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e16089 Background: There is a large unmet need for novel drug delivery systems and effective therapy for UTUC, especially for patients with CKD and anatomic solitary kidneys. A temperature sensitive water-soluble gel formulation of Mitomycin C (MMC) demonstrated increased drug delivery time (4 to 6 hrs) and safety in the pelvicalyceal system of swine and human bladders. We report the efficacy and safety of gel+MMC as primary treatment (tx) of UTUC on a compassionate use basis. Methods: Compassionate use approval was obtained on an individual patient basis from the respective regulatory authorities and IRBs. 22 patients were approved for tx to date from 14 institutions in 4 countries. Tx included 6 weekly instillations instilled via ureteral catheter or percutaneous nephrostomy. Gel volume ranged from 5-20cc and MMC concentration was 2-6 mg/cc. Adverse events were recorded throughout treatment. Ureteroscopy was performed 2-6 weeks following tx completion for response determination. Results: Median age of the cohort was 75 yrs, with 15 males. 18 patients (pts) had low-grade (LG) tumor, 2 high-grade (HG), and 2 indeterminate grade. 16 (73%) completed treatment - 9 pts had a complete response, CR (41%; 59% of those who completed tx), 5 pts had a partial response, PR (23%; 31%), and 2 pts had no response, NR (9.1%, 12.5%). 4 patients could not complete tx due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition), 1 patient was diagnosed with a non-urothelial cancer during treatment, and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with MitoGel. A total of 77 adverse events were recorded with 6 events related to MitoGel and serious (requiring intervention), and 21 events related to treatment and not serious. CR (9) and PR (5) were observed in 14 of 15 evaluable patients completing treatment for LG tumors. Conclusions: This compassionate use program of a thermosensitive gel+MMC for chemoablation of UTUC demonstrates proof of concept for treatment of low-grade tumors. A single arm Phase III multi-center registration trial to treat patients with low-grade renal pelvis tumors has been activated.

Purpose Imiquimod is a toll-like receptor agonist with proven antitumor activity as a topical treatment for skin cancer. TMX-101 (Vesimune) is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non–muscle-invasive bladder cancer in a phase 1 clinical trial. We report the results of a phase 2 prospective multicenter clinical trial assessing the safety and activity of TMX-101. Materials and methods Patients with non–muscle-invasive bladder cancer containing carcinoma in situ were eligible for inclusion. Enrolled patients received 6 weekly intravesical administrations of 200 mg/50 ml TMX-101 0.4%. End points included rate of adverse events, changes in urinary cytokine levels following treatment, and clinical response at 6 weeks following final instillation, defined as negative posttreatment bladder biopsy and urine cytology results. Results A total of 12 patients were enrolled, with 10 available for efficacy analysis. Half of the patients (6/12) had received≥2 prior induction courses of bacillus Calmette-Guerin. All patients received all 6 doses of TMX-101 per protocol. Overall, 75% of patients experienced treatment-related adverse events, only 1 of which was>grade 2 (urinary tract infection). Furthermore, 2 patients demonstrated a negative cytology and biopsy result at 6 weeks following treatment. Significant increases in urinary cytokines, including IL-6 and IL-18, were seen following treatment. Conclusion In this phase 2 pilot study in patients with carcinoma in situ bladder cancer, intravesical TMX-101 was safe and well tolerated with common, mild genitourinary adverse effects. Clinical activity was suggested by the increase in posttreatment urinary cytokines. Complete responders were seen. Further investigation of the agent is warranted.

Purpose: High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2. Experimental Design: Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with “good” predictive pathologic features based on an “integrated selection” model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results: One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%–33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC. Conclusions: In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both “good” and “poor-risk” patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation. Clin Cancer Res; 21(3); 561–8. ©2014 AACR.

Objective: Accurate postoperative stratification of patients with renal cell carcinoma (RCC) in distinct prognostic groups is essential for tailoring follow-up, medical therapy, and inclusion in clinical trials. Increasing evidence suggests that Onodera's prognostic nutritional index (PNI) is a stage- and grade-independent predictor of poor outcomes in patients with cancer, but there are no data in RCC. Materials and methods: We reviewed medical records of 1,344 patients with RCC who underwent radical or partial nephrectomy at the Medical University of Vienna and the University of California—Los Angeles between 1991 and 2012. Associations with cancer-specific survival were assessed with univariable and multivariable Cox proportional hazards models. Discrimination was measured with the C-index. Results: The median postoperative follow-up was 40 months. An increase of PNI by 1 unit was associated with a decrease in the risk of death from RCC by 7% (hazard ratio ¼ 0.93, P o 0.001). In multivariable analyses, the PNI was an independent prognostic factor (P o 0.001). Adding the PNI improved the discrimination of a base model by 0.4%. Conclusions: The PNI is an independent prognostic factor in patients with RCC. Its use increases the accuracy of established prognostic factors. PNI may be a meaningful adjunct for tailoring surveillance, medical therapy, and clinical trial design. r 2014 Elsevier Inc. All rights reserved.

