-line immunotherapy (IT) and combination targeted therapy (TT) and IT regimens compared with TT among patients with metastatic clear cell renal cell carcinoma (RCC). Generalizability of these findings in a real-world cohort outside of a clinical trial setting is unclear., Objective: To assess the association of first-line TT, IT, and combination TT and IT regimens with OS in a real-world cohort of patients with metastatic clear cell RCC., Design, Setting, and Participants: This retrospective propensity-matched cohort study identified 5872 patients with metastatic clear cell RCC in the National Cancer Database from January 1, 2015, to December 31, 2017, who received first-line TT, IT, or combination TT and IT and were not treated on a clinical trial protocol. Patients were stratified by first-line systemic treatment. Statistical analysis was conducted from October 1 to December 1, 2020., Main Outcomes and Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. After 1:1:1 nearest-neighbor caliper matching of propensity scores, survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates., Results: The final study population included 5872 patients (TT group: n = 4755 [81%]; 3332 men [70%]; median age, 64 years [interquartile range, 57-71 years]; IT group: n = 638 [11%]; 475 men [74%]; median age, 61 years [interquartile range, 54-69 years]; and combination TT and IT group: n = 479 [8%]; 321 men [67%]; median age, 62 years [interquartile range, 55-69 years]), and the matched cohort included 1437 patients (479 per treatment group). Patients in the IT and combination TT and IT groups were younger than those in the TT group, had fewer comorbid conditions (Charlson-Deyo score of 0, 480 of 638 [75%] in the TT group, 356 of 479 [74%] in the IT group, and 3273 of 4755 [69%] in the combination TT and IT group), and were more often treated at academic centers (315 of 638 [49%], 216 of 479 [45%], and 1935 of 4755 [41%], respectively). Both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC (IT group: hazard ratio [HR], 0.60 [95% CI, 0.48-0.75]; P < .001; combination TT and IT group: HR, 0.74 [95% CI, 0.60-0.91]; P = .005). No survival difference was seen between the IT and combination TT and IT groups (combination TT and IT: HR, 1.24 [95% CI, 0.98-1.56]; P = .08)., Conclusions and Relevance: This study suggests that both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC. These findings are similar to those identified in recently reported clinical trials, lending confidence to the broader applicability of these findings outside of a clinical trial setting.

Background: Relative value units (RVUs) are the measure of value used in United States Medicare and Medicaid reimbursement. The Relative Update Committee (RUC) determines physician work RVU (wRVUs) based on operative time, technical skill and effort, mental effort and judgment, and stress. The primary aim of this study was to assess whether operative time is adequately accounted for in the wRVU system in pediatric urology., Methods: The American College of Surgeons National Surgical Quality Improvement Program Pediatric Participant User File (ACS-NSQIPP-PUF) was reviewed from 2012 to 2017. Most common single pediatric urology current procedural terminology (CPT) codes were included. The primary variable was wRVU per hour of operative time (wRVU/h). Linear regression analysis was used to assess the relative influence that operative time had on wRVU/h., Results: 25,432 cases were included in the final study population from 45 unique CPT codes. The median operative time was 79 min, and the median RVU/h was 12.2. Procedures with operative time less than 79 min had higher wRVU/h compared with procedures longer than 79 min (14.5 vs 10.5, p < 0.001). Procedures with higher than average incidence of any complications had a lower wRVU/h (9.0 vs. 14.6 p < 0.001). Linear regression analysis revealed that each additional hour of operative time was expected to decrease wRVU/h by 4.2 (-0.70 per 10 min, 95% CI: -0.71 to -0.69, p < 0.001; R 2  = 0.39)., Conclusion: This analysis of contemporary large pediatric population national-level data suggests that the wRVU system significantly favors shorter and less complex procedures in Pediatric Urology. Pediatric urologists performing longer and more complex procedures are not adequately compensated for the increase in complexity., Evidence Level Iii: Retrospective comparative study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors. Significance: Increased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors., Competing Interests: The corresponding author certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (ie. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: NHC, GJK, AH, AMA, LZ, JN, JC, SF, MF, JD, SM, CM, EK, PMA, and YK have no disclosures; BJM is an NCCN Kidney Cancer Panel Member; PES is an NCCN Bladder and Penile Cancer Panel Member and Vice-Chair; JM is an Associate Center Director at Moffitt Cancer Center, has ownership interest in Fulgent Genetics, Inc., Aleta Biotherapeutics, Inc., Cold Genesys, Inc., Myst Pharma, Inc., and Tailored Therapeutics, Inc., and is a consultant/advisory board member for ONCoPEP, Inc., Cold Genesys, Inc., Morphogenesis, Inc., Mersana Therapeutics, Inc., GammaDelta Therapeutics, Ltd., Myst Pharma, Inc., Tailored Therapeutics, Inc., Verseau Therapeutics, Inc., Iovance Biotherapeutics, Inc., Vault Pharma, Inc., Noble Life Sciences Partners, Fulgent Genetics, Inc., UbiVac, LLC, Vycellix, Inc., and Aleta Biotherapeutics, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To assess whether inaccurate operative time estimates utilized by the Relative Value Update Committee (RUC) contribute to the undervaluation of longer urologic procedures., Methods: The National Surgical Quality Improvement Program (NSQIP) and Centers for Medicare and Medicaid Services (CMS) data sets were reviewed from 2015 to 2017. NSQIP operative time is directly measured, contrasting with CMS times which are