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Non-PEER CT peak signal intensity/enhancement values in RO versus ChRCC tumors according to CD117 expression. (A) Net peak enhancement using the delayed/excretory contrast phase relative to the unenhanced phase; (B) Absolute peak signal intensity using an early (arterial/cortical or venous/nephrogenic) contrast phase without subtraction of the unenhanced phase signal intensity; (C) Absolute peak signal intensity using the delayed/excretory contrast phase without subtraction of the unenhanced phase signal intensity.

Purpose: The diagnostic differential for CD117/KIT(+) oncocytic renal tumor biopsies is limited to benign renal oncocytoma versus chromophobe renal cell carcinoma (ChRCC); however, further differentiation is often challenging and requires surgical resection. We investigated clinical variables that might improve preoperative differentiation of CD117(+) renal oncocytoma versus ChRCC to avoid the need for benign tumor resection.Experimental Design: A total of 124 nephrectomy patients from a single institute with 133 renal oncocytoma or ChRCC tumors were studied. Patients from 2003 to 2012 comprised a retrospective cohort to identify clinical/radiographic variables associated with renal oncocytoma versus ChRCC. Prospective validation was performed among consecutive renal oncocytoma/ChRCC tumors resected from 2013 to 2017.Results: Tumor size and younger age were associated with ChRCC, and multifocality with renal oncocytoma; however, the most reliable variable for ChRCC versus renal oncocytoma differentiation was the tumor:cortex peak early-phase enhancement ratio (PEER) using multiphase CT. Among 54 PEER-evaluable tumors in the retrospective cohort [19 CD117(+), 13 CD117(−), 22 CD117-untested], PEER classified each correctly as renal oncocytoma (PEER >0.50) or ChRCC (PEER ≤0.50), except for four misclassified CD117(−) ChRCC variants. Prospective study of PEER confirmed 100% accuracy of renal oncocytoma/ChRCC classification among 22/22 additional CD117(+) tumors. Prospective interobserver reproducibility was excellent for PEER scoring (intraclass correlation coefficient, ICC = 0.97) and perfect for renal oncocytoma/ChRCC assignment (ICC = 1.0).Conclusions: In the largest clinical comparison of renal oncocytoma versus ChRCC to our knowledge, we identified and prospectively validated a reproducible radiographic measure that differentiates CD117(+) renal oncocytoma from ChRCC with potentially 100% accuracy. PEER may allow reliable biopsy-based diagnosis of CD117(+) renal oncocytoma, avoiding the need for diagnostic nephrectomy. Clin Cancer Res; 24(16); 3898–907. ©2018 AACR.

Representative CT imaging of CD117(-) RO/ChRCC tumors using an early contrast phase. (A) This representative CD117(-) RO tumor has relative hyperenhancement (tumor:cortex PEER 0.79) that is similar to CD117(+) RO tumors; (B) Thisrepresentative CD117(-) ChRCC tumor has relative hyperenhancement (tumor:cortex PEER 0.76) that is similar to RO tumors and in contrast to CD117(+) ChRCC tumors.

Eosinophilia in ChRCC tumors

Representative examples of CD117 and CK immunostaining in ChRCC and RO tumors. Representative staining images are shown at 100X magnification. (A-B) Hematoxylin & Eosin staining for (A) ChRCC and (B) RO. (C-D) Typical strong/diffuse CD117 staining in (C) ChRCC and (D) RO. (E-F) Atypical focal/weak CD117 staining in (E) ChRCC and (F) RO. (G-H) Typical CK7 staining that is (G) strong/diffuse in ChRCC and (H) negative in RO. (I-J) Atypical CK7 staining that is (I) focal/weak in ChRCC and (J) strong/diffuse in RO.

ImportanceChanges in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients.ObjectiveTo investigate whether postsurgical acute pain across different surgical subspecialties can be managed effectively after hospital discharge with an opioid supply of 3 or fewer days and whether this reduction in prescribed opioids is associated with reduced new, persistent opioid use.Design, Setting, and ParticipantsIn this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of 3 or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center. Participants were all patients who underwent surgery from August 1, 2018, to July 31, 2019.Main Outcomes and MeasuresMain outcomes were the rate of compliance with the ROPP in each surgical service, the mean number of prescription days and refill requests, type of opioid prescribed, and rate of conversion to chronic opioid use determined via a state-run opioid prescription program. Postsurgical complications were also measured.ResultsA total of 4068 patients (mean [SD] age, 61.0 [13.8] years; 2528 women [62.1%]) were included, with 2017 in the pre-ROPP group (August 1, 2018, to January 31, 2019) and 2051 in the post-ROPP group (February 1, 2019, to July 31, 2019). The rate of compliance with the protocol was 95%. After implementation of the ROPP, mean opioid prescription days decreased from a mean (SD) of 3.9 (4.5) days in the pre-ROPP group to 1.9 (3.6) days in the post-ROPP group (P P P = .02). There was no statistically significant difference in surgical complications. The conversion rate to chronic opioid use decreased following ROPP implementation among both opioid-naive patients with cancer (11.3% [143 of 1267] to 4.5% [118 of 2645]; P P = .02).Conclusions and RelevanceIn this cohort study, prescribing an opioid supply of 3 or fewer days to surgical patients after hospital discharge was feasible for most patients, led to a significant decrease in the number of opioids prescribed after surgery, and was associated with a significantly decreased conversion to long-term opioid use without concomitant increases in refill requests or significant compromises in surgical recovery.

