Ross Krasnow

Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance

Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.

The Relationship between Anogenital Distance, Fatherhood, and Fertility in Adult Men

Background Anogenital distance (AGD), a sexually dimorphic measure of genital development, is a marker for endocrine disruption in animal studies and may be shorter in infant males with genital anomalies. Given the correlation between anogenital distance and genital development, we sought to determine if anogenital distance varied in fertile compared to infertile adult men. Methods A cross sectional study of consecutive men being evaluated for infertility and men with proven fertility was recruited from an andrology clinic. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital calipers. ANOVA and linear regression were used to determine correlations between AGD, fatherhood status, and semen analysis parameters (sperm density, motility, and total motile sperm count). Findings A total of 117 infertile men (mean age: 35.3±17.4) and 56 fertile men (mean age: 44.8±9.7) were recruited. The infertile men possessed significantly shorter mean AGD and PL compared to the fertile controls (AGD: 31.8 vs 44.6 mm, PL: 107.1 vs 119.5 mm, p<0.01). The difference in AGD persisted even after accounting for ethnic and anthropomorphic differences. In addition to fatherhood, on both unadjusted and adjusted linear regression, AGD was significantly correlated with sperm density and total motile sperm count. After adjusting for demographic and reproductive variables, for each 1 cm increase in a mans AGD, the sperm density increases by 4.3 million sperm per mL (95% CI 0.53, 8.09, p = 0.03) and the total motile sperm count increases by 6.0 million sperm (95% CI 1.34, 10.58, p = 0.01). On adjusted analyses, no correlation was seen between penile length and semen parameters. Conclusion A longer anogenital distance is associated with fatherhood and may predict normal male reproductive potential. Thus, AGD may provide a novel metric to assess reproductive potential in men.

Robotic Intracorporeal Continent Cutaneous Urinary Diversion: Primary Description.

The purpose is to present the first report and describe our novel technique for intracorporeal continent cutaneous diversion after robotic cystectomy. After completion of robot-assisted cystectomy using a standard six-port transperitoneal technique, three additional ports are placed, and the robot is redocked laterally over the patients right side in the modified lateral position. Our technique replicates step-by-step the principles of the open approach. Ileocolonic anastomosis, ureteroenteral anastomoses, and construction of a hand-sewn right colonic pouch are all performed intracorporeally. Tapering of efferent ileal limb and reinforcement of the ileocecal valve are performed via the extraction site, while the stoma is matured through a prospective port site. Successful robotic intracorporeal creation of a modified Indiana pouch was achieved. Operative time for diversion was 3 hours, with negligible blood loss, and without any intraoperative complications. No major (Clavien III-V) 90-day complications were observed. At a follow-up of 1 year, the patient continues to catheterize without difficulty. We demonstrate the first description of robotic intracorporeal continent cutaneous urinary diversion after robot-assisted cystectomy. We present a systematic minimally invasive approach, replicating the principles of open surgery, which is technically feasible and safe with a good functional result.Abstract The purpose is to present the first report and describe our novel technique for intracorporeal continent cutaneous diversion after robotic cystectomy. After completion of robot-assisted cystectomy using a standard six-port transperitoneal technique, three additional ports are placed, and the robot is redocked laterally over the patients right side in the modified lateral position. Our technique replicates step-by-step the principles of the open approach. Ileocolonic anastomosis, ureteroenteral anastomoses, and construction of a hand-sewn right colonic pouch are all performed intracorporeally. Tapering of efferent ileal limb and reinforcement of the ileocecal valve are performed via the extraction site, while the stoma is matured through a prospective port site. Successful robotic intracorporeal creation of a modified Indiana pouch was achieved. Operative time for diversion was 3 hours, with negligible blood loss, and without any intraoperative complications. No major (Clavien III–V) 90-day compl...