determined by the RUC via survey-generated estimates. The 50 most frequently coded urology current procedural terminologies were included. Operative time difference was compared between the 2 data sets, and Spearman's correlation coefficient was utilized to assess differences in wRVU/h., Results: A total of 105,931 cases were included. Overall, RUC operative time estimates were longer than NSQIP (124.4 vs 103.5 minutes, P < .001). RUC data overestimated operative time by 42.9% for procedures ≤90 minutes and 16.4% for longer procedures (P < .001). Using NSQIP, procedures ≤90 minutes had higher wRVU/h than longer procedures (12.2 vs 8.7, P < .001), but this was not statistically different using RUC estimates (8.4 vs 7.7, P = .13). Spearman's correlation coefficient confirmed a statistically significant negative relationship between wRVU/h and operative time using NSQIP data (r = -0.57, 95% confidence interval: -7.4 to -0.36), and no statistically significant relationship using RUC data (r = -0.24, 95% confidence interval: -0.49 to 0.04)., Conclusion: The RUC-intended wRVU/h is more equitable than the NSQIP real-world wRVU/h with regard to operative time. Inaccurate RUC operative time estimates contribute to the undervaluation of longer urologic procedures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Relative value units (RVU) are the measure of value used in United States Medicare and Medicaid reimbursement. The Relative Update Committee (RUC) determine physician work RVU (wRVU) based on operative time, technical skill and effort, mental effort and judgement, and stress. In theory, wRVU should account for the complexity and operative time involved in a procedure., Objective: The primary aim of this study is to assess if operative time and complexity of hypospadias surgery is adequately accounted for by the current wRVU assignments., Study Design: The American College of Surgeons National Surgical Quality Improvement Program Participant User File (ACS-NSQIP PUF) database was utilized from 2012 to 2017. Single stage hypospadias current procedural terminology (CPT) codes (including acceptable secondary CPT codes) were extracted. Using total wRVU and total operative time, the primary variable of wRVU per hour was calculated (wRVU/hr). Multivariable linear regression analysis was used to assess the relative influence that wRVU and operative time had on the wRVU/hr variable., Results: 9810 cases were included in the final study population divided into four categories: simple distal (eg. MAGPI, V-Flap), single stage distal, single stage mid, single stage proximal. On analysis of variance, there was statistically significant different wRVU/hr for the four different types of hypospadias repairs with simple distal having the highest mean wRVU/hr of 19.5 and the lowest being proximal hypospadias repairs at 13.2. Simple distal, distal and midshaft hypospadias had statistically significantly higher wRVU/hr compared to proximal hypospadias (16.2, 95% CI: 15.8-16.5 vs. 13.2, 95% CI 10.9-15.5; p<0.001). Multivariable linear regression revealed that each additional hour of operative time was expected to decrease wRVU/hr by 10.5 (-10.5, 95% CI: -11.0 to -10.1, p < 0.001); total work wRVU had a statistically significant independent association with wRVU/hr (0.6, 95%CI: 0.5-0.7, p <0.001)., Discussion: This the first objective assessment of the current wRVU assignments with regards to one stage hypospadias repairs. More complex and longer hypospadias procedures are not adequately compensated by wRVU. Most notably, simple distal procedures are reimbursed at a mean of 19.5 wRVU/hr compared to 13.2 wRVU/hr for one stage proximal repairs., Conclusion: This analysis of national-level data suggests that the current wRVU assignments significantly favor shorter and simpler procedures in hypospadias surgery., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: There are no large multi-institutional studies reporting on perioperative complications of hypospadias repairs. We sought to determine perioperative complications of hypospadias repairs from the National Surgical Quality Improvement Program Pediatrics (NSQIP-P) to aid in patient counseling., Study Design: This cohort study from 2012 to 2017 was conducted using NSQIP-P database. Pediatric patients undergoing hypospadias surgery were identified and compared based on 4 major categories: distal/midshaft repair, one-stage repair proximal, stage one repair, and stage two repair. Baseline demographics between the four groups and perioperative parameters were compared. Multivariable logistic regression analysis models including type of repair was used to determine associations with overall complications, infectious complications, and dehiscence., Discussion: There were 11,292 patients identified in the study population. Overall, 78% underwent distal/midshaft hypospadias repair, 12% underwent one-stage proximal repair, 1.4% underwent proximal first stage repair and 9% underwent proximal second stage repair. Multivariable logistic regression analysis revealed that proximal first stage procedures had similar overall complications to distal/mid repairs but proximal one-stage and proximal second stage procedures were associated with significantly more overall complications, local infectious complications, and dehiscence. Age, race, operative time, prematurity were also independently associated with increased overall complications. As expected, complication rates are higher in those with proximal hypospadias. In staged hypospadias, first stage has a lower complication rate compared to second stage. All complications, especially of infectious and dehiscence are the highest in the one-stage proximal and proximal second stage repairs., Conclusion: We report large multi-institutional analysis of 30-day peri-operative hypospadias repair complications; this information is useful for patient counseling and education., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Importance: The