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distinguish two distinct ccRCC subtypes, termed A and B, which could be differentiated with as few as 44 mRNA probes. To validate these results, the 44-probe set was applied to an independent set of tumors on a different array platform. Clinical characteristics and outcomes of tumor subtypes A and B were examined. RESULTS: Clustering of two distinct subtypes of ccRCC was refined to a 44-probe set that was then validated on an independent set of 177 clear cell tumors. Examination of the clinical characteristics of the tumors showed that the patients in both groups were similar in terms of age, gender, stage, and pathologic characteristics, but the two clusters demonstrated a survival benefit for Cluster A compared to Cluster B with a high degree of statistical significance. CONCLUSIONS: This study has identified a simple, reliable and robust means to genetically define ccRCC subtypes with potential to impact prognosis of overall survival. The establishment of this expression signature has the potential to be a tremendous aid in clinical prognostication in ccRCC. Source of Funding: NIH
306 CHROMOSOME 9P DELETIONS IN CLEAR CELL RENAL CELL CARCINOMA ARE ASSOCIATED WITH AGGRESSIVE DISEASE. Jeffrey C La Rochelle*, Aditi Dastane, Nagesh Rao, Tobias Klatte, Brian Shuch, Michela de Martino, Nazy Zomorodian, Fairooz Kabbinavar, Jonathan W Said, Arie S Belldegrun, Allan J Pantuck, Los Angeles, CA INTRODUCTION AND OBJECTIVE: Identifying markers of adverse prognosis is useful in predicting recurrence and will help select patients for additional treatment when effective adjuvant treatements are developed. We investigated whether deletion of chromosome 9p in clear cell renal cell carcinoma (ccRCC) predicts worse disease-specific (DSS) and recurrence-free survival (RFS). METHODS: 316 patients undergoing nephrectomy prior to 2001 were included in a previously constructed tissue microarray (TMA). 9p deletions were detected in these tumors by fluorescent in situ hybridization using a commercially available probe (LSI p16/CEP 9 Dual Color Probe; Vysis, Downers Grove, IL). An additional 389 patients undergoing nephrectomy after 2001 had cytogenetics peformed on fresh tissue retrieved at the time of surgery. Clinical data was recorded, including tumor grade, stage, size, 9p deletion status, nodal involvement, and the presence of metastasis. Disease-specific survival was determined for all patients, and recurrence-free survival was determined for patients with localized disease (N0M0). Outcomes were stratified by 9p deletion status, and a Cox proportional hazards model was constructed using TNM staging, size, grade, and 9p status. For localized disease, the model contained T stage, size, grade, and 9p status. RESULTS: 9p deletions were detected in 97 tumors (14%). Fifty-four percent of 9p-deleted tumors were high grade (G3-4) vs. 38% without 9p deletions (p<0.01). Sixty percent of 9p-deleted tumors were T3-4 vs, 38% without 9p deletions (p<0.01). Fifty-five percent of those with 9p deletions had positive nodes or distant metastases vs. 34% of those without 9p deletions (P<0.01). Median DSS for those with and without 9p deletions was 80 months and 37 months, respectively (p<0.01). 9p deletion status did not have an independent effect on DSS in the overall group (HR 1.2, p=0.18). In localized disease, median RFS for those with 9p deletions was 53 months and was not reached in those without 9p deletions (p<0.01). An independent effect on RFS was seen for 9p deletions in this group (HR 2.3, p<0.01). CONCLUSIONS: Deletion of chromosome 9p in ccRCC is not infrequent and is associated with higher grade, higher T stage, and nodal or distant disease. 9p deletion also independently confers a worse prognosis in localized ccRCC. Identifying patients with 9p deletions allows better risk stratification for surveillance protocols, and eventually for adjuvant trials. Genes on chromosome 9p may be involved with progression of ccRCC. Source of Funding: Novartis