cancer with the recognition that it represents not a single entity but rather a family of tumors having a wide spectrum of behaviors and risks, while advances and increased utilization of abdominal imaging and clinical staging have led to the increased detection of incidental, lower stage, organ-confined, often indolent tumors more amendable to expanded surgical options. New research results have challenged even the concept of surgery for all rCCs itself, advocating the initial deferment of active treatment in elderly patients and in those with significant comorbidities [2]. Surgical techniques themselves have evolved to include routine use of nephron sparing techniques even in the presence of a normal contralateral kidney, and both radical and partial nephrectomy have themselves further evolved to include laparoscopic and robotic-assisted minimally invasive approaches, while advances in the development of energy ablative technology such as cryotherapy and radiofrequency ablation that can be delivered percutaneously have advanced to make possible new methods of managing renal tumors in situ. thus, the surgical management of rCC has changed dramatically approaches to the surgical treatment of renal cell carcinoma (rCC) are rapidly evolving. the foundations for what became the generally accepted principles underlying the surgical management of rCC for the latter third of the twentieth century were first annunciated in 1969 by robson et al. [1] in his classic paper describing the radical nephrectomy. Since that era, when the majority of renal tumors were large and already locally advanced at the time of diagnosis, much has changed in our understanding of the basic biology of kidney

bladder tumors Karim Chamie*, Allan J. Pantuck, Los Angeles, CA, Joel S. Bass, Herbert I. James, Vladimir B. Mouraviev, Syracuse, NY, Thomas J. Guzzo, Philadelphia, PA, Robert L. Grubb III, Saint Louis, MO, William W. Bohnert, Scottsdale, AZ Abstract: MP61-17 Introduction and Objectives Since localization of bladder tumors can vary significantly based on bladder volume and capacity, enthusiasm over targeted radiotherapy has been muted. As a result, radiotherapy as a definitive treatment option for patients with invasive bladder cancer is underutilized in the United States. In this context, we sought to evaluate the utility of a novel absorbable hydrogel as a fiducial marker designed for simple cystoscopic application and stability within the bladder wall.

INTRODUCTION AND OBJECTIVES: Urine aquaporin-1 (AQP1) is elevated in patients with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) when compared to chromophobe renal cell carcinoma (chRCC), oncocytoma (Onco), and angiomyolipoma (AML). We propose an algorithm that uses AQP1 to prevent the resection of benign renal lesions by placing patients with elevated AQP1 into a treatment arm while performing a renal mass biopsy on patients with normal AQP1 levels. METHODS: Pre-operative urine AQP1 was obtained from 57 patients with renal masses less than 4cm prior to resection. Retrospective comparisons of the pre-operative AQP1 and post-operative pathology allowed for a marker cut-off value that maximized the specificity of AQP1 for detecting ccRCC and pRCC. AQP1’s potential to direct patients into the treatment or renal biopsy arm of the algorithm was assessed. RESULTS: Pathology for the 57 renal masses included 34 ccRCCs, 8 pRCCs, 2 chRCCs, 7 Oncos, and 6 AMLs. A cut-off value of 5 for AQP1 resulted in 100% specificity, 95.2% sensitivity, 100% positive predictive value, and an 88.2% negative predictive value for detecting ccRCC or pRCC. If the algorithm was followed, then 40 patients with ccRCC and pRCC would undergo surgical removal of their mass with no patients with benign lesions undergoing unnecessary treatment. Two patients with ccRCC and all patients with chRCC, Onco, and AML would have been directed into the biopsy arm. CONCLUSIONS: Urine AQP1 could be used in conjunction with renal mass biopsies to prevent the unnecessary treatment of benign, small renal masses.

Evanguelos Xylinas*, Luis Kluth, Malte Rieken, New York, NY; Tobias Klatte, Vienna, Austria; Yair Lotan, Dallas, TX; Eiji Kikuchi, Tokyo, Japan; Alon Weizer, Ann Harbor, MI; Mesut Remzi, Vienna, Austria; Jay Raman, Hershey, PA; Karim Bensalah, Rennes, France; Francesco Montorsi, ilano, Italy; Vitaly Margulis, Dallas, TX; Juan-Ignazio Martinez-Salamanca, Madrid, Spain; Morgan Roupret, Marc Zerbib, Paris, France; Shahrokh Shariat, Vienna, Austria

To investigate whether imaging features on multiphasic multidetector computed tomography (MDCT) can predict the loss of chromosome 8p in clear cell renal cell carcinomas (RCCs), a cytogenetic abnormality associated with a higher tumor grade and greater risk of recurrence. With IRB approval for this HIPAA-compliant retrospective study, we queried our institution’s pathology database to derive all histologically proven cases of clear cell RCC with preoperative multiphasic MDCT with as many as four phases (unenhanced, corticomedullary, nephrographic, and excretory) from January 2000 to July 2010. Of 170 clear cell RCCs with preoperative multiphasic MDCT, 105 clear cell RCCs, representing 98 unique patients, had karyotypes of the resected specimens. Lesions were evaluated for magnitude and pattern of enhancement, contour, neovascularity, calcifications, and size. The corticomedullary phase mean enhancement of clear cell RCCs with a loss of 8p was significantly greater than that of clear cell RCCs without a loss of 8p (169.5 vs. 127.2 HU, p = 0.004). A threshold of 165 HU predicted the loss of 8p in clear cell RCCs with an accuracy of 78% (69/88), a specificity of 81% (62/77), and a negative predictive value of 94% (62/66). There were no significant differences in the pattern of enhancement, contour, neovascularity, calcification, or size between clear cell RCCs with a loss of 8p and those without this abnormality. Enhancement on multiphasic MDCT can predict the loss of 8p in clear cell RCCs and can thus provide a non-invasive means of guiding further management, including surgery, ablation, watchful waiting, or medical management.