OBJECTIVE To develop a structured and objective scoring tool for assessment of robot assisted partial nephrectomy (RAPN): Scoring for Partial Nephrectomy (SPaN). MATERIALS AND METHODS Content development: RAPN was deconstructed into 6 domains by a multi-institutional panel of 10 expert robotic surgeons. Performance on each domain was represented on a Likert scale of 1-5, with specific descriptions of anchors 1, 3 and 5. Content validation: The Delphi methodology was utilized to achieve consensus about the description of each anchor for each domain in terms of appropriateness of the skill assessed, objectiveness, clarity, and unambiguous wording. The content validity index (CVI) of ≥0.75 was set as cut-off for consensus. Reliability: 15 de-identified videos of RAPN were utilized to determine the inter-rater reliability using linearly weighted percent agreement, and Construct validation of SPaN was described in terms of median scores and odds ratios. RESULTS The expert panel reached consensus (CVI ≥ 0.75) after 2 rounds. Consensus was achieved for 36 (67%) statements in the first round and 18 (33%) after the second round. The final six-domain SPaN included: Exposure of the kidney; Identification and dissection of the ureter and gonadal vessels; Dissection of the hilum; Tumor localization and exposure; Clamping and tumor resection; and Renorrhaphy. The linearly weighted percent agreement was > 0.75 for all domains. There was no difference between median scores for any domain between attendings and trainees. CONCLUSION Despite the lack of signification construct validity, SPaN is a structured, reliable and procedure-specific tool that can objectively assesses technical proficiency for RAPN.

BACKGROUND: The prostatic urethra is conventionally resected during robot-assisted radical prostatectomy (RARP). We describe the technical feasibility and urinary continence outcomes of extended prostatic urethral preservation (EPUP) during RARP. METHODS: A single surgeon at a National Comprehensive Cancer Network institute performed 48 consecutive RARP operations using EPUP from March 2014 to March 2016, during which time 177 conventional non-EPUP RARP operations were performed by other surgeons. Prior to this period, the EPUP surgeon had performed 17 non-EPUP RARP operations over 15 months. Total intracorporeal urethral length (IUL) preserved during EPUP was measured intraoperatively. Associations of EPUP and IUL with continence recovery rates and/or times were tested in Fisher’s exact and log rank univariate analyses and Cox logistic regression multivariable analyses. RESULTS: Median IUL preserved during EPUP was 4.0 cm (range 2.5–6.0 cm), and urethral dissections typically spanned the prostatic apex to mid-gland or base. 7-week continence rates were significantly higher with versus without EPUP. EPUP patient rates of using 0 or 0–1 pads per day immediately after catheter removal were 19% and 35%, respectively. These rates increased significantly (53% and 76%, respectively), as did the IUL preserved (median 5.0 cm), among more recent EPUP patients (n=17), which suggested a learning curve. In multivariable analyses including all patients, an EPUP approach was an independent predictor of faster continence recovery. In multivariable analyses of the EPUP subset, a longer IUL preserved was independently associated with faster continence recovery. No EPUP patient had a urethral fossa positive margin, and apical positive margins were similarly infrequent among EPUP and non-EPUP patients. CONCLUSIONS: EPUP is technically feasible during RARP and associated with faster continence recovery. Future investigation into the generalizability of these findings and the oncologic safety of EPUP is warranted.

Purpose: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that are not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. Experimental Design: We have established and characterized a tRCC patient-derived xenograft, RP-R07, as a novel preclinical model for drug development by using next-generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway using in vitro and in vivo models. Results: The presence of a SFPQ-TFE3 fusion [t(X;1) (p11.2; p34)] with chromosomal break-points was identified by RNA-seq and validated by RT-PCR. TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway. Consistently, miRNA microarray analysis also identified PI3K/AKT/mTOR as a highly enriched pathway in RP-R07. Upregulation of PI3/AKT/mTOR pathway in additional TFE3–tRCC models was confirmed by significantly higher expression of phospho-S6 (P < 0.0001) and phospho-4EBP1 (P < 0.0001) in established tRCC cell lines compared with clear cell RCC cells. Simultaneous vertical targeting of both PI3K/AKT and mTOR axis provided a greater antiproliferative effect both in vitro (P < 0.0001) and in vivo (P < 0.01) compared with single-node inhibition. Knockdown of TFE3 in RP-R07 resulted in decreased expression of IRS-1 and inhibited cell proliferation. Conclusions: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3–tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for patients with TFE3–tRCC.

Despite general indolence of small renal masses and no known adversity from treatment delays, broad usage of active surveillance as a means to risk-stratify patients with small renal masses for more selective treatment has not been studied. We describe outcomes for a novel approach in which active surveillance was recommended to all patients with small renal masses lacking predefined progression criteria for intervention.All nondialysis dependent patients with nonmetastatic small renal masses seen by 1 urologist at a comprehensive cancer center during January 2013-September 2017 were managed with active surveillance if standardized progression criteria for intervention were absent, with delayed intervention recommended only upon progression criteria for intervention development. Progression criteria for intervention were defined prospectively as small renal mass-related symptoms, unfavorable histology, cT3a stage or either of the following without benign neoplastic biopsy histology: longest tumor diameter4 cm; growth rate5 mm/year for longest tumor diameter ≤3 cm or3 mm/year for longest tumor diameter3 cm.In all, 96% (123/128) of patients with small renal masses lacked progression criteria for intervention at presentation and underwent active surveillance. With median/mean 31/34 months followup, none developed metastasis and 30% (37/123) developed progression criteria for intervention, 78% (29/37) of whom underwent delayed intervention. One (1%) patient crossed over to delayed intervention without progression criteria for intervention. Three-year progression criteria for intervention-free and delayed intervention-free rates were 72% and 75%, respectively. Delayed intervention resections were enriched (62%) for pT3 and/or nuclear grade 3-4 malignant pathology, with no benign resections.Active surveillance using predefined progression criteria for intervention in otherwise unselected patients with small renal masses allows intervention to be focused on at-risk small renal masses with common adverse pathology, avoiding treatment for most patients with small renal masses. Long-term delayed intervention and oncologic safety require study.