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307 EXPRESSION OF AMIDATED AND NON-AMIDATED PEPTIDES DERIVED FROM PROGASTRIN-RELEASING PEPTIDE IN RENAL CANCERS, AND RENAL CANCER CELL LINES. Joseph Ischia, Damien M Bolton*, Liesl Ischia, Oneel Patel, Rachele Lockie, Graham Baldwin, Arthur S Schulkes, Melbourne, Australia INTRODUCTION AND OBJECTIVE: Tyrosine kinase inhibitors are standard of treatment for advanced renal cell cancer however resistance regularly ensues. Other growth factors potentially stimulating renal cancer include gastrin-releasing peptide (GRP, a 10 amino acid peptide processed from a 125 amino acid prohormone, proGRP, which plays a role in metabolism, organ development and behaviour. Importantly, it has been recognised as a potent mitogen in many tumours including small cell lung, pancreatic, breast and prostate cancer. Amidated GRP (GRP18-27) was thought to be the only biologically active product of proGRP, but it has been shown that fragments from the C-terminal of proGRP are biologically active and may be the predominant form in tumour tissues. While preliminary evidence has linked GRP to renal tumorigenesis, little is known about the expression of the different forms proGRP derived peptides in renal cancer. METHODS: Seven human renal cancer cell lines (ACHN, Caki-1, Caki-2, SKRC-01, SKRC-09, SKRC-17, and SKRC-52) were investigated for their expression of binding sites for amidated GRP18-27 (termed GRP) and two non-amidated fragments from proGRP: proGRP47-68 and proGRP80-97. Immunohistochemistry, radioimmunoassay, and ELISA were used to determine the relative expression of amidated and non-amidated proGRP derived peptides in ACHN, Caki-1, and Caki-2 renal cancer cell lines and in resected human renal cancers. RESULTS: GRP binding sites were found on all cell lines except Caki-1. The level of bound radioactivity ranged from 69cpm/106 cells for SKRC-17 to 885cpm/106 cells for SKRC-52. GRP receptor expression was detected in the same cell lines using immunohistochemistry. Five of the seven cell lines had binding sites for proGRP47-68 or proGRP80-97. Using immunohistochemistry, GRP, proGRP, and GRP receptor were expressed in most renal cancers although expression was often heterogenous within a tumour. RIA and ELISA revealed that ACHN, Caki-1 and Caki-2 cell lines contain non-amidated proGRP fragments but not the fully processed amidated GRP18-27. CONCLUSIONS: Non-amidated proGRP is present in renal cancers and renal cancer cell lines, but not always the fully processed amidated GRP. Receptors for GRP and proGRP are expressed on most renal cancer cell lines and certain renal cancer phenotypes. As GRP and proGRP are known stimulants of cellular proliferation and migration, it is feasible that these peptides are involved in the continuing progression of renal cancers. Source of Funding: Royal Australasian College of Surgeons
308 HEPATITIS C AS A RISK FACTOR FOR RENAL CELL CARCINOMA Craig G Rogers*, Manish N Patel, Lois Lamerato, Stuart Gordon, Detroit, MI INTRODUCTION AND OBJECTIVE: Chronic hepatitis C virus (HCV) is associated with liver and lymphoproliferative diseases as well as chronic kidney disease. We observed a higher than expected prevalence of HCV infection among patients with renal cell carcinoma (RCC) by examining our health system cancer registry. We found that 33/765 (4.3%) consecutive RCC cases diagnosed between 1997 and 2007 were HCV seropositive. We therefore sought to determine whether HCV confers an increased risk for the development of RCC. METHODS: We used administrative data from a large integrated health care system to explore the incidence of RCC among HCV infected persons. Adults testing anti-HCV positive (HCV +) between 1997 and 2006 were compared to a control cohort testing anti-HCV negative (HCV) during the same time period; HBsAg and HIV positive patients were excluded. Data from the system’s registry identified all RCC patients