Positive association of collagen type I with non-muscle invasive bladder cancer progression

PURPOSE Non-muscle invasive bladder cancers (NMIBC) are generally curable, while ~15% progresses into muscle-invasive cancer with poor prognosis. While efforts have been made to identify genetic alternations associated with progression, the extracellular matrix (ECM) microenvironment remains largely unexplored. Type I collagen is a major component of the bladder ECM, and can be altered during cancer progression. We set out to explore the association of type I collagen with NMIBC progression. EXPERIMENTAL DESIGN The associations of COL1A1 and COL1A2 mRNA levels with progression were evaluated in a multi-center cohort of 189 patients with NMIBCs. Type I collagen protein expression and structure were evaluated in an independent single-center cohort of 80 patients with NMIBCs. Immunohistochemical analysis was performed and state-of-the-art multi-photon microscopy was used to evaluate collagen structure via second harmonic generation imaging. Progression to muscle invasion was the primary outcome. Kaplan-Meier method, Cox regression, and Wilcoxon rank-sum were used for statistical analysis. RESULTS There is a significant association of high COL1A1 and COL1A2 mRNA expression in patients with poor progression-free survival (P=0.0037 and P=0.011, respectively) and overall survival (P=0.024 and P=0.012, respectively). Additionally, immunohistochemistry analysis of type I collagen protein deposition revealed a significant association with progression (P=0.0145); Second-harmonic generation imaging revealed a significant lower collagen fiber curvature ratio in patients with invasive progression (P = 0.0018). CONCLUSIONS Alterations in the ECM microenvironment, particularly type I collagen, likely contributes to bladder cancer progression. These findings will open avenues to future functional studies to investigate ECM-tumor interaction as a potential therapeutic intervention to treat NMIBCs.

The impact of age at the time of radiotherapy for localized prostate cancer on the development of second primary malignancies

PURPOSE There is a known increased risk of second primary malignancy (SPM) in patients with prostate cancer (CaP) treated with radiotherapy (RT). It is unclear how age at diagnosis influences the risk of SPMs. MATERIALS AND METHODS Using the 1973 to 2013 Surveillance, Epidemiology, and End Results Program, we studied the impact of age on SPMs (defined as a bladder or rectal tumor) after localized CaP treatment with radical prostatectomy (RP) or RT. SPM risk was compared using inverse probability of treatment weighting (IPTW)-adjusted cumulative incidence function and competing-risk proportional hazard models. Overall survival (OS) in patients with SPM was compared using Kaplan Meier and Cox regression analyses. RESULTS A total of 579,608 patients met inclusion criteria, and 51.8% of the cohort was treated with RT. The 10- and 20-year cumulative incidences of competing risk (IPTW adjusted) of SPMs were 1.9% (95%CI = 1.8-1.9%) and 3.6% (95%CI = 3.4-3.7%) after RP vs. 2.7% (95%CI = 2.6-2.8%) and 5.4%(95%CI = 5.3-5.6%) after RT. IPTW-adjusted competing risk hazard ratio (HR) of SPM after RT compared to RP was increased in the entire cohort (HR 1.46; 95%CI = 1.39-1.53, P < 0.001) and was highest in the youngest patients: Age <55 HR = 1.83 (95% confidence interval [CI] = 1.49-2.24, P<0.001), Age 55 to 64 HR = 1.66 (95%CI = 1.54-1.79, P < 0.001), Age 65-74 HR = 1.41 (95%CI = 1.33-1.48, P < 0.001), Age ≥75 HR = 1.14 (95%CI = 0.97-1.35, P = 0.112). At 10 years, SPM-specific mortality occurred in 28.9% of patients treated with RT, though OS with SPM was worse in the youngest patients: Age <55 HR = 1.88 (95%CI = 1.25-2.81, P = 0.002), Age 55-64 HR = 1.60 (95%CI = 1.42-1.81, P < 0.001), Age 65-74 HR = 1.40 (95%CI = 1.30-1.52, P < 0.001), Age ≥ 75 HR = 1.27 (95%CI = 1.06-1.53, P = 0.009). All of the age categories had similar median follow-up times. CONCLUSION At 10 years there is a 1.8% increased incidence of SPM after RT compared to RP, of which <30% of RT-treated patients with an SPM die as a result of a SPM. However, the risk of SPMs was greatest among younger men treated with RT for localized CaP, and this relationship could not be explained solely by follow-up time, latency time, or life expectancy. An improved understanding of those at the highest risk of SPMs may help tailor treatment and surveillance strategies.