Purpose: To determine oncologic outcomes and predictors of primary efficacy, including RENAL nephrometry scores (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines), after percutaneous radiofrequency (RF) ablation of proven renal cell carcinoma (RCC). Materials and Methods: Patients who underwent percutaneous computed tomography– and ultrasound-guided RF ablation for histologically proven RCC from 2004 to 2011 were evaluated. Clinical data, pathologic findings, technical details, and outcomes were reviewed. Univariate and multivariate logistic regression analysis was performed to determine predictors of primary technique effectiveness and complications. Local tumor progression–free, metastasis-free, and overall survival were calculated. One hundred RCC lesions underwent 115 RF ablation sessions in 84 patients. Median follow-up was 24 months (mean, 27 mo; range, 1–106 mo). Results: Efficacy of RF ablation was defined per International Working Group of Image-Guided Tumor Ablation criteria. Total, primary, and secondary technique effectiveness rates were 95% (95 of 100), 86% (86 of 100), and 9% (nine of 100), respectively. Primary efficacy was associated with size (P o .001), proximity to collecting system (P ¼ .001), RENAL nephrometry score (P o .001), and number of ablation zones (P o .001). Complications occurred in 13% of patients, without procedure-related deaths. The median 2.1-year local progression–free, metastasis-free, disease-specific, and overall survival rates were 86%, 98.7%, 100%, and 97.6%, respectively. Conclusions: Percutaneous image-guided RF ablation for RCC provides excellent intermediate oncologic control. Location, size, proximity to the collecting system, low RENAL nephrometry score, and number of ablation zones predict primary efficacy.

All histological subtypes of renal cell carcinoma (RCC) are capable of undergoing sarcomatous transformations that result in tumors with distinctive appearances and aggressive biologic behavior. The history of sarcomatoid renal cell carcinoma (SRCC) is traced from the time when it was thought to be a true sarcoma to the present when its epithelial origin is fully appreciated. The distinctive macroscopic and microscopic features as well as various diagnostic methods are reviewed. A description of the complex genetic aberrations associated with various types of RCC are summarized. It is apparent that the chromosomal changes known at this time are common to both SRCC and classic RCC while the unique alterations that lead to the sarcomatoid transformation remain unknown. The mode of presentation, the clinical behavior, and the prognostic factors common to SRCC are also reviewed. Finally, the various modalities that have been examined for the treatment of SRCC are detailed to evaluate for patient response and overall improvement in survival. A comparison of the treatment methods suggest that high-dose recombinant interleukin-2 may hold the greatest promise in improving the dismal prognosis associated with this disease.

The discovery of genes involved in malignant transformation and tumor growth has lead to the development of anti-cancer gene therapies. In addition, new modifications to immune based therapy have recently been developed. In this review, we focus on modern genetic and immunologic approaches to the treatment of urologic malignancy. We summarize new developments in vectors, tumor suppressors, suicide genes, gene based immunotherapy, tumor vaccines, dendritic cell therapy, and graft vs. tumor therapy. Additional topics described include prostate antigens and prostate specific promoters. Pre-clinical and clinical trials that utilize these therapies are summarized.

Purpose: Our understanding of the natural history of renal cell carcinoma, the role of nephrectomy, the benefits of immunotherapy and the possibilities of new technologies are evolving and being integrated with advances in classification and staging. We reviewed the relevant literature to clarify these pertinent questions and provide a current review of the changes in the epidemiology, treatment and prognosis of patients with renal cell carcinoma.Materials and Methods: We comprehensively reviewed the peer reviewed literature on the current management of and results of treatment for renal cell carcinoma.Results: The incidence of and mortality from renal cell carcinoma have continuously increased during the last 50 years. Despite this increase in the number of new patients and consequently the number of deaths yearly the percent of those surviving for 5 years has notably improved. Factors related to improved survival include advances in renal imaging, earlier diagnosis, improved staging, better understandin...

Conventional therapy for metastatic renal cell carcinoma is associated with a poor response rate and few patients are long-term survivors. The occurrence of spontaneous regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune responses to autologous tumor cells. With the advent of molecular gene transfer techniques and increased knowledge of the basic pathways of immune activation, the field of cancer immunotherapy has finally begun to develop novel and effective approaches for harnessing the immune system as a therapeutic agent. Current immunotherapy and gene therapy strategies, including methods of cytokine delivery and tumor-cell-based vaccines, are presented.

Purpose: We analyzed the effects of the change in TNM classification from the 1987 to the 1997 version and suggest a modified tumor size cutoff point between T stages 1 and 2 for renal cell carcinoma.Materials and Methods: We evaluated a database containing the records of 661 patients who underwent nephrectomy between 1989 and 1999. The effect of the change in TNM classification on the distribution of patients between stages, the rates of M+ and N+ disease, and the local and distant recurrence rates were outlined for 280 patients with T stages 1 and 2 disease. The Cox model was used to identify the optimal cutoff point between T1 and T2 disease, and the resulting effect of adopting this cutoff was outlined.Results: A total of 174 and 128 cases were down staged from 1987 version stage T2 to 1997 version stage T1 and from 1987 TNM stage II to 1997 TNM stage I, respectively. Survival was not significantly different in patients with 1997 TNM stages I and II disease due to a lack of survival difference during ...

The realization that prostate cancer is an immunogenic tumor, in conjunction with the discovery of novel methods for priming the immune system to generate an antitumor response, has resulted in several new approaches for prostate cancer immunotherapy. Based on these various approaches, several human clinical trials have begun using immune-based therapies for prostate cancer. These approaches can be divided into cytokine-based therapies, tumor-associated antigen-based therapies, tumor vaccines, and dendritic cell-based therapies. This review summarizes the latest findings from each of these approaches and gives results from the few completed human clinical trials.