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diagnosed between 1997 and April 2008. HCC and colorectal breast and prostate neoplasms were examined as controls. Logistic regression was used to calculate the unadjusted Odds Ratio (OR) with 95% confidence intervals (CI) for HCV status and cancer, and the adjusted odds ratios in multivariate models adjusting for age, gender, race, and kidney disease. Kaplan-Meier curves were used to show the probability of remaining free from cancer over the observation period of the cohort. RESULTS: The cohort consisted of 67,063 pts with 4.6% HCV+ (n=3,057) and 64,006 HCV negative. Males and African Americans (AA) had a higher prevalence of HCV (5.8% males vs. 3.4% females, p<0.001 and 6.6 % AA vs. 3.1 % non-AA, p<0.001). The mean age of HCV+ patients was older than the HCV-(52 vs. 48, p<0.001). There were 177 RCC patients (.3/100) in the unaffected vs. 17 (.6/100) in the HCV+ group. The unadjusted OR for RCC was 1.42 (CI: 1.107, 1.822, p<0.01). The mean age at RCC diagnosis was much younger in HCV+ individuals (53 vs 63, p<0.01). When adjusting for age, race, gender and presence of kidney disease, the overall OR for HCV among RCC patients was 1.4 (CI: 1.009, 1.676, p< 0.05). The Kaplan-Meier curve showed a statistically increased risk for RCC in the HCV+ group (log-rank p-value = 0.002). CONCLUSIONS: Chronic HCV is associated with a higher incidence of renal cell carcinoma than non-infected persons. Potential limitations include unmeasured risk factors, a referral bias at a tertiary medical center and disproportionate numbers of dialysis patients in the tested cohort; larger studies are required to confirm these findings. Source of Funding: None
Pediatrics: Congenital Anomalies - Lower Urinary Tract & Genitalia (I) Moderated Poster 11 Sunday, April 26, 2009
10:30 am - 12:30 pm
309 HOW DO TOILET-TRAINED KIDS VOID FOLLOWING TUBULARIZED INCISED PLATE REPAIR OF HYPOSPADIAS? Waleed Eassa*, Fayez Almodhen, Alexander Brzezinski, Jean Paul Capolicchio, Roman Jednak, Mohamed T El-Sherbiny, Montreal, QC, Canada INTRODUCTION AND OBJECTIVE: We report the functional outcome of asymptomatic, toilet trained children following uncomplicated tubularized incised plate (TIP) repair of hypospadias. METHODS: The records of patients who underwent a TIP repair of hypospadias at the Montreal Children Hospital between April 1997 and September 2007 were reviewed. Patients were included if they were toilet trained, asymptomatic and had flow rate data done more than 1year after TIP. Children with postoperative complications or those who required dilation were excluded. Variables predictive of outcome including the surgeon, the type of hypospadias, the presence of a hypoplastic urethra, reinforcement stitches, spongioplasty and the use of a stent were recorded. Uroflow data (peak flow, voided volume and post-void residuals (PVR) were analyzed and plotted on previously determined age-volume dependent nomograms. RESULTS: Fifty-six patients were eligible for the study. Median age at surgery was 1.5 years. Hypospadias was distal penile in 49 (87%) and mid and proximal penile in 7 (13%). Mean follow up was 3±1 years (18) years. The uroflow curve was bell shaped in 14 (25%), interrupted in 8 (14%), slightly flattened in 28 (50%) and plateau in 6 (11%). Nomograms showed that 36 (64%) were in the 80th percentile, 11 (20%) were in 95th percentile range and 9 (16%) were plotted below 5th percentile. PVR was > 10% of bladder capacity in 23 (41%). Examining the curve shape, nomograms and PVR data against variables predictive of outcome, did not generate any statistical difference outputs. CONCLUSIONS: Although asymptomatic, the majority of children after TIP repair have flattened uroflow curve of whom 41% inefficiently