PD36-12 COMPARING COMPLICATIONS AND SURVIVAL OF PRIMARY CYSTECTOMY VS. SALAVAGE CYSTECTOMY AFTER TRIMODAL THERAPY

non-muscle invasive BC is radical cystectomy (RC) with pelvic node dissection. Traditionally this has been an open approach, however recent data demonstrates that robotic RC is a safe and viable option with good oncologic outcomes. A concern is the cost differential between open RC (ORC) and robotic RC (RRC). We perform a single center matched study comparing the total 90 day cost between open and radical cystectomy. METHODS: With IRB approval, we assessed a single center prospectively collected RRC database for patients between 2007 and 2015. We matched RRC cases 1:1 by age and year of surgery with a retrospective ORC database. All patients who underwent adjunct procedures and procedures with two or more surgeons were excluded from the study. We then performed a comparison of clinical and pathological variables as well as 90 day technical, professional and total costs, including hospital readmissions and complication related costs. Costs are represented as a fraction of RRC over the ORC. Student0s unpaired t-test and Fisher0s exact tests were used to analyze data between the two cohorts. RESULTS: We identified 126 RRC patients and matched the with 106 ORC patients. 83% of the RRC was male (104/126) vs. 78% (83/126) of the ORC group (P1⁄40.501). Median age of RRC was 66.50 (61-73 IQR), and for ORC was 67 (61-74 IQR) (p1⁄40.501). 33% of RRC vs. 37% of ORC were clinical stage < T2, 49% of RRC vs. 45% of ORC were cT2, and 18% RRC vs. 18% of ORC were > cT2 (p1⁄40.491). Mean Charleston Comorbidity score was 1.3 (1.05 std. dev.) for RRC and 1.99 (1.89 std. dev) for ORC (p1⁄40.006). 21% (26/126) of RRC and 13% (14/ 104) of ORC had a continent diversion. Of the RRC cases, 52% (65/ 126) of the diversions were done robotically. Median length of hospital stay was 6.5 days (5-9 IQR) for RRC and 7 days (5-9 IQR) for ORC (p1⁄40.385). The 90 day total cost for RRC was 1.15 times greater than for the ORC cohort (p1⁄40.084). Professional Fees for the RRC were 1.05 times greater than the ORC (p1⁄40.3454) and the technical fees of RRC were 1.18 times that of the ORC (p1⁄40.074). 82% of the cost for the RRC, and 81% of the ORC costs were technical. CONCLUSIONS: In a matched cohort, the total 90 day postoperative costs for robotic approach was not statistically significantly more than the open. This was primarily related to technical costs, and the initial capital required for either approach was not included.

PD58-01 VALIDATION OF VENOUS THROMBOEMBOLISM RISK ASSESSMENT SCORE IN MAJOR UROLOGIC CANCER SURGERY: A POPULATION BASED STUDY

Log-rank comparisons showed improved recurrence-free and overall survival in NAC-responsive vs. high-risk NMIBC patients (p<0.02 and p<0.02) but not in non-NAC-responsive vs. high-risk NMIBC patients (p1⁄40.34 and p1⁄40.43). In Cox regression, tumor 2 cm was independently associated with increased risk of cancer recurrence (HR1⁄42.31, p1⁄40.02) and overall mortality (HR1⁄42.10, p1⁄40.02) CONCLUSIONS: Patients with NAC-responsive MIBC had better post-surgical outcomes than patients with high-risk NMIBC. Highrisk NMIBC patients had a higher prevalence of tumor 2 cm, which was an independant predictor of cancer recurrence. Despite being node negative, almost a quarter of recurrences in patients with high-risk NMIBC occurred distantly. Further work is needed to identify whether patients with unresectable or high volume NMIBC could benefit from NAC.

