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Summary: Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer. : Guo et al. report that sarcomatoid carcinoma of the bladder evolves by the progression of the basal subtype of conventional urothelial carcinoma with the enrichment of mutagenesis signature 1 and mutations of TP53, RB1, and PIK3CA. It is driven by the dysregulation of the EMT network and shows increased immune infiltrate with overexpression of PD-L1. Keywords: bladder cancer, sarcomatoid carcinoma, urothelial carcinoma, epithelial-mesenchymal transformation, genomic expression, chromatin remodeling, microRNA expression, molecular classification, basal subtype, immune phenotype

INTRODUCTION AND OBJECTIVE:Previous studies have demonstrated efficacy of intravesical delivery of interferon-α (IFNα) using an adenoviral vector for the treatment of bacillus-calmette guerin (BCG)...

BCG unresponsive bladder cancer is an inherently resistant disease state for which the preferred treatment is radical cystectomy. To date, no effective intravesical therapies exist for patients who possess these resistant tumors. For this reason, many research groups are actively investigating/testing novel therapeutic agents to aid in bladder preservation for this patient population. This review article describes our 15-year experience developing and testing IFN-based gene therapy. A comprehensive review was performed of all studies pertaining to IFN-based gene therapy for non-muscle invasive bladder cancer from 2003 to 2018. Over the past two decades, gene therapy has evolved into a powerful tool in our fight against cancer. After overcoming the initial barriers associated with gene delivery to the bladder, we have made significant strides forward in developing this novel therapeutic strategy for the treatment of this inherently resistant disease state. Our results to date are very encouraging; however, much work lies ahead to better understand and optimize this novel approach for treating non-muscle invasive bladder.

Platinum-based chemotherapy has served as the mainstay systemic treatment for muscle invasive bladder cancer (MIBC) for decades. Its use in the neoadjuvant (NAC), adjuvant (AC), and salvage setting...

Objectives To determine the oncologic outcomes of organ sparing surgery (OSS) for penile cancer and to determine the management of and risk factors for local recurrence at a tertiary referral center in the United States. Methods and Materials Patients undergoing OSS from 1996 to 2018 at The University of Texas, MD Anderson Cancer Center were identified using a prospective database. Organ sparing procedures included: wide local excision (WLE; including circumcision and glans resurfacing), partial or total glansectomy, laser therapy, or OSS combined with laser ablation (i.e., laser combination). Clinical and pathologic data were collected for descriptive analysis. Recurrences (local and regional) were identified, and the association between overall and local recurrences was determined using Cox proportional hazards regression. Overall and recurrence free survival analyses were performed using Kaplan-Meier estimates. Results A total of 129 patients undergoing OSS were identified with a median follow up interval of 28.0 months. The most common OSS was laser combination (38.8%), and 65.1% of patients presented with pTis or ≤pT1a disease. Twenty (15.5%) recurrences were identified, of which 17 (13.2%) were local and 3 (2.3%) were regional. There were no distant recurrences as the initial site of recurrence. The median time to local recurrence was 20.9 months, and 88.2% were identified within 5 years of surgery. Most (76.5%) local recurrences were successfully treated with further penile preservation without a detrimental impact on overall survival. Patients with pathologic Ta or T1a disease treated with laser or laser combination surgery were more likely to present with local recurrence. Conclusion OSS using a variety of techniques to achieve negative surgical margins provides long-term effective local control for localized penile cancer. Most local recurrences can be successfully treated with further penile preserving strategies and long follow-up is essential. Laser therapy or laser combination with OSS should be used with caution in patients with invasive penile cancer.

