The development of interferon-based gene therapy for BCG unresponsive bladder cancer: from bench to bedside.

BACKGROUND AND PURPOSE: 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. METHODS: A comprehensive review was performed of all studies pertaining to IFN-based gene therapy for non-muscle invasive bladder cancer from 2003 to 2018. RESULTS AND CONCLUSIONS: 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.

Lentiviral interferon: A novel method for gene therapy in bladder cancer.

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

Robotic Postchemotherapy Retroperitoneal Lymph Node Dissection for Testicular Cancer.

BACKGROUND: 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. OBJECTIVE: To demonstrate the feasibility of robotic pcRPLND (r-pcRPLND) and provide evidence for its selection criteria. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION: r-pcRPLND and o-pcRPLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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. RESULTS AND LIMITATIONS: 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%; p<0.001), resection of adjacent organs (36.5% vs 10%; p=0.007), consultation with other surgical services (46% vs 2%; p<0.001), 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; p<0.001). Median LOS was significantly shorter after r-pcRPLND (2 vs 7d; p<0.001). 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. CONCLUSIONS: With rigorous patient selection, r-pcRPLND can be safely performed and may reduce perioperative morbidity while maintaining oncologic proficiency. PATIENT SUMMARY: 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.

Variability in adherence to guidelines based management of nonmuscle invasive bladder cancer among Society of Urologic Oncology (SUO) members.

PURPOSE: 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. METHODS AND MATERIALS: 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 of <0.05 was considered statistically significant. RESULTS: 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). CONCLUSION: 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.

Detection and Treatment of Primary Prostatic Melanoma.

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.

Trends and disparities in the use of neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma.

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<0.001). Interestingly, neither sex nor race were associated with receipt of NAC. CONCLUSIONS: Use of NAC has increased significantly over time to a modest rate of 32%. However, disparities still exist in the receipt of NAC, and future efforts aimed at mitigating these disparities are warranted.

Outcomes of nonmetastatic micropapillary variant upper tract urothelial carcinoma.

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.