MP71-09 EFFECTIVENESS OF ADJUVANT CHEMOTHERAPY AFTER RADICAL NEPHROURETERECTOMY FOR LOCALLY ADVANCED AND/OR POSITIVE REGIONAL LYMPH NODE UPPER TRACT UROTHELIAL CARCINOMA

INTRODUCTION AND OBJECTIVES: Various transcription factors, including ELK1, FOXO1, NFAT, and ZKSCAN3, have been shown to contribute to bladder tumorigenesis and cancer progression. Meanwhile, we have demonstrated that androgens promote bladder cancer outgrowth via modulating the activity of some of these transcription factors. In contrast, little is known about their role in the development and growth of upper urinary tract urothelial carcinoma (UUTUC). This study aims to determine the expression status of phospho-ELK1 (pELK1) and phospho-FOXO1 (pFOXO1), their activated and inactivated forms, respectively, as well as NFATc1 and ZKSCAN3, in UUTUC and its prognostic significance. METHODS: We immunohistochemically stained for pELK1, pFOXO1, NFATc1, and ZKSCAN3 in the tissue microarrays consisting of 99 UUTUC samples and paired non-neoplastic urothelium from each case. We then evaluated the relationship between the expression of each transcription factor and clinicopathologic features available for our patient cohort. RESULTS: pELK1, pFOXO1, NFATc1, and ZKSCAN3 were positive in 47% [37% weak (1+), 10% moderate (2+), 0% strong (3+)], 100% (12% 1+, 46% 2+, 41% 3+), 51% (40% 1+, 9% 2+, 3% 3+), and 42% (26% 1+, 13% 2+, 3% 3+) of UUTUCs, respectively, which were significantly higher (pELK1: 25%, P1⁄40.002; pFOXO1: 94%, P1⁄40.018; NFATc1: 24%, P1⁄40.038) or lower (ZKSCAN3: 86%, P<0.001) than in benign urothelial tissues. Five (33%) of 15 low-grade versus 42 (50%) of 84 high-grade UUTUCs (P1⁄40.036) and 13 (35%) of 37 non-muscleinvasive (NMI) versus 34 (55%) of 62 muscle-invasive (MI) UUTUCs (P1⁄40.065) were immunoreactive for pELK1. Similarly, 29 (78%) NMI versus 58 (94%) MI UUTUCs (P1⁄40.031) were moderately or strongly positive for pFOXO1. However, there were no statistically significant associations between pELK1/pFOXO1/NFATc1/ZKSCAN3 expression and pN/M status. Kaplan-Meier and log-rank tests revealed that patients with high (2+) pELK1 tumor (P1⁄40.008), high (3+) pFOXO1 tumor (P1⁄40.059), high (2+/3+) NFATc1 tumor (P1⁄40.005), or high (3+) ZKSCAN3 MI tumor (P1⁄40.069) had higher risks of cancer-specific mortality. CONCLUSIONS: Compared with non-neoplastic urothelium, significant increases and a decrease in the expression of pELK1/ pFOXO1/NFATc1 and ZKSCAN3, respectively, in UUTUC were seen. The current results also support our preclinical findings indicating correlations of ELK1/FOXO1 activation with urothelial tumor progression/ regression, respectively. Furthermore, pELK1/NFATc1 overexpression was found to serve as predictors of poor prognosis.

MP04-04 CHARACTERIZING THE COSTS OF COMPLICATIONS AFTER CYSTECTOMY: CAN WE TARGET THE PRIMARY DRIVERS?

