Nichols, Paige

Context.— Epithelioid angiomyolipomas (eAMLs) are rare tumors of the kidney that occur in patients with tuberous sclerosis complex or in a sporadic setting; a subset of these tumors exhibit metastatic behavior. Objective.— To analyze molecular profiling data to identify pathogenic alterations in rare cases of metastatic eAML, and to identify immunohistochemistry (IHC)-based surrogate markers. Design.— Molecular profiling data from the American Association for Cancer Research GENIE registry was accessed for 23 patients with angiomyolipomas, and 9 of 16 patients with eAMLs in our institutional registry were evaluated with next-generation sequencing. IHC was performed to screen for alterations of P53, RB, and ATRX for all 16 institutional cases. Results.— Combined alterations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1) were identified using next-generation sequencing in 7 of 8 (88%) patients with metastatic disease compared to a single patient with nonmetastatic disease (RB1 variant of uncertain significance; 1 of 24, 4%). No cases with abnormal IHC results were identified in 11 patients with nonmetastatic disease compared to 3 of 5 patients with metastatic disease. Conclusions.— Our results show that the majority of metastatic eAMLs have mutations of 5 tumor-suppressor genes (TP53, ATRX, RB1, APC, and NF1), while these are rare in patients with nonmetastatic disease. Furthermore, IHC for P53, RB, and ATRX may serve as a screen for a subset of these alterations in resource-limited settings. These findings, if validated in larger data sets, have the potential to predict metastatic behavior in eAMLs.

Abstract Purpose: The use of postoperative prophylactic antibiotics in pediatric upper urinary tract reconstruction remains controversial. In this study, we elected to examine if low dose antibiotics (Abx) post pediatric dismember pyeloplasty reduce the incidence of urinary tract infections (UTIs) in our institution. As a secondary outcome, in patients who present with post op febrile UTIs, additional analysis was performed to better quantify which patient population benefits the most from low dose Abx. Methods: Institutional review board approval (IRB) was obtained. A retrospective study was performed in patients who underwent dismember pyeloplasty (2011-2017) at our institution. Patients with prior history of urologic interventions or other abnormalities of the genitourinary tract were excluded. Demographics (age, gender, ethnicity, insurance status), prior history of culture proven UTIs, surgical details (administration of perioperative antibiotics), and postoperative outcomes, including any readmission 30 days post repair, any urine samples, and culture results were collected. Results: 209 patients (149 boys, 60 girls) met our inclusion criteria. The average age was 6 years (range: 2 months-18 years). 160 patients (77%) underwent robotic-assisted pyeloplasty. Thirty-one patients underwent open repair (15%). 176 (84%) had an indwelling ureteral stent. Eleven patients (5%) had a culture-proven febrile UTI within 30-days postoperatively. No significant differences were seen in postoperative complications or incidence of UTIs when comparing surgical approaches, ureteral stent, or the use of prophylactic post-operative Abx. Secondary review of patients with post-operative febrile UTIs noted younger age (2.8 v. 6.2 years, p = 0.02) and positive intraoperative urine culture (p = 0.01) as significant risk factors. Conclusion: The incidence of postoperative UTIs in our cohort is relatively low. There is a higher incidence of febrile UTIs in patients less than 3 years old and those with positive intraoperative urine culture. The use of prophylactic Abx in patients post dismember pyeloplasty did not appear to affect the incidence of febrile culture proven UTIs, however, might be important in younger patients pre-potty training.

509 Background: Bladder cancer is a leading cause of cancer death in the United States. The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity. MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile. This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy. Methods: Bladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ̃1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate. Results: Intravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade > 2 were related to post-surgical complications. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissue. Conclusions: The higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ̃1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies. Clinical trial information: NCT03171493.

Abstract Background: Bladder cancer is a leading cause of cancer death in the United States1. The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG)2. Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity3. MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile4. This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy. Methods: Bladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ~1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate. Results: Intravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade>2 were related to post-surgical complications. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissue. Conclusions: The higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ~1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies. References 1. Siegel, R.L., Miller, K.D. & Jemal, A. CA Cancer J Clin 69, 7-34 (2019). 2. Knowles, M.A. & Hurst, C.D. Nature reviews. Cancer 15, 25-41 (2015). 3. Zakaria, A.S., et al. Can Urol Assoc J 8, 259-267 (2014). 4. Galanis, E., et al. Cancer research 75, 22-30 (2015). Citation Format: Tanner S. Miest, Bradley Leibovich, Stephen Bardot, Paul R. Young, Stephen A. Boorjian, Mark Gonzalgo, Loren Herrera-Hernandez, Matthew K. Tollefson, Jeffrey Karnes, Paige Nichols, Tessa Kroeninger, Rachel Graham, Carole Lahana, Monica Reckner, Alysha Newsom, Nandakumar Packiriswamy, Janice Anoka, Kah Whye Peng, Erol Wiegert, Alice Bexon, Shruthi Naik. Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients with urothelial carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P190.

