Daniel Kedar

Blockade of Epidermal Growth Factor Receptor Signaling on Tumor Cells and Tumor-Associated Endothelial Cells for Therapy of Human Carcinomas

The purpose of this study was to determine whether the expression of epidermal growth factor receptor (EGF-R) and activated EGF-R by tumor-associated endothelial cells is influenced by interaction with specific growth factors in the microenvironment. Different human carcinoma cell lines expressing EGF-R with low or high levels of EGF/transforming growth factor (TGF)-alpha were implanted into orthotopic organs of nude mice. In the EGF/TGF-alpha-positive bladder cancer (253J-BV), pancreatic cancer (L3.6pl), and renal cancer (RBM1-IT) but not in the EGF/TGF-alpha-negative renal cancer SN12-PM6, tumor-associated endothelial cells expressed EGF-R and activated EGF-R. Mice were implanted with human 253J-BV bladder tumors (EGF+) or human SN12-PM6 renal tumors (EGF-). Treatment with oral PKI 166 (a specific inhibitor of EGF-R phosphorylation) alone, intraperitoneal paclitaxel alone (253J-BV), gemcitabine alone (SN12-PM6), or combination of PKI 166 and chemotherapy produced a 60%, 32%, or 81% reduction in the volume of 253J-BV bladder tumors, respectively, and 26%, 23%, or 51% reduction in the volume of SN12-PM6 kidney tumors, respectively. Immunohistochemical analyses demonstrated down-regulation of activated EGF-R in EGF/TGF-alpha-positive and EGF/TGF-alpha-negative lesions from mice treated with PKI 166, although apoptosis of tumor-associated endothelial cells was found only in EGF/TGF-alpha-positive tumors. Collectively, these data suggest that expression of activated EGF-R by tumor-associated endothelial cells provides an important target for therapy.

PD19-10 THE CHEMOABLATIVE EFFECT OF VESIGEL INSTILLATION IN PATIENTS WITH NMIBC – RESPONSE RATE AND 1-YEAR DURABILITY

Randomisation was stratified by centre, CIS and prior BCG response. Primary outcomes were DFS and complete response (CR) at three months in patients with CIS at randomisation. A log-rank test was performed to compare arms on an intention-to-treat basis. RESULTS: Between May 2010 and July 2013, 104 patients were randomised. 48 (46%) assigned to RITE and 56 (54%) control. Median DFS was 35.1 months (IQR: 23.1-445.3 months) with no difference between treatment arms (HR 1.32, [0.83-2.1], p1⁄40.23). Three-month CR in CIS patients for both treatment arms were similar (RITE: 75% vs control: 80%, p1⁄40.62). DFS in patients with papillaryonly disease was higher in RITE patients (HR 0.42, [0.19-1.03], p1⁄40.0531) but not significantly different in CIS-only patients (HR 1.61, [0.8-3.2], p1⁄40.17). Papillary disease and concurrent CIS patients had significantly better DFS in the control arm (HR 6.9, [2.0623.25], p<0.001). No difference in adverse events between treatment arms were observed. CONCLUSIONS: The HYMN trial did not show an overall difference between RITE and the control arm. However, there was a benefit for RITE in participants with papillary-only disease. RITE was well tolerated with comparable adverse events compared with BCG. Further trials are needed to investigate the efficacy of RITE in CIS patients.

Heat shock proteins 60 and 70 are associated with long-term outcome of T1-stage high-grade urothelial tumors of the bladder treated with intravesical Bacillus Calmette-Guérin immunotherapy

OBJECTIVES High-grade nonmuscle-invasive urothelial tumors of the bladder that fail intravesical Bacillus Calmette-Guérin (BCG) immunotherapy are at the highest risk of progression. Initial evidence links heat shock protein expression levels and outcome of bladder cancer after BCG treatment. We aimed to determine the association between HSP60, 70, and 90 expression levels and long-term outcomes of T1 high-grade (T1HG) urothelial bladder tumors treated with BCG immunotherapy. MATERIALS AND METHODS Data of 54 consecutive patients with primary T1HG bladder tumors who underwent transurethral resection between 2002 and 2008 and received at least an induction course of BCG were reviewed. Immunohistochemical staining for heat shock protein (HSP)60, 70, and 90 were performed on resected specimens. Study outcomes included disease recurrence and progression. The association between HSP expression levels and outcomes were evaluated with univariable and multivariable Cox proportional hazards models. RESULTS During a median follow-up of 9.6 years, 25 patients had a disease recurrence and 14 patients a disease progression. Estimated 5-year recurrence and progression-free survival were 59% and 81%, respectively. On multivariable analyses, HSP60 staining >65% was associated with a higher risk for progression (hazard ratio [HR] = 3.96, 95% confidence interval [CI] 1.35-11.58, P = 0.012), and HSP70 staining >5% was associated with a decreased risk for progression (HR = 0.33, 95% CI 0.11-0.98, P = 0.045), and recurrence (HR = 0.29, 95% CI 0.13-0.65, P = 0.003). HSP90 expression was not associated with disease recurrence or progression. Five patients had both a HSP60 staining >65% and a HSP70 staining ≤5% all of whom recurred at a median time of 6 months (interquartile range 3, 16) and 80% of whom progressed at a median time of 26 months (interquartile range 5, 60). CONCLUSIONS HSP60 and 70 cellular expression levels are associated with long-term outcome following BCG treatment of T1HG urothelial bladder tumors. These findings, if further validated, may be used to better stratify the risk of disease recurrence and progression in this group of patients.

MP23-11 SURGICAL SITE INFECTION AFTER RADICAL CYSTECTOMY – INCIDENCE AND RISK FACTORS

underwent partial nephrectomy (2 robotic, 1 open). Conversion to open was performed in 3 of the laparoscopic cases. The probability of undergoing laparoscopic nephrectomy significantly increased over time (p1⁄40.063). RESULTS: There were no differences in overall complication rate (38.9% vs. 53.8%, p1⁄40.48), Clavien I and II complications (22.2% vs. 30.8%, p1⁄40.689), Clavien III and IV complications (16.7% vs. 23.1%, p1⁄40.67), readmissions (22.2% vs. 23.1%, p1⁄41.0), or mean operative time (191 vs 209, p1⁄40.31). Blood loss (350 vs. 775, p1⁄4 0.009) and intraoperative transfusion rate (11.1% vs. 53.8%, p 1⁄40.017) were significantly higher in the open group. There were no perioperative mortalities in either group. The mean hospital length of stay was 8 days for the open group and 3.2 in the laparoscopic group (p<0.001). Median follow-up was 47 days. Patients with preoperative glomerular filtration rate of <60, blood loss >1 liter, or hospital stay >9 days were more likely to suffer a major complication or require readmission. CONCLUSIONS: Although early reported experience with laparoscopic nephrectomy for XGP was not favorable, our larger and more contemporary series demonstrates it can be performed safely, with less blood loss and shorter hospital stays. Complication rates and readmission rates are high regardless of approach.