A missense SNP in the tumor suppressor SETD2 reduces H3K36me3 and mitotic spindle integrity in Drosophila.

Mutations in SETD2 are among the most prevalent drivers of renal cell carcinoma (RCC). We identified a novel single nucleotide polymorphism (SNP) in SETD2, E902Q, within a subset of RCC patients, which manifests as both an inherited or tumor-associated somatic mutation. To determine if the SNP is biologically functional, we used CRISPR-based genome editing to generate the orthologous mutation within the Drosophila melanogaster Set2 gene. In Drosophila, the homologous amino acid substitution, E741Q, reduces H3K36me3 levels comparable to Set2 knockdown, and this loss is rescued by reintroduction of a wild-type Set2 transgene. We similarly uncovered significant defects in spindle morphogenesis, consistent with the established role of SETD2 in methylating α-Tubulin during mitosis to regulate microtubule dynamics and maintain genome stability. These data indicate the Set2 E741Q SNP affects both histone methylation and spindle integrity. Moreover, this work further suggests the SETD2 E902Q SNP may hold clinical relevance.

Treatment Patterns and Overall Survival Outcomes Among Patients Aged 80 yr or Older with High-risk Prostate Cancer.

BACKGROUND: Elderly patients diagnosed with high-risk prostate cancer (PCa) present a therapeutic dilemma of balancing treatment of a potentially lethal malignancy with overtreatment of a cancer that may not threaten life expectancy. OBJECTIVE: To investigate treatment patterns and overall survival outcomes in this group of patients. DESIGN SETTING AND PARTICIPANTS: A retrospective cohort study was conducted. We queried the National Cancer Database for high-risk PCa in patients aged 80 yr or older diagnosed during 2004-2016. INTERVENTION: Eligible patients underwent no treatment following biopsy (ie, observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier, log rank, and multivariate Cox proportional hazard regression was performed to compare overall survival (OS). RESULTS AND LIMITATIONS: A total of 19 920 men were eligible for analysis, and the most common treatment approach was RT + ADT (7401 patients; 37.2%). Observation and ADT alone declined over time (59.3% in 2004 vs 47.5% in 2016). There was no observed difference in OS between observation and ADT alone (adjusted hazard ratio [HR] 1.04, 95% confidence interval [CI], 0.99-1.09; p = 0.105). Definitive local treatment was associated with improved OS compared with ADT alone (RT alone, HR 0.54, 95% CI, 0.50-0.59, p < 0.0001; ADT + RT, HR 0.48, 95% CI, 0.46-0.50, p < 0.0001; surgery, HR 0.50, 95% CI, 0.42-0.59, p < 0.0001). CONCLUSIONS: This analysis demonstrates that the use of definitive local therapy, including surgery or RT ± ADT, is increasing and is associated with a 50% reduction in overall mortality compared with observation or ADT alone. While prospective validation is warranted, elderly men with high-risk disease eligible for definitive management should be counseled on the risks, including a possible compromise in OS, with deferring definitive management. PATIENT SUMMARY: Elderly men are more often diagnosed with higher-risk prostate cancer but are less likely to receive curative treatment options than younger men. Our analysis demonstrates that for men ≥80 yr of age with high-risk prostate cancer, definitive local therapy, including surgery or radiation therapy and/or androgen deprivation therapy, is associated with a 50% reduction in overall mortality compared with observation or androgen deprivation therapy alone. We therefore recommend that life expectancy (ie, physiologic age) be taken into account, over chronologic age, and that elderly men with good life expectancy (eg, >5 yr; minimal comorbidity) should be offered definitive, life-prolonging therapy.

Molecular characteristics and markers of advanced clear cell renal cell carcinoma: Pitfalls due to intratumoral heterogeneity and identification of genetic alterations associated with metastasis.