Purpose: The diagnostic differential for CD117/KIT(+) oncocytic renal tumor biopsies is limited to benign renal oncocytoma versus chromophobe renal cell carcinoma (ChRCC); however, further differentiation is often challenging and requires surgical resection. We investigated clinical variables that might improve preoperative differentiation of CD117(+) renal oncocytoma versus ChRCC to avoid the need for benign tumor resection. Experimental Design: A total of 124 nephrectomy patients from a single institute with 133 renal oncocytoma or ChRCC tumors were studied. Patients from 2003 to 2012 comprised a retrospective cohort to identify clinical/radiographic variables associated with renal oncocytoma versus ChRCC. Prospective validation was performed among consecutive renal oncocytoma/ChRCC tumors resected from 2013 to 2017. Results: Tumor size and younger age were associated with ChRCC, and multifocality with renal oncocytoma; however, the most reliable variable for ChRCC versus renal oncocytoma differentiation was the tumor:cortex peak early-phase enhancement ratio (PEER) using multiphase CT. Among 54 PEER-evaluable tumors in the retrospective cohort [19 CD117(+), 13 CD117(−), 22 CD117-untested], PEER classified each correctly as renal oncocytoma (PEER >0.50) or ChRCC (PEER ≤0.50), except for four misclassified CD117(−) ChRCC variants. Prospective study of PEER confirmed 100% accuracy of renal oncocytoma/ChRCC classification among 22/22 additional CD117(+) tumors. Prospective interobserver reproducibility was excellent for PEER scoring (intraclass correlation coefficient, ICC = 0.97) and perfect for renal oncocytoma/ChRCC assignment (ICC = 1.0). Conclusions: In the largest clinical comparison of renal oncocytoma versus ChRCC to our knowledge, we identified and prospectively validated a reproducible radiographic measure that differentiates CD117(+) renal oncocytoma from ChRCC with potentially 100% accuracy. PEER may allow reliable biopsy-based diagnosis of CD117(+) renal oncocytoma, avoiding the need for diagnostic nephrectomy. Clin Cancer Res; 24(16); 3898–907. ©2018 AACR.

// Christopher J. Greene 1 , Kristopher Attwood 2 , Nitika J. Sharma 1 , Kenneth W. Gross 3 , Gary J. Smith 1 , Bo Xu 4 and Eric C. Kauffman 1, 5, 6 1 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 2 Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 3 Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 4 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 5 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 6 Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA Correspondence to: Eric C. Kauffman, email: eric.kauffman@roswellpark.org Keywords: transferrin receptor; iron; renal cell carcinoma; clear cell; immunohistochemistry Received: May 19, 2017 Accepted: August 31, 2017 Published: November 06, 2017 ABSTRACT The central dysregulated pathway of clear cell (cc) renal cell carcinoma (RCC), the von Hippel Lindau/hypoxia inducible factor-α axis, is a key regulator of intracellular iron levels, however the role of iron uptake in human RCC tumorigenesis and progression remains unknown. We conducted a thorough, large-scale investigation of the expression and prognostic significance of the primary iron uptake protein, transferrin receptor 1 (TfR1/CD71/TFRC), in RCC patients. TfR1 immunohistochemistry was performed in over 1500 cores from 574 renal cell tumor patient tissues (primary tumors, matched benign kidneys, metastases) and non-neoplastic tissues from 36 different body sites. TfR1 levels in RCC tumors, particularly ccRCC, were significantly associated with adverse clinical prognostic features (anemia, lower body mass index, smoking), worse tumor pathology (size, stage, grade, multifocality, sarcomatoid dedifferentiation) and worse survival outcomes, including after adjustments for tumor pathology. Highest TfR1 tissue levels in the non-gravid body were detected in benign renal tubule epithelium. Opposite to TfR1 changes in the primary tumor, TfR1 levels in benign kidney dropped during tumor progression and were inversely associated with worse survival outcomes, independent of tumor pathology. Quantitative measurement of TfR1 subcellular localization in cell lines demonstrated mixed cytoplasmic and membranous expression with increased TfR1 in clusters in ccRCC versus benign renal cell lines. Results of this study support an important role for TfR1 in RCC progression and identify TfR1 as a novel RCC biomarker and therapeutic target.