INTRODUCTION AND OBJECTIVES: The effect of non-muscle invasive bladder cancer (NMIBC) on health-related quality of life (HRQOL) is poorly understood. We evaluated changes in HRQOL in patients with a new diagnosis of NMIBC compared with the general population using the Surveillance Epidemiology and End Results (SEER) Medicare Health Outcomes Survey (MHOS) database. METHODS: We identified 325 Medicare beneficiaries diagnosed with NMIBC between initial and 2-year follow-up using SEERMHOS data (1998-2013). NMIBC patients who underwent cystoscopy with biopsy or transurethral resection of bladder tumor(s) for bladder cancer were propensity matched 1:5 to non-cancer controls (n1⁄41685). Changes from baseline in the physical component score (PCS) and mental component score (MCS), which are normalized to between 0-100, where 50 represents the US population mean, were compared between NMIBC patients and non-cancer controls with c testing and multivariate linear regression analysis. We secondarily assessed differences in urinary symptoms on post-diagnosis surveys with univariate and multivariate models. RESULTS: Pre-diagnosis, mean PCS (39.94 vs 39.54, p 1⁄4 0.71) and mean MCS (52.03 vs 52.17, p 1⁄4 0.82) scores were similar between NMIBC patients and matched non-cancer controls. Postdiagnosis, NMIBC patients had a significantly greater decrease in PCS compared with controls (-2.87 (95% CI -3.87, -1.86) vs. -1.47 (95% CI -1.93, -1.02), p 1⁄4 0.02). Conversely, mean MCS change did not vary between groups (-1.79 (95% CI -2.76, -0.81) vs. -0.72 (95% CI -1.21, -0.23), p 1⁄4 0.09). With respect to urinary function, NMIBC pts were more likely to have worsening of urinary leakage (38.0 % vs 18.7 %, p1⁄4 < 0.01), require physician intervention for urinary symptoms (33.9 % vs 13.7 %, p1⁄4 <0.01 ), and receive treatment for urine leakage (31.6 % vs 12.0 %, p1⁄4 <0.01 ) compared with non-cancer controls (p 1⁄4 <0.01). CONCLUSIONS: The diagnosis of NMIBC is associated with a significant decrease in physical HRQOL, including a significant impact on urinary symptoms and leakage. Further efforts to prospectively evaluate HRQOL in patients with NMIBC should be pursued to inform and improve patient counseling.

MP86-03 A PREDICTIVE RISK STRATIFICATION MODEL FOR DELIRIUM AFTER MAJOR UROLOGIC CANCER SURGERIES

INTRODUCTION AND OBJECTIVES: Post-operative delirium is a common complication in the elderly and contributes to increased healthcare costs, mortality, cognitive decline, and hospital length of stay. No definitive pre-operative risk prediction model for patients undergoing major urologic cancer surgeries is currently available. METHODS: Using the Premier Hospital Database, we retrospectively identified patients who had undergone radical prostatectomy (RP), radical nephrectomy (RN), partial nephrectomy (PN), and radical cystectomy (RC) from 2003 to 2013. Post-operative delirium was defined using International Classification of Disease, Ninth Revision (ICD-9) codes, as well as post-operative use of antipsychotics, sitters, and restraints. Potential pre-operative risk factors of delirium were extrapolated from patient, hospital, and surgical characteristics. A preoperative delirium risk prediction score was developed from our multivariate model. Its performance was quantified using Receiver Operating Characteristic (ROC) analysis. All analyses were survey-weighted and clustered by hospitals to achieve estimates generalizable to the US population. RESULTS: We identified 165,387 patients representing a weighted total of 1,097,355 patients from 490 hospitals who had undergone RP, RN, PN, or RC. Our model revealed a wide range of clinical and demographic factors that significantly contribute to the risk for post-operative delirium (Figure A). Our delirium risk score was associated with the development of post-operative delirium (Odds Ratio: 1.31, 95% CI 1.29-1.33, p <0.001, Figure B), and it demonstrated good discrimination in the prediction of delirium (Receiver Operator Characteristic [ROC] area 1⁄4 0.76, 95% CI, 0.76-0.77, Figure C). The ability of the risk score to predict delirium was consistent across surgical subgroups, and the risk score was also predictive of the duration of delirium (Incidence Rate Ratio 1⁄4 1.07, 95% CI 1.04-1.11, p<0.001). CONCLUSIONS: The preliminary results of our pre-operative delirium risk prediction tool are promising given its consistency with published delirium risk factors and ease of use. Further validation of this model will shed insight about its clinical utility to identify patients at highrisk of post-operative delirium who may benefit from early therapeutic intervention. Source of Funding: None