OBJECTIVES: To identify clear cell renal cell carcinoma-related gene mutations potentially associated with aggressive disease, sarcomatoid differentiation or poor prognosis. METHODS: We carried out genomic analysis of 217 tumor foci from 25 patients with conventional clear cell renal cell carcinoma (14 patients), clear cell renal cell carcinoma with sarcomatoid differentiation (six patients) and non-clear cell renal cell carcinoma (five patients). Each tumor nodule on the tissue block that corresponded to the same focus on the slide was separated from the normal parenchyma and other histologically distinct areas of tumor. The isolated tumor foci were used for subsequent analyses and sequencing. Deoxyribonucleic acid from the formalin-fixed paraffin-embedded tissues was extracted. Multiplex bar-coded polymerase chain reaction amplification was carried out using next-generation sequencing libraries. RESULTS: Overall, 67 protein alterations, including amino acid alterations, frame shifts and splice site mutations in seven genes were identified in the cohort of renal cell carcinoma tumors included in this study. Fewer patients with clear cell renal cell carcinoma with sarcomatoid differentiation had clear cell renal cell carcinoma-related mutations in comparison with patients with conventional clear cell renal cell carcinoma. Additionally, the average number of unique clear cell renal cell carcinoma-related protein alterations per patient was significantly lower in clear cell renal cell carcinoma with sarcomatoid differentiation than in conventional clear cell renal cell carcinoma. Mutations in PBRM1 were identified in a higher proportion of patients with high-grade tumors (World Health Organization/International Society of Urological Pathology grade 4) and in the primary tumors of six of 10 (60%) patients with metastatic disease. CONCLUSIONS: Although there are pitfalls due to intratumoral heterogeneity and sampling bias, mutations in PBRM1 may be associated with metastasis and aggressive disease in clear cell renal cell carcinoma.

Overall survival comparison between androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) vs ADT plus EBRT with brachytherapy boost in clinically node-positive prostate cancer.

PURPOSE: Optimal therapy for clinically node-positive, nonmetastatic (cN1) prostate cancer (PC) patients remains controversial, ranging from aggressive local therapy to palliative systematic therapy alone. Despite guideline support, it is unclear if a brachytherapy (BT) boost should be considered for cN1 patients as these patients were excluded from randomized trials establishing its benefit. Herein, we compare definitive radiation therapy (RT) with or without a BT boost in cN1 PC. METHODS AND MATERIALS: The National Cancer Database was used to identify men with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy between 2004 and 2013. Overall survival (OS) was compared between those who received external beam RT (EBRT) or combination EBRT plus BT boost (EBRT + BT) using Kaplan-Meier with propensity score matching and Cox proportional hazards. RESULTS: With a median followup of 48.5 months, 1,650 patients were eligible for this analysis, 103 (6.2%) of whom received EBRT + BT. Younger age, no medical comorbidities, and Gleason score of six were associated with higher likelihood of receiving EBRT + BT over EBRT alone. The mean (median) OS for EBRT and EBRT + BT was 99.0 (110.6) months vs 109.2 (not reached) months, respectively (p = 0.048). However, no significance difference in OS was observed between the groups after propensity score matching. On multivariable analysis, EBRT + BT was not significantly associated with improved OS (adjusted HR 0.67, 95% CI, 0.41-1.07, p = 0.098). CONCLUSIONS: In this retrospective, observational study of patients with cN1 PC treated with definitive RT and concomitant androgen deprivation therapy, EBRT + BT had an unadjusted improvement in OS compared with EBRT alone that lost statistical significance after multivariable adjustment and propensity score matching.

Dynamic Evaluation of the Modified Glasgow Prognostic Scale in Patients With Resected, Localized Clear Cell Renal Cell Carcinoma.