Cigarette smoking has been consistently associated with increased risk of overall mortality, but the importance of smoking for patients with prostate cancer (CaP) who are candidates for curative radical prostatectomy (RP) has received less attention. This retrospectively designed cohort study investigated the association of smoking history at RP with subsequent CaP treatment outcomes and overall mortality. A total of 1981 patients who underwent RP at Roswell Park Cancer Institute (RPCI) between 1993 and 2014 were studied. Smoking history was considered as a risk factor for overall mortality as well as for currently accepted CaP treatment outcomes (biochemical failure, treatment failure, distant metastasis, and disease‐specific mortality). The associations of smoking status with these outcomes were tested by Cox proportional hazard analyses. A total of 153 (8%) patients died during follow‐up. Current smoking at diagnosis was a statistically significant predictor of overall mortality after RP (current smokers vs. former and never smokers, hazards ratio 2.07, 95% confidence interval [CI]: 1.36–3.14). This association persisted for overall mortality at 3, 5, and 10 years (odds ratios 2.07 [95% CI: 1.36–3.15], 2.05 [95% CI: 1.35–3.12], and 1.8 [95% CI: 1.18–2.74], respectively). Smoking was not associated with biochemical failure, treatment failure, distant metastasis, or CaP‐specific mortality, and the association of smoking with overall mortality did not appear to be functionally related to treatment or biochemical failure, or to distant metastasis. Smoking is a non‐negligible risk factor for death among CaP patients who undergo RP; patients who smoke are far more likely to die of causes other than CaP.

BackgroundRenal cell carcinomas (RCC) harboring aTFE3gene fusion (TfRCC) represent an aggressive subset of kidney tumors. Key signaling pathways of TfRCC are unknown and preclinical in vivo data are lacking. We investigated Akt/mTOR pathway activation and the preclinical efficacy of dual mTORC1/2 versus selective mTORC1 inhibition in TfRCC.MethodsLevels of phosphorylated Akt/mTOR pathway proteins were compared by immunoblot in TfRCC and clear cell RCC (ccRCC) cell lines. Effects of the mTORC1 inhibitor, sirolimus, and the dual mTORC1/2 inhibitor, AZD8055, on Akt/mTOR activation, cell cycle progression, cell viability and cytotoxicity were compared in TfRCC cells. TfRCC xenograft tumor growth in mice was evaluated after 3-week treatment with oral AZD8055, intraperitoneal sirolimus and respective vehicle controls.ResultsThe Akt/mTOR pathway was activated to a similar or greater degree in TfRCC than ccRCC cell lines and persisted partly during growth factor starvation, suggesting constitutive activation. Dual mTORC1/2 inhibition with AZD8055 potently inhibited TfRCC viability (IC50 = 20-50 nM) due at least in part to cell cycle arrest, while benign renal epithelial cells were relatively resistant (IC50 = 400 nM). Maximal viability reduction was greater with AZD8055 than sirolimus (80–90% versus 30–50%), as was the extent of Akt/mTOR pathway inhibition, based on significantly greater suppression of P-Akt (Ser473), P-4EBP1, P-mTOR and HIF1α. In mouse xenograft models, AZD8055 achieved significantly better tumor growth inhibition and prolonged mouse survival compared to sirolimus or vehicle controls.ConclusionsAkt/mTOR activation is common in TfRCC and a promising therapeutic target. Dual mTORC1/2 inhibition suppresses Akt/mTOR signaling more effectively than selective mTORC1 inhibition and demonstrates in vivo preclinical efficacy against TFE3-fusion renal cell carcinoma.

4568 Background: Advanced sRCC is an aggressive disease with limited responsiveness to chemotherapy and VEGF-targeted therapies. Subgroup analyses from randomized trials showed improved outcomes with ICI, though sample sizes were relatively small. Methods: We conducted a multi-institutional retrospective analysis of consecutive patients (pts) who had RCC with any sarcomatoid component and received systemic therapy for advanced disease. The pts were classified into ICI+ and ICI- groups (gp) based on whether they had received ICI in any treatment line. Overall survival (OS) was measured from the initiation of first systemic therapy. Time to ICI failure (TIF) was defined as the interval from initiation of ICI to subsequent therapy or death. Survival distributions were estimated using the Kaplan-Meier method. Association between covariates and survival was analyzed using multivariate Cox regression. Two-tailed P < 0.05 was considered statistically significant. Results: 203 pts from 6 US academic cancer centers met the inclusion criteria – 155 in ICI+ gp and 48 in ICI- gp. Overall, 137 (67%) pts were male and 181 (89%) were white; median age at mRCC diagnosis was 59.7 (IQR 52.4-67.7) years; 129 (63%) pts presented de novo with distant metastases, 154 (76%) had clear cell (CC) histology, and 182 (90%) had intermediate/poor risk by IMDC criteria. ICI+ had a higher proportion of purely CC tumors (81% vs 64%, P =.02); other demographic and clinical features were similar between the two gps. After a median follow-up of 48.1 (95% CI 40.7-55.5) months (mos), median OS and response rates were significantly higher in the ICI+ gp (Table). OS benefit, compared to ICI-, was maintained in pts who received ICI in ≥ second line (39.6 vs 7.6 mos, HR 0.33, 95% CI 0.22-0.51, log-rank P - (HR 2.50, 95% CI 1.61-3.88, P + had higher OS (18.0 vs 5.5 mos, HR 0.20, 95% CI 0.09-0.44, P -. Conclusions: Treatment with ICI led to markedly higher survival and response rates in advanced sRCC. OS benefit was maintained with ICI in the second line and beyond. Significant benefit was also noted among pts with non-CC or mixed histology sRCC.[Table: see text]