Abstract Background: The use of postoperative prophylactic antibiotics in pediatric upper urinary tract reconstruction remains controversial. In this study, we elected to examine if prophylactic antibiotics post pediatric dismember pyeloplasty reduce the incidence of clinically symptomatic urinary tract infections (UTIs) in our institution. As a secondary outcome, we also examine which patient population benefits the most from low dose prophylactic antibiotics. Methods: Institutional review board approval (IRB) was obtained. A retrospective study was performed in patients who underwent dismember pyeloplasty (2011-2017) at our institution. Patients with prior history of urologic interventions or other abnormalities of the genitourinary tract were excluded. Demographics (age, gender, ethnicity, insurance status), prior history of culture proven UTIs, surgical details (administration of perioperative antibiotics), and postoperative outcomes, including any readmission 30 days post repair, any urine samples, and culture results were collected. Results: 209 patients (149 boys, 60 girls) met our inclusion criteria. The average age was 6 years (range: 2 months-18 years). 160 patients (77%) underwent robotic-assisted pyeloplasty. Thirty-one patients underwent open repair (15%). 176 (84%) had an indwelling ureteral stent. Eleven patients (5%) had a culture-proven febrile UTI within 30-days postoperatively. No significant differences were seen in postoperative complications or incidence of UTIs when comparing surgical approaches, ureteral stent, or the use of prophylactic post-operative antibiotics. Secondary review of patients with post-operative febrile UTIs noted younger age (2.8 v. 6.2 years, p = 0.02) and positive intraoperative urine culture (p = 0.01) as significant risk factors. Conclusion: The incidence of postoperative UTIs in our cohort is relatively low. There is a higher incidence of febrile UTIs in patients less than 3 years old and those with positive intraoperative urine culture. The use of prophylactic antibiotics in patients post dismember pyeloplasty did not appear to affect the incidence of febrile culture proven UTIs, however, might be important in younger patients pre potty training.

TPS380 Background: Radical prostatectomy (RP) is the most common surgical treatment for prostate cancer (PC). Yet even with nerve-sparing RP (NS-RP), a significant proportion of men experience transient or permanent erectile dysfunction (ED) partially due to intraoperative neurovascular bundle (NVB) damage from thermal or mechanical trauma. Studies have shown that platelet released growth factors counteract trauma and facilitate healing. We evaluate the use of platelet rich plasma (PRP) to facilitate early nerve healing and decrease ED after NS-RP. Methods: A prospective, open label, 20 subject human trial evaluating intraoperative topical NVB PRP application was approved by the IRB and FDA under an Investigational Device Exemption (IDE 16915) for the investigational use of an approved blood separation device. Men aged 50-60 with newly diagnosed, localized PC and normal preoperative sexual and urinary function, defined as a Sexual Health Inventory for Men (SHIM) score of >19 and an answer of “none” on question 5 of the Expanded Prostate Cancer Index Composite (EPIC) are eligible. Intraoperatively, a 10ml PRP product is created from a 180 mL sample of the patient’s whole blood using the Angel Concentrated Platelet Rich Plasma System (Cytomedix, Inc., Gaithersburg, MD USA). PRP is applied via mechanical transfer to the NVB after completion of the vesicourethral anastomosis. The primary endpoint is the safety and tolerability of PRP on the NVB after NS-RP. Secondary endpoints include feasibility of intraoperative PRP application and longitudinal assessment of erectile function and urinary continence by questionnaire administration at 3, 6, 9, 12 and 18 months after NS-RP. Clinical trial information: NCT02957149.

430 Background: Malignant melanoma of the female urethra accounts for less than 1% of all melanoma and less than 4% of urethral cancer. Due to limited data regarding management and outcomes of this condition, we evaluated the management and outcomes of urethral melanoma in females over the last 20 years at our institution. Methods: Patients were identified via retrospective review of the medical record. Those with metastatic disease at initial diagnosis were excluded. We evaluated primary and adjuvant treatments, disease recurrence and overall survival. Results: Fifteen women (median age 71, range 55, 82) were identified. Majority of masses involved the distal urethra (86.6%). All patients underwent primary surgical resection (60.0% partial urethrectomy, 40.0% radical urethrectomy). Disease recurrence and metastatic spread occurred in 73.3% (median 7 months, IQR 4, 12) and 60% (median 6 months, IQR 3, 9) of patients, respectively. 90.9% of patients with recurrence received adjuvant therapy: 5 chemotherapy and radiation, 4 chemotherapy only, 1 anterior exenteration. Of the 9 patients undergoing chemotherapy, treatment regimens were varied and included checkpoint inhibitors (2/9), platinum-based chemotherapy (3/9), tyrosine kinase inhibitors (2/9), taxels (2/9), and alkylating agents (1/9). Median overall survival was 27 months (IQR 7.5, 57.5). Conclusions: Malignant melanoma of the urethra is locally aggressive with a high likelihood of recurrence and metastases resulting in poor long-term survival. Despite high recurrence rates, our data highlight the lack of consensus adjuvant treatment regimens. Future research is required to identify neoadjuvant, combination, and adjuvant treatment approaches to improve disease outcomes.