OBJECTIVE: To evaluate the relationship between dynamic changes in the modified Glasgow Prognostic Scale (mGPS) and postnephrectomy survival among localized clear cell renal cell carcinoma (ccRCC) patients. METHODS: We retrospectively identified patients who underwent nephrectomy for localized ccRCC with preoperative mGPS = 0 from 2005 to 2018. The primary exposure of interest was ΔmGPS between 2 points - 60 days prior to surgery and 1 year after surgery. We assessed the relationship between ΔmGPS and survival outcomes. Kaplan-Meier curves were generated to determine survival estimates and Cox proportional hazards models were fit to estimate hazard ratios (HRs). Multivariable models were constructed using both ΔmGPS and clinical variables known to be associated with differences in survival. RESULTS: We identified 313 patients for our analytic cohort with a median follow-up time of 20.2 months. Thirty-seven (11.9%) patients died and 39 (12.54%) showed recurrence during follow-up. Two hundred sixty-three (84.6%) patients had unchanged mGPS before and after surgery, while 48 (15.4%) patients showed an increase in postoperative mGPS from preoperative mGPS. Compared to patients with unchanged mGPS, patients with a higher postoperative mGPS had an increased risk of death (HR = 3.05 [1.39-6.68], P = .005) and recurrence (HR = 2.98 [1.34-6.64], P = .008). CONCLUSION: Patients with an increase in mGPS following nephrectomy for ccRCC were more likely to die and experience cancer recurrence. Assessing dynamic changes in this cheap, validated, and reproducible test may be useful in identifying patients at higher risk for more aggressive disease or for counseling patients regarding risk of cancer recurrence.

High-dose-rate prostate brachytherapy appears safe in patients with high baseline International Prostate Symptom Scores.

PURPOSE: The purpose of the study was to report our institutional quality of life data for those undergoing high-dose-rate brachytherapy with an International Prostate Symptom Score (IPSS) ≥15 compared with those with an IPSS <15. METHODS AND MATERIALS: The charts of 95 patients with localized adenocarcinoma of the prostate treated with high-dose-rate as monotherapy or as a boost after external beam radiation therapy at a single institution between 2012 and 2015 were reviewed. All patients completed the IPSS and Expanded Prostate Index for Prostate Cancer-Clinical Practice quality of life assessments before treatment and at least one followup survey. Linear mixed models were performed to test for significant changes and differences in each outcome over time. RESULTS: Median followup in the IPSS <15 group was 23 months and 16 months in the IPSS ≥15 group. Median prostate volume was 46.3 cc and 45.4 cc, respectively (p = 0.901). IPSS, incontinence, and urinary irritation/obstruction scores were significantly higher in the IPSS ≥15 group compared with the IPSS <15 group at baseline (all p ≤ 0.05). By the >24 months time point, these scores had decreased below baseline and were not significantly different from those with a baseline IPSS <15 (all p > 0.1). 12.5% in the IPSS ≥15 group developed a new Grade 2 genitourinary toxicity requiring an alpha blocker compared with 26.5% in the IPSS <15 group (p = 0.34). No patients required emergency placement of a foley catheter within 30 days of treatment. CONCLUSIONS: Given the low rates of genitourinary toxicity, this technique appears appropriate even for those with high baseline urinary symptoms.

Patient-reported health-related quality of life outcomes after HDR brachytherapy between small (<60 cc) and large (≥60 cc) prostate glands.

PURPOSE: Patients with large prostate glands are underrepresented in clinical trials incorporating brachytherapy due to concerns for excessive toxicity. We sought to compare health-related quality of life (HRQOL) outcomes between small (<60 cc) and large (≥60 cc) prostates treated with high-dose-rate brachytherapy (HDR-B). METHODS AND MATERIALS: One hundred thirty patients at Emory University were treated with HDR-B monotherapy (n = 75) or HDR-B in combination with external beam radiation therapy (n = 55). American Urologic Association Symptom Score (AUASS) and expanded prostate cancer index composite for clinical practice (EPIC-CP) scores were recorded. A linear mixed model was performed dichotomizing prostate volume (<60 and ≥ 60 cc) with AUASS, individual EPIC-CP domains (urinary incontinence, urinary irritation/obstruction [UIO], bowel function, sexual function, and vitality/hormonal function), and overall EPIC-CP HRQOL scores. RESULTS: Median followup was 22.6 months (range 2.2-55.8). The median gland volume for the entire cohort (n = 130), <60 cc cohort (n = 104), and ≥60 cc cohort (n = 26) was 44 cc, 41.1 cc, and 68.0 cc, respectively. There were no baseline differences in HRQOL scores between cohorts. At 2 months, AUASS and UIO scores increased similarly between cohorts (AUASS p = 0.807; UIO p = 0.539), then decreased (longitudinal effect p < 0.001 and p = 0.005, respectively) to remain not significantly different at 12 months (AUASS p = 0.595; UIO p = 0.673). Overall, prostate volume was not significantly associated with change in AUASS (p = 0.403), urinary incontinence (p = 0.322), UIO symptoms (p = 0.779), bowel symptoms (p = 0.757), vitality/hormonal symptoms (p = 0.503), or overall HRQOL (p = 0.382). CONCLUSIONS: In appropriately selected patients, HDR-B appears well tolerated in patients with ≥60 cc prostate glands without an increase in patient-reported toxicity. Volume should not be a strict contraindication in those with adequate baseline function.

