- Email: [email protected]
892 PRELIMINARY RESULTS OF PERIOPERATIVE OUTCOMES AND ONOCOLIGIC EFFICACY FROM A SINGLE INSTITUTION RANDOMIZED CONTROLLED TRIAL OF OPEN VERSUS ROBOTIC ASSISTED RADICAL CYSTECTOMY
Vol. 187, No. 4S, Supplement, Monday, May 21, 2012
proved to be one of the most effective treatments for superficial bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, which limits the improvement of BCG therapy. Vitamin D deficiency has been associated with the high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy for BCa. METHODS: We applied a transwell migration assay to examine vitamin D signal¡s impact on the BCG-mediated innate immune cells¡ migration. The corresponding pro-inflammatory cytokines induced by vitamin D/vitamin D receptor were screened by cytokine array and confirmed by ELISA. Preclinical evaluation of efficacy of intravesical BCG with 1£,25-dihydroxyvitamin D3 (1,25-VD) therapy was performed using Nbutyl- N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model. RESULTS: ELISA assay revealed that treatment of BCa cells with 1,25-VD promotes BCG-induced interleukin 8 (IL-8) production, consequently inducing the migration of neutrophil-like cells, HL-60, and monocyte-like cells, THP-1. This 1,25-VD-mediated IL-8-induced innate immune cells migration was blocked by IL-8 neutralized antibody. These in vitro studies suggest that 1,25-VD could improve BCG responsiveness by enhancing recruitment of innate immune cells to promote cytotoxic killing of BCa cells. More importantly, our in vivo data revealed that intravesical treatment of 1,25-VD improves BCG efficacy where 1,25-VD⫹BCG treatment increased the survival rate of mice with BCa induced by BBN compared to BCG treatment alone. CONCLUSIONS: The results of these studies indicate that 1,25-VD signaling is critical for success of BCG immunotherapy and co-treatment with 1,25-VD will enhance BCG’s anti-tumor effects in BCa. Source of Funding: Pardee Foundation
892 PRELIMINARY RESULTS OF PERIOPERATIVE OUTCOMES AND ONOCOLIGIC EFFICACY FROM A SINGLE INSTITUTION RANDOMIZED CONTROLLED TRIAL OF OPEN VERSUS ROBOTIC ASSISTED RADICAL CYSTECTOMY Jamie Messer*, John Fitzgerald, Barbara Ercole, Robert Svatek, Dipen Parekh, San Antonio, TX INTRODUCTION AND OBJECTIVES: Robotic assisted Radical Cystectomy (RARC) for bladder cancer has been reported with the promise for improvement in perioperative morbidity compared to open approach. However, most studies are retrospective with significant selection bias. Our objective was to determine feasibility of conducting a prospective randomized trial comparing robotic to the open approach. We present preliminary data from a single institution prospective randomized clinical trial of open radical cystectomy (ORC) versus RARC. METHODS: Prospective randomized single institution series evaluating the feasibility of ORC versus RARC for consecutive patients was performed from July 2009 to June 2011. Oncologic efficacy was assessed based on the surrogates of total number of lymph nodes removed and positive surgical margins. Perioperative morbidity was assessed evaluating for estimated blood loss, transfusion requirements, length of stay and perioperative complications. RESULTS: To date 46 patients have been randomized with data available on 39 patients for analysis. Each group was similar with regards to age, sex, race, BMI, comorbidities, and previous abdominal procedures, operative time, and final pathologic stage. We observed no significant difference between oncologic outcomes of positive surgical margins (5% vs 5.263%, p 0.97) or number of LN removed (11 vs 23, p 0.40) for the RARC versus ORC groups respectively. The RARC group was noted to have decreased estimated blood loss (400 mL vs 800 mL, p 0.008) and a trend towards decreased rate of excessive length of stay (⬎5 days) (65% vs 84%, p 0.24) for the RARC versus ORC groups. The robotic group had a trend towards decreased rate of transfusion however this was not statistically significant (40% versus 53%, p 0.429).