appropriate use of adjuvant targeted therapy (TT) for high-risk locoregional renal cell carcinoma (RCC) after nephrectomy is currently unclear due to mixed results from the relevant randomized controlled trials. National-level survival outcomes and practice trends for the use of adjuvant TT in the United States have not been reported., Objective: To compare overall survival for patients who did and did not receive adjuvant TT after nephrectomy for high-risk locoregional RCC., Design, Setting, and Participants: This cohort study reviewed the National Cancer Database from 2006 to 2015. Patients with nonmetastatic clear cell RCC who underwent nephrectomy with either stage pT3a or greater or pN+ were included., Main Outcomes and Measures: Adjuvant TT was defined as receipt of TT within 3 months of nephrectomy. The primary end point was overall survival from initial diagnosis to date of death or censored at last follow-up. Baseline characteristics were described, and a multivariable analysis identified associations for receipt of adjuvant TT. Nearest-neighbor propensity matching was performed to create similar groups for comparison. A survival analysis was performed using Kaplan-Meier analysis and log-rank test., Results: The final study population included 41,127 patients. Two thousand seventy-one patients (5.04%) received off-label adjuvant TT. Younger age, white race, private insurance, positive margins, pT4, and pN+ were associated with receipt of adjuvant TT. After nearest-neighbor propensity matching for clinically and statistically relevant covariates, 1,604 patients remained in the matched cohort, with statistically nonsignificant differences between the groups for all baseline characteristics. Median overall survival was 52 months for patients in the Adjuvant TT group versus 79 months for those who did not receive adjuvant TT (P < 0.001). Decreased overall survival for patients receiving adjuvant therapy was also seen in pathologic subgroups with and without lymph node involvement., Conclusions: The propensity matched survival analysis revealed significantly decreased overall survival in patients who received off-label adjuvant TT for high-risk locoregional RCC., Competing Interests: Conflicts of interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the patterns of financial transaction between industry and urologists in the first 5 years of reporting in the Open Payments Program (OPP) by comparing transactions over time, between academic and nonacademic urologists, and by provider characteristics among academic urologists., Methods: The Center for Medicare & Medicaid Services OPP database was queried for General Payments to urologists from 2014-2018. Faculty at ACGME-accredited urology training programs were identified and characterized via publicly available websites. Industry transfers were analyzed by year, practice setting (academic vs nonacademic), provider characteristics, and AUA section. Payment nature and individual corporate contributions were also summarized., Results: A total of 12,521 urologists - representing 75% of the urology workforce in any given year - received $168 million from industry over the study period. There was no significant trend in payments by year (P = .162). Urologists received a median of $1602 over the study period, though 14% received >$10,000. Payment varied significantly by practice setting (P <.001), with nonacademic urologists receiving more but smaller payments than academic urologists. Among academic urologists, gender (P <.001), department chair status (P <.001), fellowship training (P <.001), and subspecialty (P <.001) were significantly associated with amount of payment from industry. Annual payments from industry varied significantly by AUA section., Conclusion: Reporting of physician-industry transactions has not led to a sustained decline in transactions with urologists. Significant differences in industry interaction exist between academic and nonacademic urologists, and values transferred to academic urologists varied by gender, chair status, subspecialty, and AUA section., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Physician work relative value units are determined based on operative time, technical skill, mental effort and stress. In theory, work relative value units should account for the operative time involved in a procedure, resulting in similar work relative value units per unit time for short and long procedures. We assessed whether operative time is adequately accounted for by the current work relative value units assignments., Materials and Methods: The American College of Surgeons National Surgical Quality Improvement Program database was reviewed from 2015 to 2017. The 50 most frequently coded urology CPT codes were included in the study. The primary variable was work relative value units per hour of operative time (work relative value units per hour). Linear regression analysis was used to assess the associations between work relative value units, operative time and the work relative value units per hour variable., Results: A total of 105,931 cases were included in the study. Among the included urology CPTs the median work relative value units was 15.26, median operative time was 48 minutes and median work relative value units per hour was 11.2. CPTs with operative time less than 90 minutes had higher work relative value units per hour compared with longer procedures (12.2 vs 8.7, p <0.001). Univariable analysis revealed that each additional hour of operative time was associated with a decrease in work relative value units per hour by 1.32 (-0.022 per minute, 95% CI -0.037 - -0.001, p <0.001) and that work relative value units were not statistically associated with work relative value units per hour (-0.093, 95% CI -0.193 - 0.007, p=0.07)., Conclusions: This analysis of large population, national level data suggests that the current work relative value units assignments do not proportionally compensate for longer operative times.