The incidence of renal cell carcinoma (RCC) is rising steadily, but the ability to cure patients with metastatic RCC unfortunately remains limited. Emerging interest in gene therapy performance and safety is expressed by patients, medical institutes, and other agencies. It has become evident that better understanding of the genetic impairments and immune pathophysiology in RCC is essential for future improvement in patient care. Clinical trials now underway that are focusing on genetic and immune impairments will hopefully lead to future breakthroughs in RCC therapy. This paper reviews available gene therapies and other related therapeutic approaches for RCC and lists some of the current clinical trials focused on molecular-based therapies.

Purpose: The mechanisms responsible for tumor progression to androgen independence in prostate cancer (CaP) remain unknown. To characterize these changes and provide a basis for rational therapeutic strategies for advanced CaP, an in vivo model from a highly aggressive androgen independent CaP cell line with distinct cellular and molecular properties was developed.Materials and Methods: An aggressive androgen-independent cell line designated CL1 was derived from a slow-growing, and androgen-dependent, parental LNCaP cell line through in-vitro androgen-deprivation and selection. CL1 was stably transfected with a green fluorescence protein gene (CL1-GFP) and orthotopically injected into SCID mice. The pathologic behavior, histology, and molecular determinants of CL1 tumor and metastases were determined and characterized by standard light and fluorescent microscopy, and quantitative RT-PCR analysis.Results: CL1 is an anaplastic prostate cancer cell line which demonstrates extensive local invasion and metasta...

Controversy exists over the importance of antireflux mechanisms in large volume, low pressure intestinal bladder substitutions. Despite the theoretical benefits of reflux prevention, antirefluxing ureteral reimplantations may have a greater risk of anastomotic stricture. We hypothesize that this inherent stricture rate may outweigh the potential benefits associated with reflux prevention. To assess this question critically we compare our results to those of direct and nonrefluxing techniques of ureterointestinal anastomosis during continent diversion.Between 1990 and 1998, 58 patients underwent continent urinary diversion using an Indiana pouch or ileal orthotopic neobladder following cystectomy for muscle invasive bladder cancer. A total of 56 renal units were implanted using an end-to-side Nesbit direct anastomosis and 60 were implanted in a nonrefluxing manner. Clinical end points included anastomotic stricture formation, hydronephrosis, pyelonephritis, upper tract stone formation and renal deterioration, and were assessed with a mean followup of 41 months.Of 60 nonrefluxing ureteroenteric anastomoses 8 (13%) resulted in nonneoplastic stricture formation compared to 1 of 56 (1.7%) direct anastomoses, which was statistically significant (Fisher's exact test p0.05). Strictures occurred up to 6 years following the original surgery. There was no significant difference between the 2 groups in regard to hydronephrosis, pyelonephritis, upper tract stone formation or azotemia.Nonrefluxing methods of ureterointestinal reimplantation resulted in a statistically significant higher rate of anastomotic stricture than the end-to-side direct anastomosis. This finding appears to outweigh any theoretical benefits of preventing pyelonephritis, stones or azotemia. For patients undergoing large volume, low pressure continent diversion the refluxing ureterointestinal anastomosis may be the technique of choice since it preserves renal function as well as the nonrefluxing method, is technically easier to perform and poses less risk of stricture. Delayed stricture formation years after surgery underscores the necessity for long-term radiological followup in patients following continent diversion.

Experts’ summary: This multi-institutional, double-blind, randomized, phase 3 study evaluated the efficacy of everolimus (RAD-001) as compared with placebo in patients with metastatic clear-cell renal cell carcinoma (RCC) who had progressed while on or within 6 mo of stopping vascular endothelial growth factor (VEGF)–targeted therapy (eg, sunitinib and/or sorafenib). The primary outcome of interest was progression-free survival, defined as the time from randomization to documented progression of disease or death, regardless of cause. Secondary end points of the study included overall survival, drug safety, objective tumor response rate based on measurable lesions, symptoms related to disease, and quality of life (QoL) evaluation. Overall, 272 and 138 patients were randomized to receive everolimus or placebo, respectively. An intention-to-treat analysis was used, and patients were stratified based on previous anti-VEGF therapy and Memorial Sloan-Kettering Cancer Center prognostic score. Although the study was designed to stop after 290 documented progression events, findings demonstrated a significant efficacy of everolimus over placebo at the second interim analysis; therefore, the study was discontinued after only 191 observed progression events. Patients receiving everolimus demonstrated both a decreased risk of progression (hazard ratio [HR]: 0.30; 95% confidence interval [CI]: 0.22–0.40) and increased median progression-free survival (4.0 versus 1.9 mo) compared with those receiving placebo, and this effect was seen across all subgroups. There was no significant difference in overall survival between the two groups, but this was likely due to a majority of the placebo arm crossing over to the everolimus group once disease progression had occurred. Although adverse events were more common in the everolimus group, no difference in health-related QoL was seen between the two arms.

Purpose: Prostate cancer foci have a characteristic appearance on endorectal magnetic resonance imaging (MRI) which might be useful for prostate cancer detection. In this pilot study the ability of endorectal MRI to detect prostate cancer foci prospectively in men at risk for a malignant prostatic neoplasm is assessed.Materials and Methods: Endorectal MRI was performed in 33 consecutive men with 1 or more prior negative prostatic biopsies. All studies were read by 2 MRI dedicated study radiologists in consensus before and after receiving patient clinical data. Areas of interest on endorectal MRI were mapped as low, moderate or high suspicion for carcinoma on a prostate model. Directed needle biopsy cores of the prostate were obtained based on this model, and the histopathological findings were compared with MRI results.Results: Carcinoma was detected in 7 of 33 men (21.2%) on post-MRI biopsy, including 1 of 18 (5.6%) with low, 1 of 8 (12.5%) with moderate and 5 of 7 (71.4%) with high suspicion MRI...