THE JOURNAL OF UROLOGY姞
e363
CONCLUSIONS: Our study confirms feasibility of randomizing patients undergoing radical cystectomy to open or robotic approach. Our preliminary findings from a single institution randomized trial of RARC versus ORC indicates that RARC has equivalent oncologic outcomes as measured by positive surgical margins and total number of lymph node removed. RARC demonstrates perioperative benefits of decreased blood loss, fewer excessive hospital stays, and a trend toward fewer blood transfusions.
Source of Funding: Institutional
893 DEFINING THE MOLECULAR DETERMINANTS OF SENSITIVITY TO EGFR INHIBITION IN UROTHELIAL CARCINOMA Ian Udell*, Raj Kurpad, Angela Smith, Matthew Nielsen, Raj Pruthi, Eric Wallen, Michael Woods, William Kim, Chapel Hill, NC INTRODUCTION AND OBJECTIVES: EGFR is over⫺expressed in urothelial carcinomas (UC) and has been shown to correlate with increasing stage and grade as well as a decreased progression⫺free and overall survival. Multiple EGFR inhibitors are FDA approved and a phase II clinical trial of neoadjuvant erlotinib in patients with muscle invasive UC suggested possible clinical activity. We hypothesized that we could define molecular determinants of sensitivity or resistance to EGFR inhibition in UC by assessing if EGFR⫺associated gene expression signatures are predictive of response to erlotinib. METHODS: Correlative tumor samples from a phase II clinical trial of neoadjuvant erlotinib in muscle invasive UC of the bladder were analyzed to define molecular determinants in response to EGFR inhibition. An in vitro EGFR⫺associated signature was developed and then evaluated on primary human bladder tumors. Several candidate molecular determinants of sensitivity to EGFR inhibition were characterized and examined for their ability to predict resistance to EGFR inhibitors. RESULTS: While our in vitro EGFR⫺associated gene expression profile did not have predictive value in our tumor set, AKT2, MAPK6 and HRAS were significantly elevated in non⫺pT0 patients relative to pT0 patients, suggesting that increased EGFR signaling may be predictive of resistance to EGFR inhibitors. Furthermore, elevated HRAS seemed to promote resistance to EGFR inhibition because knockdown of HRAS in cells expressing constitutively active HRAS resulted in a significant reduction of IC50. CONCLUSIONS: These findings confirm that increased HRAS expression is correlated with a lack of response to erlotinib in vivo while silencing of HRAS results in enhanced sensitivity to erlotinib in vitro.
proved to be one of the most effective treatments for superficial bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, which limits the improvement of BCG therapy. Vitamin D deficiency has been associated with the high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy for BCa. METHODS: We applied a transwell migration assay to examine vitamin D signal¡s impact on the BCG-mediated innate immune cells¡ migration. The corresponding pro-inflammatory cytokines induced by vitamin D/vitamin D receptor were screened by cytokine array and confirmed by ELISA. Preclinical evaluation of efficacy of intravesical BCG with 1£,25-dihydroxyvitamin D3 (1,25-VD) therapy was performed using Nbutyl- N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model. RESULTS: ELISA assay revealed that treatment of BCa cells with 1,25-VD promotes BCG-induced interleukin 8 (IL-8) production, consequently inducing the migration of neutrophil-like cells, HL-60, and monocyte-like cells, THP-1. This 1,25-VD-mediated IL-8-induced innate immune cells migration was blocked by IL-8 neutralized antibody. These in vitro studies suggest that 1,25-VD could improve BCG responsiveness by enhancing recruitment of innate immune cells to promote cytotoxic killing of BCa cells. More importantly, our in vivo data revealed that intravesical treatment of 1,25-VD improves BCG efficacy where 1,25-VD⫹BCG treatment increased the survival rate of mice with BCa induced by BBN compared to BCG treatment alone. CONCLUSIONS: The results of these studies indicate that 1,25-VD signaling is critical for success of BCG immunotherapy and co-treatment with 1,25-VD will enhance BCG’s anti-tumor effects in BCa. Source of Funding: Pardee Foundation