Purpose: To determine practice patterns for the extent of lymphadenectomy at radical prostatectomy and associations with detection of pN1 prostate cancer, as well as the impact of lymphadenectomy extent on underdetection of pN1 disease and overall survival., Materials and Methods: Prostatectomy cases in the NCDB from 2004 to 2013 were included. Lymphadenectomy extent was defined by the number of nodes examined. Logistic regression was used to identify risk factors for the top quartile of lymph node count and pN1 disease. This model was created to estimate the expected prevalence of pN1, and generated observed over expected ratios. A Cox regression model was used to evaluate the effect of lymph node count on overall survival., Results: Lymphadenectomy was performed in 209,789 (60%) of 358,522 surgeries, with pN1 in 6,428 (3.08%). Increasing quartiles for lymph node count was associated with pN1 (3-5 nodes OR 2.11; 6-8 nodes OR 3.12; ≥9 nodes OR 5.91, all P< 0.001). The logistic regression model suggested that 59% of pN1 cases are missed due to low lymph node count. Increased lymph node count was associated with increasing pN1 detection (O/E: 1-2 nodes = 0.18; 3-5 nodes = 0.37; 6-8 nodes = 0.56; ≥9 nodes = 1.01). Cox proportional hazards modeling demonstrated that the top quartile for lymph node count had improved overall survival (HR 0.93, CI 0.87-0.99, P= 0.03)., Conclusions: Increasing lymphadenectomy extent was associated with pN1 disease on multivariate analysis, and logistic regression modeling suggested a substantial proportion of pN1 were missed due to low lymphadenectomy extent across all risk groups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Malignant Leydig cell tumor is a rare entity that has been previously described as rapidly progressive and uniformly fatal. We present the case of a malignant Leydig cell tumor that presented 14 years after orchiectomy with an isolated retroperitoneal metastasis. Our patient underwent a retroperitoneal lymph node dissection and has been free of recurrence or progression at 12 months of follow up. Additionally, we describe the symptomatic hormone dysfunction experienced by our patient as a result of his tumor.

Introduction: Pelvic congestion syndrome (PCS) is a complex condition of the pelvic venous system leading to nonspecific pelvic pain that was initially described in females alone. The underlying abnormalities, though diverse, all result in increased pressure in the left gonadal vein which is transmitted retrograde into the pelvic venous system. Our primary aim was to describe our findings of secondary PCS as a distinct entity from primary PCS in that it has an identifiable vascular etiology and is gender nonspecific. We also aimed to assess the adequacy of late-arterial phase CT urography (CTU) as the initial imaging modality in diagnosing and evaluating secondary PCS., Materials and Methods: We retrospectively reviewed 59 patients with PCS, 36 males and 23 females ages 24 to 63, from 2000-2011. To maximize opacification, CTU images were taken in the late-arterial phase with a 35-50 second delay after contrast administration., Results: Review of our cases revealed multiple etiologies for PCS, including: Nutcracker syndrome (19 cases), cirrhosis (17), retroaortic left renal vein (11), tumor thrombosis of the IVC (5), portal vein thrombosis (4), renal cell carcinoma with left renal vein thrombosis (2), and left kidney AVF (1). The most common symptom was unexplained chronic pelvic pain. The patients in our series had clearly identifiable vascular flow abnormalities leading to the development of PCS, and were therefore diagnosed as having secondary PCS. All cases were easily identified utilizing CTU to visualize and measure dilation of the left gonadal vein and pelvic varices. This modality also proved valuable in the identification and management of the various underlying causes of secondary PCS., Conclusion: Secondary PCS is distinct from primary PCS in that it arises from clearly identifiable vascular flow abnormalities and occurs in both males and females. The diverse set of underlying etiologies, as well as the resulting congested varices, can be reliably and adequately visualized using CTU as the initial imaging modality.