103 Background: Opioids are routinely given for postoperative pain management with limited evidence on the amount needed to be dispensed. Prescribed opioids increase the risk of chronic use, abuse, and diversion, which contribute to the opioid epidemic. We sought to demonstrate that postsurgical acute pain can be effectively managed across different surgical specialties with a markedly reduced number of opioids. Methods: A prospective case-control study of restrictive opioid prescription protocol (ROPP) was implemented in all surgical services from February 2019 through July 2019 at a tertiary comprehensive cancer center for all patients undergoing a surgery for which opioids would be routinely prescribed at discharge (n = 2,015). Data from surgeries performed by the same services from August 2018 through January 2019 were used for comparison (n = 2,051). At discharge, patients did not routinely receive opioids unless they had a maximally invasive procedure or if they required multiple doses of opioids during hospitalization (maximum 3-day supply). Compliance with the protocol was tracked by pharmacists daily. Patient demographics and surgical details were collected. State-run opioid prescription database was used to determine the number of opioids prescribed to all surgical patients within a 120-day surgical window. Validated patient satisfaction surveys were used at postoperative visits to assess patient experience. Results: After implementation of the ROPP, 45% less opioids were prescribed after surgery for all participating patients (323,674 morphine milligram equivalents (MME) vs 179,458 MME, p < 0.001). The majority of services complied with the ROPP in more than 95% of cases. There was no difference in postsurgical pain intensity between cohorts. Patients in the ROPP cohort had less refill requests compared to the control group (20.9% vs 17.9%, p value = 0.016). Surveys were completed by 338 patients in the control group (16.5%) and 360 in the ROPP group (17.9%). There was no significant difference in patient reported satisfaction with postoperative pain control or on the impact of pain on daily activities between the cohorts. Conclusions: Implementation of a ROPP by multiple surgical services at a tertiary cancer center was feasible and resulted in substantial decrease in the number of opioids prescribed while not compromising patient experience. Patients did not require more prescription refills despite being provided no opioids or a limited supply. This study provides evidence to support reducing the number of opioids routinely prescribed after surgery.[Table: see text]

Active surveillance is a first line treatment option for patients with low risk prostate cancer but standardized regimens are lacking, including uniform protocols for surveillance prostate biopsy. We compared the outcomes of 2 active surveillance regimens that differ in whether a scheduled biopsy was performed in the absence of clinical progression.We retrospectively reviewed the records of 313 consecutive patients with prostate cancer at a NCCN® (National Comprehensive Cancer Network®) institution who were assigned prospectively to 1 of 2 active surveillance biopsy regimens. A total of 149 patients underwent biopsy only for clinical concern (for-cause only) while 164 underwent for-cause biopsy plus scheduled annual or biannual biopsy. Times to biopsy, clinical progression, pathological reclassification and treatment were compared using Kaplan-Meier methodology.The for-cause only and scheduled plus for-cause biopsy groups were similar in NCCN risk category at active surveillance initiation. Median followup was 48 and 38 months, respectively. No significant difference was observed in prostate specific antigen dynamics or clinical progression rates. However, patients in the scheduled plus for-cause group underwent significantly more frequent biopsies (p0.001) and experienced more biopsy related complications (p = 0.04), pathological reclassification (p = 0.02) and treatment conversion (p = 0.001). Adverse prostatectomy pathology (pT3 or greater and/or Gleason primary pattern 4) and early metastasis events were rare in both groups.Omitting a scheduled biopsy during active surveillance is associated with a decreased biopsy burden and treatment conversion. Although no increase in adverse pathology or early metastasis was observed in this study, longer followup in larger cohorts is necessary to determine the impact of scheduled biopsy omission on these adverse outcomes.

We compare oncologic outcomes of minimally invasive and open nephrectomy for locally advanced kidney cancer.A retrospective review of a single-institutional, prospectively maintained database from a National Comprehensive Cancer Network-designated center was conducted. All patients who underwent radical nephrectomy at Roswell Park Cancer Institute with diagnosis of pT3 and pT4 renal-cell carcinoma (RCC) between years 1998 and 2015 were reviewed. Patients who underwent partial nephrectomy and nephroureterectomy were excluded.We identified 172 patients with pT3 or pT4 tumors resected by minimally invasive (laparoscopic and robotic) or open radical nephrectomy. Demographic characteristics were similar between the two groups. Patients in the minimally invasive group had a higher mean body mass index (31.9 vs 28.1, p = 0.002), radiologically smaller tumors (7.7 cm vs 9.1 cm, p = 0.008), lower mean estimated blood loss (277 vs 1429, p 0.001), lower rate of blood transfusion (4.7% vs 45.5%, p 0.001), and a shorter mean length of stay (3.5 days vs 5.7 days, p 0.001) compared with patients who underwent open surgery. At a median follow-up of 32.8 months, there was no significant difference in overall survival (p = 0.8) between the two groups.Minimal invasive nephrectomy is a safe approach with similar oncologic outcomes to open nephrectomy for select patients with locally advanced RCC.

BACKGROUND Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men. METHODS A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database. RESULTS Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15 ng/dl with 95% of men having a PSA>3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%). CONCLUSIONS BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate © 2016 Wiley Periodicals, Inc.

To analyze the functional and oncologic outcomes of minimally invasive cytoreductive nephrectomy (CN) in three high-volume cancer centers. Three prospectively maintained, IRB-approved kidney surgery databases were queried from three high-volume cancer centers. All patients who underwent minimally invasive surgery (laparoscopic, hand-assisted laparoscopic, or robotic) partial or radical CN with existing measurable extra-renal metastatic disease between May 2001 and May of 2013 were included in this analysis. We identified 120 patients who underwent minimally invasive CN for metastatic renal cell carcinoma. Most of the surgeries were radical (93.3 %) and performed laparoscopically (96.6 %). Median operative time was 210 min, with a median estimated blood loss of 150 cc, and 11 (9.2 %) patients received blood transfusions. Four (3.3 %) patients were converted to open surgery due to locally advanced disease and/or bleeding. Postoperative complications were seen in 28 (23.3 %) patients, of which 20 (71.4 %) were classified as minor (Clavien–Dindo I–II). The median survival of the entire cohort was 25.7 months, with a 3-year survival rate of 35 %. Multivariate analysis indicated that only hypertension, brain metastasis, and pT stage were independently associated with worse overall survival (HR > 1). Minimally invasive cytoreductive nephrectomy is feasible and safe in experienced hands with acceptable morbidity and oncological outcomes.