892 PRELIMINARY RESULTS OF PERIOPERATIVE OUTCOMES AND ONOCOLIGIC EFFICACY FROM A SINGLE INSTITUTION RANDOMIZED CONTROLLED TRIAL OF OPEN VERSUS ROBOTIC ASSISTED RADICAL CYSTECTOMY Jamie Messer*, John Fitzgerald, Barbara Ercole, Robert Svatek, Dipen Parekh, San Antonio, TX INTRODUCTION AND OBJECTIVES: Robotic assisted Radical Cystectomy (RARC) for bladder cancer has been reported with the promise for improvement in perioperative morbidity compared to open approach. However, most studies are retrospective with significant selection bias. Our objective was to determine feasibility of conducting a prospective randomized trial comparing robotic to the open approach. We present preliminary data from a single institution prospective randomized clinical trial of open radical cystectomy (ORC) versus RARC. METHODS: Prospective randomized single institution series evaluating the feasibility of ORC versus RARC for consecutive patients was performed from July 2009 to June 2011. Oncologic efficacy was assessed based on the surrogates of total number of lymph nodes removed and positive surgical margins. Perioperative morbidity was assessed evaluating for estimated blood loss, transfusion requirements, length of stay and perioperative complications. RESULTS: To date 46 patients have been randomized with data available on 39 patients for analysis. Each group was similar with regards to age, sex, race, BMI, comorbidities, and previous abdominal procedures, operative time, and final pathologic stage. We observed no significant difference between oncologic outcomes of positive surgical margins (5% vs 5.263%, p 0.97) or number of LN removed (11 vs 23, p 0.40) for the RARC versus ORC groups respectively. The RARC group was noted to have decreased estimated blood loss (400 mL vs 800 mL, p 0.008) and a trend towards decreased rate of excessive length of stay (⬎5 days) (65% vs 84%, p 0.24) for the RARC versus ORC groups. The robotic group had a trend towards decreased rate of transfusion however this was not statistically significant (40% versus 53%, p 0.429).
THE JOURNAL OF UROLOGY姞
e363
CONCLUSIONS: Our study confirms feasibility of randomizing patients undergoing radical cystectomy to open or robotic approach. Our preliminary findings from a single institution randomized trial of RARC versus ORC indicates that RARC has equivalent oncologic outcomes as measured by positive surgical margins and total number of lymph node removed. RARC demonstrates perioperative benefits of decreased blood loss, fewer excessive hospital stays, and a trend toward fewer blood transfusions.
Source of Funding: Institutional
893 DEFINING THE MOLECULAR DETERMINANTS OF SENSITIVITY TO EGFR INHIBITION IN UROTHELIAL CARCINOMA Ian Udell*, Raj Kurpad, Angela Smith, Matthew Nielsen, Raj Pruthi, Eric Wallen, Michael Woods, William Kim, Chapel Hill, NC INTRODUCTION AND OBJECTIVES: EGFR is over⫺expressed in urothelial carcinomas (UC) and has been shown to correlate with increasing stage and grade as well as a decreased progression⫺free and overall survival. Multiple EGFR inhibitors are FDA approved and a phase II clinical trial of neoadjuvant erlotinib in patients with muscle invasive UC suggested possible clinical activity. We hypothesized that we could define molecular determinants of sensitivity or resistance to EGFR inhibition in UC by assessing if EGFR⫺associated gene expression signatures are predictive of response to erlotinib. METHODS: Correlative tumor samples from a phase II clinical trial of neoadjuvant erlotinib in muscle invasive UC of the bladder were analyzed to define molecular determinants in response to EGFR inhibition. An in vitro EGFR⫺associated signature was developed and then evaluated on primary human bladder tumors. Several candidate molecular determinants of sensitivity to EGFR inhibition were characterized and examined for their ability to predict resistance to EGFR inhibitors. RESULTS: While our in vitro EGFR⫺associated gene expression profile did not have predictive value in our tumor set, AKT2, MAPK6 and HRAS were significantly elevated in non⫺pT0 patients relative to pT0 patients, suggesting that increased EGFR signaling may be predictive of resistance to EGFR inhibitors. Furthermore, elevated HRAS seemed to promote resistance to EGFR inhibition because knockdown of HRAS in cells expressing constitutively active HRAS resulted in a significant reduction of IC50. CONCLUSIONS: These findings confirm that increased HRAS expression is correlated with a lack of response to erlotinib in vivo while silencing of HRAS results in enhanced sensitivity to erlotinib in vitro.