Urethral adenocarcinoma is a rare malignancy whose origin remains controversial. The monoclonal antibody mAbDas1 (formerly 7E12H12) was developed against a unique colonic epithelial epitope and is reactive in areas of intestinal metaplasia. Recently the antibody was shown to react in cystitis glandularis as well as adenocarcinoma of the bladder, suggesting that cystitis glandularis may be the precursor of bladder adenocarcinoma. We examined urethral adenocarcinomas and benign urethral specimens using mAbDas1 to determine whether it could provide insight into their histogenesis.Archival tissue from 12 cases of primary female urethral adenocarcinoma and urethral specimens of inflamed urethral mucosa, urethritis glandularis and transitional cell carcinoma was studied. Immunohistochemical analysis of formalin fixed, paraffin embedded archival tissue was done using the monoclonal antibody mAbDas1. Tumors were also evaluated with a prostate specific antigen (PSA) polyclonal antibody as previous studies have noted PSA reactivity in these tumors.Of the 12 cases 9 were columnar/mucinous adenocarcinoma, 2 clear cell adenocarcinoma and 1 a cribriform pattern resembling adenocarcinoma of the prostate. All columnar/mucinous adenocarcinomas reacted positively (6 strongly and 3 focally) with the mAbDas1 antibody but did not react with the PSA antibody. The tumor with a cribriform pattern reacted strongly with PSA but did not react with mAbDas1. The 2 clear cell adenocarcinomas did not react with either antibody. The benign urethral specimens demonstrated strong reactivity to the mAbDas1 antibody in areas of urethritis glandularis but normal and inflamed urethral mucosa and transitional cell carcinoma did not react.Primary adenocarcinoma of the female urethra arises from more than 1 tissue of origin. Columnar/mucinous adenocarcinomas of the female urethra and urethritis glandularis demonstrate consistent reactivity with the mAbDas1 antibody, suggesting that these tumors arise from glandular metaplasia analogous to the potential histogenesis previously demonstrated in the bladder. PSA reactivity occurred in 1 tumor with a cribriform pattern and likely represents origin from Skene's glands. Clear cell adenocarcinomas did not react with either antibody, suggesting a third possible pathway in the development of this rare subset of adenocarcinomas.

Primary adenocarcinoma of the bladder is a rare neoplasm whose histogenesis is poorly understood. Current data support the concept that adenocarcinoma of the bladder and urachus evolves from zones of intestinal metaplasia that become dysplastic and invasive. To address this hypothesis further we determined the immunoreactivity of benign and malignant epithelial tissue from the bladder and urachus with a monoclonal antibody that is reactive with colonic epithelium to evaluate the presence of a common reactive epitope.The monoclonal antibody 7E12H12 (IgM isotype), developed against a colonic epithelial protein, was used in an immunoperoxidase assay to survey formalin fixed, paraffin embedded archival tissue specimens. A total of 26 specimens obtained by endoscopic biopsy or extirpative surgery, including benign and malignant bladder and urachal epithelial abnormalities, was chosen for retrospective evaluation.All adenocarcinoma reacted positively regardless of the histological variant, differentiation, or bladder or urachal origin. In contrast, transitional cell and squamous cell carcinomas were nonreactive. Also, the pattern of reactivity in tissues that contained benign epithelial proliferations suggested a stepwise transition with no reactivity in normal urothelium or Brunn's epithelial nests, rare staining of cystitis cystica, and uniformly positive reactivity in cystitis glandularis and frank colonic intestinal metaplasia of the bladder and urachus.The shared, aberrant phenotypic expression of a unique colonic epitope in benign epithelial metaplasia, and adenocarcinoma of the bladder and urachus suggests a common underlying pathway toward adenocarcinoma in cystic and urachal adenocarcinoma. The implications for diagnostic pathology are discussed.

Pre-clinical studies have implicated hypoxia inducible factor (HIF)-2α as an important oncogene for clear cell renal cell carcinoma (ccRCC). Generally considered to act as a nuclear transcription factor, a recent study has also implicated HIF-2α as a protein translational initiation complex function within the cytoplasm (Uniacke et al., 2012). We hypothesised that both the absolute expression as well as the sub-cellular localisation of HIF-2α would predict clinicopathological features and cancer specific survival (CSS) in ccRCC.A tissue microarray (TMA) study was conducted on three hundred and eight ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values.High HIF-2α nuclear (N) (cutoff32%) expression was associated with smaller tumour sizes (p=0.002) and lower Fuhrman grades (p=0.044), whereas tumours with high cytoplasmic (C) HIF-2α (0%) more often had positive lymph nodes (p=0.004), distant metastases (p=0.021) and higher Fuhrman grades (p0.0001). After adjustment for TNM stage, Eastern Cooperative Oncology Group performance status (ECOG PS), and Fuhrman grade, both continuous (p0.0001) and dichotomised (p0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained.Our investigation supports that HIF-2α may have a unique tumour promoter role in the cytoplasm. This preliminary finding justifies further experimental and mechanistic studies that examine the biological functions of HIF-2α when located in the cytoplasm.

The over-arching objective of this research project is to identify a panel of diagnostic miRNAs that are measurable in serum and will be able to identify kidney cancer in its earliest stages. We hypothesized that serum levels of miR-21O would be significantly elevated in patients with clear cell renal carcinoma and that a panel of serum miRNAs could be defined and optimized for use as a diagnostic tool in patients presenting with a renal mass. To achieve this objective, we proposed three Specific Aims to test our hypotheses. Institutional IRB approvals have been obtained (Specific Aim 1, task 1). Retrospectively collected samples have been transferred and analyzed (Specific Aim 1, task 3). Prospective sample collection has been completed (Specific Aim 3, task 1). Task 2 will be completed by Initiating PI (Tewari) during the remainder of this no-cost grant extension necessitated by his relocation to the University of Michigan.