PURPOSE: While the significance of circulating tumor cells in clinically localized cancer remains controversial, it has been reported that surgical tumor manipulation can increase circulating tumor cells, including during open prostatectomy. To our knowledge it is unknown whether this cell shedding also occurs during minimally invasive prostatectomy, which minimizes tumor palpation and uses earlier vascular control. We tested the impact of robotic assisted laparoscopic radical prostatectomy on intraoperative circulating tumor cell levels. MATERIALS AND METHODS: Circulating tumor cell counts were compared in peripheral blood specimens from 25 patients treated with robotic assisted laparoscopic radical prostatectomy preoperatively vs intraoperatively after prostate excision, in addition to 11 healthy blood donors. Circulating tumor cell detection was performed using EpCAM immunomagnetic enrichment and multiparametric flow cytometry quantification of viable EpCAM positive/prostate specific membrane antigen positive/CD45 negative cells. Intraoperative cell counts and increases were tested in univariable analyses for associations with perioperative variables, histopathology and postoperative progression. RESULTS: Circulating tumor cells were detected in 0% of healthy controls compared to 48% and 52% of prostatectomy cases preoperatively and intraoperatively, respectively (range 1 to 8 cells). There was no difference in the incidence or mean number of circulating tumor cells preoperatively vs intraoperatively. Of the patients 60% had no intraoperative change from preoperative levels. Intraoperative cell increases vs decreases were equally infrequent (each 20%) with no intraoperative increase greater than 1 circulating tumor cell. Intraoperative circulating tumor cell detection was not significantly associated with prostatectomy operative characteristics, histopathology or early postoperative progression at a median 21-month followup. CONCLUSIONS: Robotic assisted laparoscopic radical prostatectomy does not cause significant intraoperative increases in circulating tumor cells in contrast to historical reports of open prostatectomy. These findings may aid urologists in counseling candidates for robotic assisted laparoscopic radical prostatectomy regarding the possibility of intraoperative tumor cell shedding.

OBJECTIVE To determine the oncologic impact of prospectively assigned tertiary pattern 4 in contemporary Gleason score (GS) 3 + 3 = 6 radical prostatectomy (RP) specimens. PATIENTS AND METHODS Oncologic outcomes were retrospectively reviewed for 720 consecutive patients from a single National Comprehensive Cancer Network (NCCN) center with at least 6 months follow-up after RP for GS3 + 3 = 6 (GS6, N = 222), GS6 with tertiary pattern 4 (GS6t4, N = 62), or GS3 + 4 = 7 (N = 436) prostate cancer, as prospectively graded since 2006 using the 2005 International Society of Urologic Pathologists criteria. Preoperative NCCN risk category, RP pathology, progression-free survival (PFS) and metastasis-free survival (MFS) were compared among the GS6, GS6t4, and GS3 + 4 = 7 groups using χ2, Kaplan–Meier, and log-rank analyses. RESULTS The incidence of low NCCN preoperative risk classification for GS6t4 patients (63%) was less than that for GS6 patients (77%) while greater than that for GS3 + 4 = 7 patients (30%, P

BACKGROUND AND OBJECTIVES: Accumulating data implicate iron accumulation in tumorigenesis of the kidney, particularly the clear cell renal cell carcinoma (ccRCC) subtype. The von Hippel Lindau (VHL)/hypoxia inducible factor-α (HIF-α) axis is uniquely dysregulated in ccRCC and is a major regulator and regulatory target of iron metabolism, yet the role of iron in ccRCC tumorigenesis and its potential interplay with VHL inactivation remains unclear. We investigated whether ccRCC iron accumulation occurs due to increased cell dependency on iron for growth and survival as a result of VHL inactivation. MATERIALS AND METHODS: Free iron levels were compared between four VHL-mutant ccRCC cell lines (786–0, A704, 769-P, RCC4) and two benign renal tubule epithelial cell lines (RPTEC, HRCEp) using the Phen Green SK fluorescent iron stain. Intracellular iron deprivation was achieved using two clinical iron chelator drugs, deferasirox (DFX) and deferoxamine (DFO), and chelator effects were measured on cell line growth, cell cycle phase, apoptosis, HIF-1α and HIF-2α protein levels and HIF-α transcriptional activity based on expression of target genes CA9, OCT4/POU5F1 and PDGFβ/PDGFB. Similar assays were performed in VHL-mutant ccRCC cells with and without ectopic wild-type VHL expression. RESULTS: Free iron levels were significantly higher in ccRCC cell lines than benign renal cell lines. DFX depleted cellular free iron more rapidly than DFO and led to greater growth suppression of ccRCC cell lines (>90% at ~30–150 μM) than benign renal cell lines (~10–50% at up to 250 μM). Similar growth responses were observed using DFO, with the exception that a prolonged treatment duration was necessary to deplete cellular iron adequately for differential growth suppression of the less susceptible A704 ccRCC cell line relative to benign renal cell lines. Apoptosis and G1-phase cell cycle arrest were identified as potential mechanisms of chelator growth suppression based on their induction in ccRCC cell lines but not benign renal cell lines. Iron chelation in ccRCC cells but not benign renal cells suppressed HIF-1α and HIF-2α protein levels and transcriptional activity, and the degree and timing of HIF-2α suppression correlated with the onset of apoptosis and differential growth suppression. Restoration of wild-type VHL function in ccRCC cells was sufficient to prevent chelator-induced apoptosis and G1 cell cycle arrest, indicating that ccRCC susceptibility to iron deprivation is VHL inactivation-dependent. CONCLUSION: ccRCC cells are characterized by high free iron levels and a cancer-specific dependency on iron for HIF-α overexpression, cell cycle progression and apoptotic escape. This iron dependency is introduced by VHL inactivation, revealing a novel interplay between VHL/HIF-α dysregulation and ccRCC iron metabolism. Future study is warranted to determine if iron deprivation using chelator drugs provides an effective therapeutic strategy for targeting HIF-2α and suppressing tumor progression in ccRCC patients.