The American Urological Association (AUA) introduced evidence-based guidelines for the management of nonmuscle invasive bladder cancer (NMIBC) in 2016. We sought to assess the implementation of these guidelines among members of the Society of Urologic Oncology (SUO) with an aim to identifying addressable gaps.An SUO approved survey was distributed to 747 members from December 28, 2018 to February 2, 2019. This 14-question online survey (Qualtrics, SAP SE, Germany) consisted of 38 individual items addressing specific statements from the AUA NMIBC guidelines within 3 broad categories - initial diagnosis, surveillance, and imaging/biomarkers. Adherence to guidelines was assessed by dichotomizing responses to each item that was related to recommended action statement within the guidelines. Statistical analysis was applied using Pearson's chi-squared test, where a P-value of0.05 was considered statistically significant.A total of 121 (16.2%) members completed the survey. Members reported a mean of 71% guidelines adherence; adherence was higher for the intermediate- and high-risk subgroups (82% and 76%, respectively) compared to low-risk (58%). Specifically, adherence to guideline recommended cystoscopic surveillance intervals for low-risk disease differed based on clinical experience (60.9% [10 years] vs. 36.8% [≥10 years], P = 0.01) and type of fellowship training (55.2% [urologic oncology] vs. 28.0% [none/other], P = 0.02).Adherence to guidelines across risk-categories was higher for intermediate- and high-risk patients. Decreased adherence observed for low-risk patients resulted in higher than recommended use of cytology, imaging, and surveillance cystoscopy. These results identify addressable gaps and provide impetus for targeted interventions to support high-value care, especially for low-risk patients.

Purpose Micropapillary variant upper tract urothelial cancer (MP-UTUC) is a rare malignancy with little known regarding its clinical course and/or optimal treatment. In this case series, we describe patient characteristics, surgical treatment, oncologic outcomes, and response to perioperative chemotherapy. Materials and Methods We conducted a review to identify patients with MP-UTUC treated at our center between January 1994 and October 2017. Clinicopathologic data was obtained. Descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards, and nearest neighbor matching were used to examine the cohort. Results Eighteen, (4.3%) of 416 patients were found to have MP-UTUC at our institution over a 23-year period. The majority of patients had ≥pT3 disease at the time of extirpative surgery (13/18, 72%) and one was identified as MP-UTUC prior to surgery. Seven patients received neoadjuvant chemotherapy and six patients received adjuvant chemotherapy. Median overall, cancer specific, and recurrence free survival were 3.29, 3.29, and 1.69 years, respectively for MP-UTUC. There was no survival difference between conventional UTUC and MP-UTUC when matched for age, stage, grade, lymphovascular invasion, and margins (HR 1.18, P = 0.567). No MP-UTUC patients receiving neoadjuvant and adjuvant chemotherapy had apparent pathologic down staging, and of those receiving adjuvant chemotherapy two-thirds died of disease within 2 years. Conclusions MP-UTUC is a rare, and in most cases aggressive malignancy that commonly presents as locally advanced disease. In this case series, MP-UTUC does not appear to respond to perioperative chemotherapy as neoadjuvant and adjuvant chemotherapy did not result in apparent pathologic down staging and the majority of those receiving adjuvant chemotherapy died from MP-UTUC.

Introduction: Neoadjuvant chemotherapy (NAC) prior to radical or partial cystectomy is considered the standard of care for eligible patients with muscle-invasive urothelial carcinoma. Despite guideline recommendations, adoption of NAC has historically been low, although prior studies have suggested that use is increasing. In this contemporary study, we examine trends in the use of NAC and explore factors associated with its receipt. Methods: We identified patients in the National Cancer Database who underwent radical or partial cystectomy for cT2-cT4N0M0 urothelial carcinoma from 2006–2014. The proportion of patients receiving NAC during each year was examined. Logistic regression models were used to evaluate clinical and socioeconomic factors associated with the receipt of NAC. Results: A total of 18 188 patients were identified who underwent radical or partial cystectomy for muscle-invasive bladder cancer. Overall, 3940 (21.7%) received NAC. We noted a significant increase in the use of NAC over time, from 9.7% in 2006 to 32.2% in 2014. Factors associated with lower use of NAC include older age, higher comorbidity score, lower cT stage, lower hospital radical cystectomy volume, treatment at a non-academic facility, lower patient income, and receipt of partial cystectomy (all p

Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is mandated in patients with nonseminomatous germ cell tumor found to have residual masses after chemotherapy. Performed via the open approach, pcRPLND can incur significant perioperative morbidity.To demonstrate the feasibility of robotic pcRPLND (r-pcRPLND) and provide evidence for its selection criteria.A retrospective search identified 93 patients undergoing pcRPLND between April 2007 and March 2018, comprising 30 r-pcRPLND and 63 open pcRPLND (o-pcRPLND) procedures performed by a single surgeon.r-pcRPLND and o-pcRPLND.Baseline clinicopathologic characteristics and intraoperative variables including operating room (OR) time, estimated blood loss (EBL), resection of adjacent organs, and intraoperative consultation with other surgical services were recorded. Hospital length of stay (LOS) and perioperative complications were assessed as per the Clavien-Dindo classification, and oncologic outcomes such as nodal yield, histologic distribution, pathologic staging, time to recurrence, and cancer-specific survival were compared.r-pcRPLND was performed in a well-selected cohort with lower clinical stage (p=0.006), favorable International Germ Cell Cancer Collaborative Group classification (p=0.01), and smaller retroperitoneal mass (p=0.001). o-pcRPLND required more frequent bilateral template dissection (88.9% vs 43.3%; p0.001), resection of adjacent organs (36.5% vs 10%; p=0.007), consultation with other surgical services (46% vs 2%; p0.001), and auxiliary procedures (54.0% vs 20%; p=0.003) to achieve complete oncologic control. OR time was similar between the two groups (o-pcRPLND 375min vs r-pcRPLND 388min; p=0.16) and EBL was significantly lower in r-pcRPLND (234 vs 825ml; p0.001). Median LOS was significantly shorter after r-pcRPLND (2 vs 7d; p0.001). A total of 31 patients (33%) suffered postoperative complications, of whom 18 (19.4%) had major complications. Nodal yield was similar (o-pcRPLND 23 vs r-pcRPLND 24; p=0.8). The distribution of lesion histology (necrosis/teratoma/GCT) was also similar pcRPLND (o-pcRPLND 25.4%/57.1%/17.4% vs r-pcPLND 33.3%/50%/16.7%; p=0.51). Overall, tumor recurred in 15 patients (16.1%), including three following r-pcRPLND (10%), all outside the operative field. On univariate analysis, surgical approach was not a significant predictor of time to recurrence (p=0.34). One limitation was that antegrade ejaculation was not assessed.With rigorous patient selection, r-pcRPLND can be safely performed and may reduce perioperative morbidity while maintaining oncologic proficiency.Resection of residual retroperitoneal mass after chemotherapy in patients with metastatic testicular cancer can be performed safely via a robotic approach. Robotic surgery can reduce the morbidity of the procedure.

SUMMARYThe sarcomatoid variant of urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment ofTP53, RB1, and PIK3CAmutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

Objective To describe a case of primary melanoma of the prostate gland, then review the published literature of similar cases. Methods Presentation of the clinical course of a 42-year-old man diagnosed with primary melanoma of the prostate after presenting with gross hematuria. Review of published literature. Results Primary melanoma of the genitourinary tract is a very rare disease, representing less than 1% of all melanomas in men. Only 6 cases of primary melanomas have been previously reported in the English literature. Conclusion The current report emphasizes the importance of a multidisciplinary approach and adherence to treatment principles in cutaneous melanoma. With complete surgical extirpation (including extended pelvic lymphadenectomy as needed), close surveillance using 18F-FDG PET/CT, and aggressive systemic treatment in patients with good performance status, cure can be achieved.

33 Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. LV can infect non-dividing cells and integrate into the host’s genome, making it more efficient gene delivery vectors. As treatment with IFN upregulates checkpoint inhibitors, we also wanted to investigate the role of checkpoint inhibitors with and without IFN gene therapy. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα (MOI 2:1). IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, the MB49 intravesical tumor model and p53+/- C57/B6 mouse model were employed. We also assessed the role of combination therapy with immune checkpoint blockade using PD1 antibody using our MB49 intravesical model. Results: Efficient LV-IFNα transduction of BLCA cells resulted in increased expression of IFNα and its target genes and reduced cell viability vs. controls (p

456 Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. Unlike the adenovirus, LV can infect non-dividing cells and integrate into the host’s genome, making it one of the most efficient gene delivery vectors. The objective of this study was to investigate lentiviral interferon-alpha (LV-IFNα) BLCA gene therapy in preclinical models. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα using a multiplicity of infection (MOI) of 2:1. IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, p53+/- C57/B6 mice were exposed to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) to induce CIS and then treated with LV-IFNα or control virus, and sacrificed when moribund. Results: Efficient LV-IFNα transduction of BLCA cells was observed at an MOI of 2:1, resulting in increased expression of IFNα and its target genes PDL-1, TRAIL, and IRF7 (p