Hypofractionated external beam radiation therapy in combination with HDR boost for localized prostate cancer: patient reported quality of life outcomes.

PURPOSE: There is limited data to support the use of hypofractionated external beam radiation (HypoF) in combination with high-dose-rate brachytherapy (HDR). We report our quality of life (QOL) outcomes when treating intermediate and high-risk prostate cancer patients with external beam radiation (EBRT) plus HDR. MATERIAL AND METHODS: The charts of 54 patients with localized adenocarcinoma of the prostate treated with standard fractionation (SF) or HypoF EBRT plus HDR boost at a single institution between 2012 and 2015 were reviewed. All patients completed the American Urological Association Symptom Score (AUASS) and Expanded Prostate Index for Prostate Cancer - Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and completed at least one follow-up survey. Linear mixed models were performed to test for significant changes and differences in each outcome over time. RESULTS: There was no significant difference in AUA score (p = 0.98), incontinence (urge) and urinary irritation/obstruction scores (p = 0.81 and p = 0.62, respectively), and bowel QOL (p = 0.97) between the two dosing groups over time or at any discrete time point. For both groups, AUA scores peaked at 0-2 months before improving. Likewise, sexual function, vitality score, and QOL scores were also not significantly different between the dose groups over time (p = 0.59, p = 0.37, and p = 0.71, respectively). All QOL categories, except sexual function, trended toward baseline with increasing time from intervention. CONCLUSIONS: Our study suggests HypoF EBRT can be delivered in combination with HDR for patients with ntermediate-risk and high-risk adenocarcinoma of the prostate without increasing toxicity compared to SF with an HDR boost.

Brachytherapy for localized prostate cancer in the modern era: a comparison of patient-reported quality of life outcomes among different techniques.

PURPOSE: To report our institutional quality of life (QOL) data for low-dose-rate (LDR) monotherapy (LDR mono), high-dose-rate (HDR) monotherapy (HDR mono), and EBRT with an HDR brachytherapy boost (HDR boost). MATERIAL AND METHODS: The charts of 165 patients with localized adenocarcinoma of the prostate treated with LDR monotherapy (LDR mono), HDR monotherapy (HDR mono), and EBRT with an HDR brachytherapy boost (HDR boost) at a single institution between 2012 and 2015 were reviewed. All patients completed the American Urological Association symptom score (AUASS) and Expanded Prostate Index for Prostate Cancer - Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and at least one follow-up survey. Time points included baseline, ≤ 2 months, 2-≤ 6 months, 6-≤ 12 months, 12-≤ 18 months, 18-≤ 24 months, 24-≤ 30 months, and > 30 months. Linear mixed models were performed to test for significant changes and differences in each outcome over time. RESULTS: Mean follow-up was 19.5 months. All major functional QOL domains were affected after treatment with brachytherapy for localized prostate cancer. All domains improved over time, with the exception of sexual function scores for all groups and urinary incontinence scores for the HDR mono group. Patients treated with LDR did have higher AUA, irritability/obstructive symptoms, incontinence, bowel, and QOL scores acutely compared to the HDR and HDR + boost groups. Vitality scores were significantly worse in the HDR boost group both acutely and at the > 30-month time point. CONCLUSIONS: Patients receiving HDR brachytherapy had lower acute urinary and rectal toxicity compared to the patients receiving LDR, even when combined with EBRT. However, long-term toxicity was similar.

Upper pole urologist-obtained percutaneous renal access for PCNL is safe and efficacious.