Objectives: To develop a methodology for predicting operative times for robot-assisted radical prostatectomy (RARP) using preoperative patient, disease, procedural, and surgeon variables to facilitate operating room (OR) scheduling. Methods: The model included preoperative metrics: body mass index (BMI), American Society of Anesthesiologists score, clinical stage, National Comprehensive Cancer Network risk, prostate weight, nerve-sparing status, extent and laterality of lymph node dissection, and operating surgeon (six surgeons were included in the study). A binary decision tree was fit using a conditional inference tree method to predict operative times. The variables most associated with operative time were determined using permutation tests. Data were split at the value of the variable that results in the largest difference in mean for surgical time across the split. This process was repeated recursively on the resultant data. Results: A total of 1709 RARPs were included. The variable most strongly associated with operative time was the surgeon (surgeons 2 and 4—102 minutes shorter than surgeons 1, 3, 5, and 6, p

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognized subtype of renal cell carcinoma entity after 2004 World Health Organization classification of renal tumors. CCPRCC has unique histomorphological and immunohistochemical characteristics. The distinction of CCPRCC from renal cell carcinoma (RCC) with clear cell morphology is crucial because the former is considered to have a favorable clinical outcome. CCPRCC may be interpreted in the past as other renal cell carcinomas, particularly low-grade clear cell RCC. In this study, the frequency of CCPRCC in previously diagnosed low-grade RCC and its clinicopathologic features were examined. A total of 126 cases of stage T1a with low nuclear grade RCC were identified from 625 consecutive RCCs removed by radical/partial nephrectomy over 12-year period (2000-2011). Archival tissue sections were retrospectively reviewed along with patient medical charts. Eight cases (1.3% of all RCC, 6.3% of pT1a low grade RCC) with characteristic histologic features of CCPRCC were confirmed by immunohistochemical studies. Seven cases were previously diagnosed as clear cell RCC and one as multilocular cystic RCC. Radiographically, CCPRCC favored a mid-pole location in the kidneys. At a median follow-up period of 52 months (range 20-114.5 months), there were no cases of local or distant recurrence. In conclusion, CCPRCC is not uncommon among small low-grade RCC tumors. CCPRCC can be correctly recognized by its unique histomorphological features and confirmed by immunohistochemistry studies, which is important due to the excellent clinical outcome following resection.

Despite nearly two decades since the discovery of gene fusions involving TFE3 or TFEB (“TFE”) in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis remains largely unclear. The recent publication of the TCGA Network's clear cell kidney cancer paper provides further evidence for the importance of gene fusions by identifying 5 tumors harboring SFPQ-TFE3 fusions that otherwise lacked the common clear cell RCC associated mutation. Herein, we review key molecular features of TFE-fusion RCC, including candidate signaling pathways contributing to oncogenesis and a detailed overview of gene fusion isoforms based on an updated knowledge of TFE genetic organization. A total of 5 TFE3 gene fusions (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3, CLTC-TFE3) and 1 TFEB gene fusion (MALAT1-TFEB) have been identified in RCC tumors and characterized at the mRNA transcript level, with considerable heterogeneity in exon structure across different tumors, even for the same fusion partners. Common to all TFE3 and TFEB fusion isoforms is the retention of the wild-type protein C-terminus, including domains for DNA-binding, dimerization, and nuclear localization, but interestingly, not transcriptional activation. Despite this, the most widely accepted model explaining TFE-fusion oncogenesis remains the introduction of a constitutively active promoter leading to dysregulated TFE transcriptional activity. A multitude of molecular pathways well-implicated in carcinogenesis are regulated in part by TFE3 and/or TFEB protein, including activation of TGFβ and ETS transcription factors, E-cadherin expression, CD40L-dependent lymphocyte activation, mTORC1 signaling, insulin-dependent metabolism regulation, folliculin signaling, and Rb-dependent cell cycle arrest. Determining which pathways are most important will be critical to discovering the most promising therapeutic targets for this disease. Useful to this goal is a panel of cell lines derived from different TFE3-fusion RCC patient tumors, representing multiple fusion isoforms.