Pomegranates slow prostate cancer xenograft growth and prolong prostate-specific antigen (PSA) doubling times in single-arm human studies. Pomegranates' effects on human prostate tissue are understudied. We hypothesized that orally administered pomegranate extract (POMx; Pom Wonderful) would lower tissue 8-hydroxy-2′-deoxyguanosine (8-OHdG), an oxidative stress biomarker. Seventy men were randomized to two tablets, POMx or placebo, daily up to four weeks before radical prostatectomy. Tissue was analyzed for intraprostatic urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NF-κB, and Ki67. Primary endpoint was differences in 8-OHdG, and the study was powered to detect 35% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (P = 0.095), which was not statistically significant. POMx was well tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21 of the 33 patients in the POMx group versus 12 of the 35 in the placebo group (P = 0.031). Cancer pS6 kinase, NF-κB, Ki67, and serum PSA changes were similar between arms. POMx before surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary endpoint in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitively test whether POMx reduces prostate oxidative stress, as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology. Cancer Prev Res; 6(10); 1120–7. ©2013 AACR.

An in-depth understanding of metastatic renal cell carcinoma (mRCC) is important so that practitioners can make informed evidenced-based decisions with patients to optimize not only quantity of life but quality of life as well. Therefore, this review focuses on the biology of mRCC as it relates to targets for therapy, as well as on the small molecules rationally designed with these targets in mind. In addition, anticipated emerging therapies are highlighted, including the new tyrosine kinase inhibitors axitinib and tivozanib, as well as new immune-based therapies such as dendritic cell-based vaccines and antibodies. We also briefly review recent reports from the emerging field of predicting drug response based on molecular markers. And finally, management of metastatic non-clear cell RCC histologies are discussed focusing on available evidence to direct decision making when assessing therapeutic options.

To determine whether enhancement at multiphasic multidetector computed tomography (CT) can help differentiate clear cell renal cell carcinoma (RCC) from oncocytoma, papillary RCC, and chromophobe RCC.With institutional review board approval for this HIPAA-compliant retrospective study, the pathology database was queried to derive a cohort of 298 cases of RCC and oncocytoma with preoperative multiphasic multidetector CT with as many as four phases (unenhanced, corticomedullary, nephrographic, and excretory). A total of 170 clear cell RCCs, 57 papillary RCCs, 49 oncocytomas, and 22 chromophobe RCCs were evaluated for multiphasic enhancement and compared by using t tests. Cutoff analysis was performed to determine optimal threshold levels to discriminate among the four groups.Mean enhancement of clear cell RCCs and oncocytomas peaked in the corticomedullary phase; mean enhancement of papillary and chromophobe RCCs peaked in the nephrographic phase. Enhancement of clear cell RCCs was greater than that of oncocytomas in the corticomedullary (125 HU vs 106 HU, P = .045) and excretory (80 HU vs 67 HU, P = .034) phases. Enhancement of clear cell RCCs was greater than that of papillary RCCs in the corticomedullary (125 HU vs 54 HU, P.001), nephrographic (103 HU vs 64 HU, P.001), and excretory (80 HU vs 54 HU, P.001) phases. Enhancement of clear cell RCCs was greater than that of chromophobe RCCs in the corticomedullary (125 HU vs 74 HU, P.001) and excretory (80 HU vs 60 HU, P = .008) phases. Thresholding of enhancement helped to discriminate clear cell RCC from oncocytoma, papillary RCC, and chromophobe RCC with accuracies of 77% (83 of 108 cases), 85% (101 of 119 cases), and 84% (81 of 97 cases).Enhancement at multiphasic multidetector CT, if prospectively validated, may assist in the discrimination of clear cell RCC from oncocytoma, papillary RCC, and chromophobe RCC.

The dendritic cell vaccine DC-Ad-GM·CAIX is an active, specific immunotherapy with the potential of providing a safe and effective therapy against renal cell carcinoma (RCC). Using immunocompetent Balb/c mouse models we tested the efficacy and mechanism of the vaccine to prevent and treat the growth of a syngeneic RCC (RENCA) engineered to overexpress the human TAA carbonic anhydrase IX (NPR-IX). In a prevention model, NPR-IX tumor development was specifically and significantly delayed by 13 days in DC-Ad-GM·CAIX-treated mice (P0.001), tumor volumes were 79% smaller (day 24, P0.007), and body weight was maintained at study termination compared with the controls. Six of these mice remained tumor-free for1 year. In a treatment model, NPR-IX tumors remained smaller in DC-Ad-GM·CAIX-treated mice for 8 days (P0.002), achieving a 60% growth inhibition at termination. No vaccine-related organ toxicity was observed in either model. The critical mechanistic parameter separating responsive from nonresponsive tumors was hCAIX protein expression, demonstrated by aggressive growth of tumors that did not express hCAIX protein and in sham-treated mice (DC-Ad-Null). No murine serum anti-hCAIX antibodies were detected. Moreover, altered mechanisms of immunoediting as a means for immune evasion were suggested by differential gene expression (Ccl1, Hmgb1, Fgl2, Cd209a, and Klra2) and therapy evasion miRNAs (miR-1186, miR-98, miR-5097, miR-1942, and miR-708) in tumors that evaded DC-Ad-GM·CAIX immunotherapy. This is the first study in immunocompetent mice that provides a proof of concept for the specificity, efficacy, safety, and activity of the DC-Ad-GM·CAIX immunotherapy, forming the basis for a first-in-human phase I trial in RCC patients.

e14129Background: ASN001 is a novel non-steroidal CYP17 lyase inhibitor. In preclinical studies, ASN001 shows potent inhibition of CYP17 lyase with selective inhibition of testosterone synthesis ov...