INTRODUCTION: Interventional radiologist may be hesitant to obtain upper pole access for percutaneous nephrolithotomy (PCNL) due to a higher complication rate. Renal access gained by urologists may achieve higher stone-free rates with similar complication rates. We evaluate our institution's contemporary results of percutaneous renal access in the upper pole for nephrolithotomy by urologists, which we believe both safe and efficacious. MATERIALS AND METHODS: This retrospective chart review included all PCNL's performed by fellowship-trained endourologists from 2003 to 2014 at a single institution. Inclusion criteria included patients in which renal access was obtained by the urologist via the upper pole for PCNL. Stone-free status was determined by either KUB or CT scan on POD #1. Patients without stones visible on KUB or less than 4 mm on CT were considered stone-free. RESULTS: A total of 144 patients obtained upper pole access for PCNL. There were a total of 53 (37%%) staghorn calculi, of which 35 (66%) were partial staghorn stones. Renal access was obtained above 11th rib in 12.5% (n = 18), between the 11th and 12th rib in 57.6% (n = 83), subcostal in 14.6% (n = 21) and undetermined in the rest. Complications were seen in 18 (12.5%) of patients. Hydropneumothorax requiring chest tube was seen in 8 (5.6%) patients. Postoperative imaging confirmed 93 (64.5%) patients stone-free, and 35 (24.3%) required a second look PCNL. CONCLUSIONS: Our experience with upper pole percutaneous renal access for nephrolithotomy has shown that it has an acceptable complication risk. It should be a part of an endourologist's armamentarium that operate on large burden, complex stones or ureteral pathology.

A novel preoperative inflammatory marker prognostic score in patients with localized and metastatic renal cell carcinoma.

OBJECTIVE: Several inflammatory markers have been studied as potential biomarkers in renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of specific inflammatory markers into an RCC Inflammatory Score (RISK) could serve as a rigorous prognostic indicator of overall survival (OS) in patients with clear cell and non-clear cell RCC. METHODS: Combination of preoperative C-reactive protein (CRP), albumin, erythrocyte sedimentation rate (ESR), corrected calcium, and aspartate transaminase to alanine transaminase (AST/ALT) ratio was used to develop RISK. RISK was developed using grid-search methodology, receiver-operating-characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. Prognostic value of RISK was analyzed using the Kaplan-Meier method and Cox proportional regression models. Predictive accuracy was compared with RISK to Size, Size, Grade, and Necrosis (SSIGN) score, University of California-LOS Angeles (UCLA) Integrated Staging System (UISS), and Leibovich Prognosis Score (LPS). RESULTS: Among 391 RCC patients treated with nephrectomy, area under the curve (AUC) for RISK was 0.783, which was comparable to SSIGN (AUC 0.776, p = 0.82) and UISS (AUC 0.809, p = 0.317). Among patients with localized disease, AUC for RISK and LPS was 0.742 and 0.706, respectively (p = 0.456). On multivariate analysis, we observed a step-wise statistically significant inverse relationship between increasing RISK group and OS (all p < 0.001). CONCLUSION: RISK is an independent and significant predictor of OS for patients treated with nephrectomy for clear cell and non-clear cell RCC, with accuracy comparable to other histopathological prognostic tools.

Onodera's Prognostic Nutritional Index as an Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma.

OBJECTIVE: To evaluate the relationship between the Onodera Prognostic Nutritional Index (OPNI) and overall survival, as well as recurrence-free survival, in clear cell renal cell carcinoma (ccRCC) patients following nephrectomy. MATERIALS AND METHODS: Three hundred forty-one patients who underwent nephrectomy for ccRCC were analyzed. The optimum OPNI cutoff score of 44.7 was determined by receiver operating characteristic analysis and patients were placed in either the low or high OPNI group, with OPNI values of ≤44.7 and ≥44.8, respectively. Kaplan-Meier analysis was performed to evaluate the univariate impact of the OPNI groups on overall survival and recurrence-free survival. OPNI's association with overall survival and recurrence-free survival, with adjustments for other patient and tumor qualities, was assessed with univariate and multivariate Cox regression analysis. RESULTS: Median (95% CI) overall survival times for the low and high OPNI groups were 21.1 months and 37.9 months, respectively. OPNI was determined to be an independent prognostic factor in multivariate analysis, and after controlling for patient and tumor characteristics, the low OPNI group experienced a 1.67-fold (hazard ratio: 1.67, 95% confidence interval: 1.05-2.68) increased risk of overall mortality. CONCLUSION: Preoperative OPNI is a valuable independent prognostic indicator of overall survival and recurrence-free survival in patients with ccRCC following nephrectomy.