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empty their bladders and 16% have peak flow plotted below 5th percentile. The long-term outcome after puberty remains to be determined. Source of Funding: None
310 A LONGITUDINAL OBSERVATIONAL STUDY OF FLOW RATE (FR) PARAMETERS IN A COMPLICATION-FREE DISTAL HYPOSPADIAS COHORT FOLLOWING TUBULARIZED INCISED PLATE (TIP) REPAIR Yaser El-Hout*, Darius J Bagli, Walid A. Farhat, Toronto, ONCanada; Luis H. Braga, Hamilton, ONCanada; Joao L. Pippi Salle, Armando J. Lorenzo, Toronto, ON, Canada INTRODUCTION AND OBJECTIVE: Uroflowmetry (UF) remains an objective evaluation of functional outcome following hypospadias repair in toilet trained patients (pts). Longitudinal studies demonstrating the evolution of flow rate parameters would be a useful determinant of neourethral function over time. We attempt to compare at least two postoperative FR in distal hypospadias pts following TIP repairs. METHODS: Postoperative hypospadias pts visiting our clinic over the last year were identified. A convenience sample was selected to include only pts after uncomplicated distal TIPs. This population was selected to avoid confounding factors. Data was collected retrospectively, including initial meatus location, age at surgery and follow-up, peak FR(Qmax), average FR(Qav), voided volume(Vv), post-void residual volume(PVR), and shape of the voiding curve (flat, bell-shaped or intermittent). The earliest available FR and the FR on last follow-up were compared. RESULTS: Analysis included 41 pts. Initial location of meatus was 7 glanular, 7 coronal, 13 subcoronal, 4 distal penile and 10 midshaft. Age on last follow-up was 69.7 months with a mean follow-up of 44 months and a mean interval of 27.6 months between uroflows. Flow parameters were compared: 7.3 vs. 9.1 mL/sec, 5.3 vs. 6.1 mL/sec, and 123 vs. 185 mL for early vs. last Qmax, Qav, and Vv, respectively (p <0.01). Early vs. last PVR were 7.8 vs.7.7 mL (p=0.8). When adjusted for Vv, (Qmax/ Vv0.29, Qav/Vv0.41), and plotted against age, Qmax and Qav maintained an increasing trend. Voiding curves were 26 flat, 10 bell-shaped and 5 intermittent on early study, and shifted to 15 flat, 15 bell-shaped and 11 intermittent on last follow-up. Of note, 37% of the initially flat curves became bell-shaped, and 30% of the initially bell-shaped curves became intermittent. CONCLUSIONS: In this population, FR parameters changed over time, even after adjustment for voided volume and age. Evolution of curve shapes warrants further evaluation. Variation of these parameters over time is of importance when considering UF as an outcome measure in hypospadias. Source of Funding: None
311 SATISFACTION WITH VOIDING, APPEARANCE, AND SEXUAL FUNCTION IN ADOLESCENTS AFTER HYPOSPADIAS REPAIR DURING CHILDHOOD Akihiro Nakane*, Yutaro Hayashi, Satoshi Kurokawa, Hideyuki Kamisawa, Makoto Imura, Kentaro Mizuno, Toshiki Kato, Yoshiyuki Kojima, Tetsuji Maruyama, Kenjiro Kohri, Nagoya, Japan INTRODUCTION AND OBJECTIVE: Hypospadias surgery can adversely affect the future sexual life of a patient. We aimed to study whether erection, ejaculation, voiding, and appearance were satisfactory in adolescents who had undergone hypospadias repair during childhood. We also sought to identify the kinds of problems and dissatisfaction associated with the long-term outcome of the surgery. METHODS: A detailed questionnaire was conducted among 44 patients over 10 years old who had undergone hypospadias repair between 1979 and 2002. Patients with intersex were excluded from the study even though they had a hypospadiac meatus. The same questionnaire was sent to 20 male patients (age-matched controls) over 10 years old who visited our hospital and had no history of hypospadias or any other penile disease.