534 Background: Currently no predictive markers exist for choosing second-line targeted therapy (2L) in metastatic renal cell carcinoma (mRCC). A change in IMDC prognostic group when calculated at first-line therapy (1L) and 2L and its association with 2L efficacy was examined. Methods: The IMDC database was interrogated for patients who received 1L VEGF inhibitors (VEGFi) and then 2L with VEGFi or an mTOR inhibitor (mTORi). IMDC prognostic categories (Favorable, F; Intermediate, I; Poor, P) were defined prior to each line of therapy. Overall survival (OS), time to treatment failure (TTF) and response to 1L or 2L were assessed in relation to change in IMDC prognostic risk category. Results: Data for 1516 patients were analyzed; 89% had clear cell histology. Prognostic risk categories at 1L were F: 21.7%; I: 59.5%; P: 18.8%. 60.3% of patients remained in the same risk category at start of 2L; 9.0% improved (3% I→F; 6% P→I); 30.7% deteriorated (14% F → I or P; 16% I → P). Improvement in prognostic risk category was associated with better response and longer duration of 1L. Patients who improved prognostic risk (I → F or P → I), or maintained I or F grouping, had longer TTF if they remained on VEGFi for 2L compared to those who switched to mTORi (p < 0.05). In contrast, patients whose risk category deteriorated (F → I or P) may be more likely to benefit from switching to mTORi. Conclusions: Changes in IMDC prognostic category may predict the subsequent clinical course of patients with aRCC and provide a rational basis for selection of subsequent therapy. [Table: see text]

552 Background: Smoking increases the risk of developing renal cell carcinoma (RCC). The prognosis of active smokers compared with non-smokers with metastatic RCC (mRCC) has not been well characterized. Methods: Smoking data from 1,842 patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium (IMDC) from 8 Cancer Centers. Patients were categorized as current, former and non-smokers at the time of starting targeted therapy, and analyzed for differences in IMDC risk criteria, response rate (RR), progression- free-, (PFS) and overall survival (OS). Results: Overall, 292 (15.9%), 755 (41.0%), and 795 (43.1%) were current, former, and non-smokers. There were no differences in sarcomatoid features, number of metastatic sites or non-clear cell histology in either former or current smokers when compared with non-smokers. Likewise, former smokers had statistically similar IMDC risk groups compared to non-smokers. However, current smokers were more likely to have hypercalcemia (p=0.004), neutrophilia (p=0.038), thrombophilia (p=0.002), and more patients had higher numbers of IMDC risk features (p=0.014) when compared with non-smokers. The RR at first-line targeted therapy of former (p=0.89) and current smokers (p=0.13) were similar to non-smokers. No differences in PFS were noted: 7.7 vs. 7.6 vs. 6.2 months (mo) in non-, former (p=0.92), and current smokers (p=0.66). Interestingly, while former- and non-smokers had comparable OS times (23.7 vs. 23.1 mo; p=0.71), current smokers had significantly shorter OS (15.8 mo; p=0.001) than non-smokers. Current but not former smoking status was an independent poor prognosis factor (HR=1.28; p=0.006) when adjusted for the IMDC risk criteria. Moreover, each pack year increased the risk of death 1% (HR=1.01; p=0.039). Conclusions: Active smoking is associated with more advanced IMDC risk criteria and diminished OS in mRCC patients treated with targeted therapy agents. On the other hand, patients who quit smoking returned to a similar risk of death compared to patients who never smoked. Smoking cessation should be a counselling priority among mRCC patients receiving targeted agents.

513 Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.

509 Background: Sarcomatoid transformation in renal cell carcinoma (ccRCC) is one of the worst prognostic factors and outcome is extremely poor. We evaluate genetic alterations implicated in this process. Methods: Nephrectomy specimens from ccRCC with sarcomatoid transformation had DNA extracted from carcinoma, sarcomatoid, and normal kidney regions. Exome capture/Illumina sequencing was performed in 21 samples. Somatic mutation calling was accomplished by comparing sarcomatoid-normal and carcinoma-normal pairs. Results: Two tumors had evidence of hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining tumors, 42.6% of somatic mutations were shared. Sarcomatoid regions had a greater mutation burden (p = 4.0x10-4). A low percentage (57.9%) of tumors had mutations in VHL. Mutations in ccRCC driver genes, including PBRM1, PTEN, SETD2, ARID1A, and BAP1, were common. All mutations in ARID1A and BAP1 were specific to sarcomatoid regions. A high percentage (31.5%) of TP53 mutations were observed, all specific to sarcomatoid regions and occurring with loss of heterozygosity. Lastly, mutations in genes not previously described in ccRCC were observed, most sarcomatoid-specific. These include genes implicated in cell adhesion, polarity, motility, and WNT signaling (FAT1, FAT2, FAT3, PTK7), retinoic acid-regulated cell differentiation (RQCD1, LRIF1), and ubiquitinated protein trafficking and cytokinesis (TSG101). Conclusions: Sarcomatoid transformation in ccRCC results from clonal divergence from a common somatic cell of origin. The sarcomatoid region has significantly greater mutational burden of known cancer driver genes. TP53 mutations occurred at a high frequency and were exclusive to the sarcomatoid region. Hypermutation is a unique characteristic observed in a subset of tumors. Additional cohorts and mechanistic studies are critical to elucidate the role of candidate driver alterations.