Ureteroscopy versus Shock Wave Lithotripsy: Factors Influencing Patient Treatment Preferences.

INTRODUCTION: Shock wave lithotripsy and ureteroscopy are considered first line treatment options for patients with urolithiasis. However, these interventions have significant variation in rates of stone-free success, procedure related complications and need for reoperation. We examined patient preferences in treatment selection for urolithiasis and factors associated with choice of treatment. METHODS: Patients with a history of urolithiasis were self-administered or mailed a questionnaire with a clinical scenario of a stone in the ureter and outcome statistics derived from a Cochrane Review for ureteroscopy and shock wave lithotripsy comparing stone-free success rates, complication rates, need for ureteral stent placement and need for additional surgery. Subjects were asked to choose ureteroscopy or shock wave lithotripsy and to indicate the relative importance that each of the 4 outcome parameters had on their treatment selection. RESULTS: A total of 163 patients returned complete surveys and a majority preferred ureteroscopy to shock wave lithotripsy (63% vs 37%, p=0.001) for the clinical scenario presented. For factors influencing procedure preference success was indicated as extremely important by 94% (152 of 163) of respondents, followed by complications, need for second surgery and, finally, need for stent. CONCLUSIONS: A majority of patients preferred ureteroscopy to shock wave lithotripsy after reviewing the evidence-based rates of stone-free success, complications and need for second surgery. Shared decision making and patient centered care should be the focus of surgical treatment selection when there is no consensus regarding a superior treatment for urolithiasis.

R.E.N.A.L. (Radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, and location relative to polar lines) nephrometry score predicts early tumor recurrence and complications after percutaneous ablative therapies for renal cell carcinoma: a 5-year experience.

PURPOSE: To investigate the prognostic value of R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, and location relative to polar lines) nephrometry score after percutaneous ablation of renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective 5-year study was performed. Participants were 87 consecutive patients (median age, 67.1 y; 59.7% male, 40.3% female) with 101 biopsy-proven RCCs who underwent percutaneous ablation (54.0% cryoablation, 46.0% radiofrequency ablation). Follow-up computed tomography or magnetic resonance imaging was performed in all cases (mean follow-up, 34.6 mo ± 23.5). R.E.N.A.L. scores were analyzed to determine the association of the score with treatment outcomes and complications. RESULTS: All tumors corresponded to stage 1A disease. Mean tumor size was 2.05 cm (range, 0.7-3.9 cm), and 50.5% of the lesions measured > 2 cm. Nephrometry score was > 8 in 31.4% of lesions. Overall recurrence rate was 16.8%, first-year recurrence rate was 7.9%, and complication rate was 9.9%. A nephrometry score > 8 was associated with increased complications after percutaneous ablation (P < .0001), increased overall recurrence (P < .0001), and increased risk of first-year recurrence (P < .0001). Immediate complications were associated with tumor size > 2 cm (P < .0001) and risk of local recurrence (P < .001). Age, gender, and percutaneous ablation technique were not correlated with recurrence or immediate complications. Patients undergoing cryoablation had a higher nephrometry score with no significant differences in recurrence rate compared with RF ablation (P = .199). CONCLUSIONS: A R.E.N.A.L. nephrometry score ≥ 8 predicts recurrence and complications after percutaneous renal ablation.

International Robotic Radical Cystectomy Consortium: A way forward.

Robot-assisted radical cystectomy (RARC) is an emerging operative alternative to open surgery for the management of invasive bladder cancer. Studies from single institutions provide limited data due to the small number of patients. In order to better understand the related outcomes, a world-wide consortium was established in 2006 of patients undergoing RARC, called the International Robotic Cystectomy Consortium (IRCC). Thus far, the IRCC has reported its findings on various areas of operative interest and continues to expand its capacity to include other operative modalities and transform it into the International Radical Cystectomy Consortium. This article summarizes the findings of the IRCC and highlights the future direction of the consortium.