The short arm of chromosome 3 (3p) harbors the von Hippel-Lindau (VHL) tumor suppressor gene, and the long arm of chromosome 14 (14q) harbors the hypoxia-inducible factor 1α (HIF-1α) gene. The objective of this study was to evaluate the significance of 3p loss (loss VHL gene) and 14q loss (loss HIF-1α gene) in clear cell renal cell carcinoma (ccRCC).In total, 288 ccRCC tumors underwent a prospective cytogenetic analysis for alterations in chromosomes 3p and 14q. Tumors were assigned to 1 of 4 possible chromosomal alterations: VHL +3p/+14q (VHL wild type [VHL-WT]), VHL +3p/-14q (VHL-WT plus HIF2α [WT/H2]), -3p/+14q (HIF1α and HIF2α [H1H2]), and -3p/-14q (HIF2α [H2]).Among patients who had loss of 3p, tumors with -3p/-14q (H2) alterations were larger (P = .002), had higher grade (P = .002) and stage (P = .001), and more often were metastatic (P = .029) than tumors that retained 14q (H1H2). All patients who had tumors with -3p/-14q (H2) had worse cancer-specific survival (P = .014), and patients who had localized disease (P = .012) and primary T1 (pT1) tumors (P = .008) had worse recurrence-free survival. In patients who had pT1 tumors, combined 3p/14q loss was an independent predictor of recurrence-free survival (hazard ratio, 11.19; 95% confidence interval, 1.91-65.63) and cancer-specific survival (hazard ratio, 15.93; 95% confidence interval, 3.09-82.16). The current investigation was limited by its retrospective design, single-center experience, and a lack of confirmatory protein analyses.Loss of chromosome 3p (the VHL gene) was associated with improved survival in patients with ccRCC, whereas loss of chromosome 14q (the HIF-1α gene) was associated with worse outcomes. The results of the current study support the hypothesis that HIF-1α functions as an important tumor suppressor gene in ccRCC.

The worldwide incidence of kidney cancer has been increasing for many years likely as a consequence of numerous factors, including the increased utilization of abdominal imaging with an increased incidental diagnosis of small renal tumors, the aging of the population, and the increased prevalence of environmental and lifestyle risk factors for renal cell carcinoma (RCC). A wide variability in geographic, gender, and ethnic differences has been observed relative to RCC around the world, with tobacco use, obesity, and hypertension emerging as the primary environmental factors that predispose to RCC.

Insulin-like growth factor binding protein-3 (IGFBP-3) is a pro-apoptotic, anti-metastasic, and anti-angiogenic protein. Low serum IGFBP-3 has been associated with risk of more aggressive prostate cancer (PCa). We investigated the impact of nuclear and cytoplasmic IGFBP-3 protein expression levels in PCa by examining their in situ expression across a wide spectrum of primary tumors by immunohistochemical analysis of tissue microarrays. Immunohistochemistry was performed on PCa microarrays constructed from 226 hormone naive patients who underwent radical prostatectomy. Both cytoplasmic and nuclear IGFBP-3 expressions were scored in a semi-quantitative fashion using an integrated measure of intensity and positivity. The distribution of IGFBP-3 protein expression was examined across the spectrum of epithelial tissues, and its association with standard clinicopathological covariates and tumor recurrence was examined. There was a broad range of IGFBP-3 staining across all histologies examined. Tumor had higher IGFBP-3 cytoplasmic and nuclear staining than benign histologies. For IGFBP-3 nuclear staining, PCa was significantly different than benign prostatic hyperplasia, normal prostate, and prostate intraepithelial neoplasia. As both a continuous and dichotomized variable, higher nuclear IGFBP-3 expression had statistically significant associations with PCa recurrence. The cytoplasmic staining had no significance in any patient subgroup. In patients with low-grade cancer, IGFBP-3 nuclear positivity was a better predictor of recurrence than baseline PSA, tumor margin status, TNM tumor stage, or presence of capsular invasion. High nuclear IGFBP-3 is amongst the strongest predictors of cancer recurrence in patients with low-grade prostate cancers and may therefore play an important role in risk stratification.

Introduction Robotic assistance during laparoscopic surgery for pelvic organ prolapse rapidly disseminated across the United States without level I data to support its benefit over traditional open and laparoscopic approaches [1]. This manuscript describes design and methodology of the Abdominal Colpopexy: Comparison of Endoscopic Surgical Strategies (ACCESS) Trial. Methods ACCESS is a randomized comparative effectiveness trial enrolling patients at two academic teaching facilities, UCLA (Los Angeles, CA) and Loyola University (Chicago, IL). The primary aim is to compare costs of robotic assisted versus pure laparoscopic abdominal sacrocolpopexy (RASC vs LASC). Following a clinical decision for minimally-invasive abdominal sacrocolpopexy (ASC) and research consent, participants with symptomatic stage ≥ II pelvic organ prolapse are randomized to LASC or RASC on the day of surgery. Costs of care are based on each patient's billing record and equipment costs at each hospital. All costs associated with surgical procedure including costs for robot and initial hospitalization and any re-hospitalization in the first 6 weeks are compared between groups. Secondary outcomes include post-operative pain, anatomic outcomes, symptom severity and quality of life, and adverse events. Power calculation determined that 32 women in each arm would provide 95% power to detect a $2500 difference in total charges, using a two-sided two sample t -test with a significance level of 0.05. Results Enrollment was completed in May 2011. The 12-month follow-up was completed in May 2012. Conclusions This is a multi-center study to assess cost as a primary outcome in a comparative effectiveness trial of LASC versus RASC.