Aquaporin-1 protein levels elevated in fresh urine of renal cell carcinoma patients: potential use for screening and classification of incidental renal lesions.

INTRODUCTION AND OBJECTIVES: There are over 65,000 new cases of renal cell carcinoma (RCC) each year, yet there is no effective clinical screening test for RCC. A single report claimed no overlap between urine levels of aquaporin-1 (AQP1) in patients with and without RCC (Mayo Clin Proc. 85:413, 2010). Here, we used archived and fresh RCC patient urine to validate this report. METHODS: Archived RCC, fresh prenephrectomy RCC, and non-RCC negative control urines were processed for Western blot analysis. Urinary creatinine concentrations were quantified by the Jaffe reaction (Nephron 16:31, 1976). Precipitated protein was dissolved in 1x SDS for a final concentration of 2 µg/µL creatinine. RESULTS: Negative control and archived RCC patient urine failed to show any AQP1 protein by Western blot analysis. Fresh RCC patient urine is robustly positive for AQP1. There was no signal overlap between fresh RCC and negative control, making differentiation straightforward. CONCLUSIONS: Our data confirms that fresh urine of patients with RCC contains easily detectable AQP1 protein. However, archival specimens showed an absence of detectable AQP1 indistinguishable from negative control. These findings suggest that a clinically applicable diagnostic test for AQP1 in fresh urine may be useful for detecting RCC.

von Hippel-Lindau exonic methylation analysis using MALDI-TOF mass spectrometry.

PURPOSE: Aberrant promoter methylation turns off gene expression and is involved in human malignancy. Studies show that first exon methylation has a tighter association with gene silencing compared to promoter methylation or gene mutation. However, to our knowledge the clinical importance of exonic methylation in renal cell carcinoma is unknown. We analyzed renal cell carcinoma for VHL gene exonic methylation using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. MATERIALS AND METHODS: In 48 institutionally banked renal cell carcinoma patient tissue samples VHL exon sequencing was done as well as methylation analysis of promoter and exon 1 by mass spectrometry or conventional bisulfite analysis. Methylated human lymphocytic DNA (0% and 100%), nontemplate distilled H2O, and the UOK121 and UOK171 human renal cell carcinoma cell lines served as assay controls. Samples were considered hypermethylated if a CpG site showed greater than 50% methylation. RESULTS: Nine of the 43 patient samples read by our exon 1 assay had methylated VHL exon 1 sites, including 3 showing hypermethylation. The exon 1 methylation assay was robust and reproducible. Samples with exon 1 hypermethylation showed no exonic mutations. All samples assayed at VHL exon 2 were hypermethylated. CONCLUSIONS: To assay renal cell carcinoma tumors for VHL methylation matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is robust and reproducible, and capable of quantifying the methylation status of individual DNA bases. Exon 1 methylation may be an alternate mechanism of VHL gene silencing in renal cell carcinoma in addition to mutation and promoter methylation. Applying this assay in patient populations may allow enhanced diagnosis or tumor typing in the future.

Renal cell carcinoma in patients with end-stage renal disease has favorable overall prognosis.

Patients with end-stage renal disease (ESRD) demonstrate a greater risk for renal cell carcinoma (RCC) than the general population. This study compared pathological and clinical outcomes in patients with RCC with and without ESRD. Patients with ESRD who underwent nephrectomy and were found to have RCC at our institution since 1999 were identified. The control group was composed of patients from the general population with RCC. The primary outcome was risk of cancer recurrence. The study included 338 RCC patients: 84 with ESRD and 243 without ESRD. In the ESRD group, mean tumor size was smaller, there was decreased prevalence of advanced T category (>3) , and the average Karakiewicz nomogram score was lower. ESRD was associated with decreased tumor recurrence and clear cell pathology. No patients with ESRD had metastatic disease. There was no difference in overall or cancer-specific mortality between the ESRD and control groups. Patients with ESRD who develop RCC have a better prognosis compared to RCC in patients without ESRD, which is likely secondary to favorable histopathologic phenotype as well as the likelihood of early diagnosis. Thus, the delay between nephrectomy and renal transplantation may not be necessary, especially in patients with asymptomatic, low grade tumors.