Objective To characterise the surgical feasibility and outcomes of robot-assisted radical cystectomy (RARC) for pathological T4 bladder cancer. Patients and Methods Retrospective evaluation of a prospectively maintained International Radical Cystectomy Consortium database was conducted for 1118 patients who underwent RARC between 2003 and 2012. We dichotomised patients based on pathological stage (≤pT3 vs pT4) and evaluated demographic, operative and pathological variables in relation to morbidity and mortality. Results In all, 1000 ≤pT3 and 118 pT4 patients were evaluated. The pT4 patients were older than the ≤pT3 patients (P = 0.001). The median operating time and blood loss were 386 min and 350 mL vs 396 min and 350 mL for p T4 and ≤pT3, respectively. The complication rate was similar (54% vs 58%; P = 0.64) among ≤pT3 and pT4 patients, respectively. The overall 30- and 90-day mortality rate was 0.4% and 1.8% vs 4.2% and 8.5% for ≤pT3 vs pT4 patients (P < 0.001), respectively. The body mass index (BMI), American Society of Anesthesiology score, length of hospital stay (LOS) >10 days, and 90-day readmission were significantly associated with complications in pT4 patients. Meanwhile, BMI, LOS >10 days, grade 3–5 complications, 90-day readmission, smoking, previous abdominal surgery and neoadjuvant chemotherapy were significantly associated with mortality in pT4 patients. On multivariate analysis, BMI was an independent predictor of complications in pT4 patients, but not for mortality. Conclusions RARC for pT4 bladder cancer is surgically feasible but entails significant morbidity and mortality. BMI was independent predictor of complications in pT4 patients.

Objective To present our experience of high-dose interleukin-2 (HDIL-2) in a high-volume National Cancer Institute–designated center for patients with metastatic renal cell carcinoma (mRCC). Methods Patients with mRCC who received HDIL-2 monotherapy as a first- or second-line therapy during 2004-2011 were identified. Demographics, pathologic variables, renal function, time until the start of HDIL-2 therapy, number of cycles (1-3), responses (complete response, partial response, stable disease, and progressive disease), and primary renal cell carcinoma treatment were analyzed. Progression-free survival and overall survival (OS) were determined. Results Of 906 patients in the kidney cancer database, 91 patients with mRCC were treated with HDIL-2 and 18 patients (20.5%) underwent prior cytoreductive nephrectomy. Median age was 51 years, and 73.9% were men. Median follow-up was 45 months. Pretreatment renal function impairment led to more treatment cycles (2-3) than in those with adequate initial kidney function (92.3% vs 50.6%, respectively; P = .002). Lower tumor stage correlated with a better response ( P = .023) and with longer time from diagnosis to initiation of HDIL-2 ( P = .011). Complications included hypotension (67.4%), renal impairment (63%), impaired liver function (42.4%), and thrombocytopenia (31.5%). Four patients (4.5%) had a complete response, 10 (11.4%) had a partial response, and 28 (31.8%) had a stable disease. Median progression-free survival and OS were 8.6 and 35.5 months, respectively. The estimated 2-year OS rate was 60.6%. Conclusion Incorporating HDIL-2 therapy in the treatment strategies for mRCC added to the patients' survival in this series. HDIL-2 therapy is well tolerated in patients with pre-existing renal impairment with no long-term renal toxicity.

Objective To externally validate currently available bladder cancer nomograms for prediction of all-cause survival (ACS), cancer-specific survival (CSS), other-cause mortality (OCM) and progression-free survival (PFS). Patients and Methods Retrospective analysis of a prospectively maintained database of 282 patients who underwent robot-assisted radical cystectomy (RARC) at a single institution was performed. The Bladder Cancer Research Consortium (BCRC), International Bladder Cancer Nomogram Consortium (IBCNC) and Lughezzani nomograms were used for external validation, and evaluation for accuracy at predicting oncological outcomes. The 2- and 5-year oncological outcomes were compared, and nomogram performance was evaluated through measurement of the concordance (c-index) between nomogram-derived predicted oncological outcomes and observed oncological outcomes. Results The median (range) patient age was 70 (36–90) years. At a mean follow-up of 20 months, local or distant disease recurrence developed in 30% of patients. With an overall mortality rate of 33%, 17% died from bladder cancer. The actuarial 2- and 5-year PFS after RARC was 62% (95% confidence interval [CI] 54–68) and 55% (95% CI 46–63), respectively. The actuarial 2- and 5-year ACS was 66% (95% CI 59–72) and 47% (95% CI 37–55), respectively, and the 2- and 5-year CSS was 81% (95% CI 74–86) and 67% (95% CI 57–76), respectively. The PFS c-index for IBCNC was 0.70 at 5 years, and for BCRC was 0.77 at both the 2 and 5 years. The accuracy of ACS and CSS prediction was evaluated using the BCRC and Lughezzani nomograms. Using the BCRC nomogram, c-indices of for 2- and 5-year ACS were each 0.73 and c-indices for 2- and 5-year CSS were 0.70 each. The performance of Lughezzani nomogram for 5-year ACS, cancer-specific mortality and OCM were 0.73, 0.72 and 0.40, respectively. The BCRC nomogram prediction of advanced pathological stage and lymph node metastasis was modest, with c-indices of 0.66 and 0.61, respectively. Conclusions Bladder cancer nomograms available from the current open RC literature adequately predict ACS, CSS and PFS after RARC. However, prediction of advanced tumour stage and lymph node metastasis was modest and the Lughezzani nomogram failed to predict OCM.

Background Retrospective identification of Gleason pattern 4 in metastatic Gleason score 3 + 3 = 6 (GS6) radical prostatectomy (RP) specimens has suggested true GS6 prostate cancer (CaP) lacks metastatic potential. However, pathologist awareness of study design and metastasis outcomes at the time of RP review might have introduced upgrading bias. We used pathologist-blinded methodology for unbiased characterization of metastasis rates for contemporarily defined pathologic GS6 (pGS6) CaP. Methods An institutional RP database was queried to identify pGS6 patients with metastasis or concern for micrometastasis based on: 1) biochemical failure (BF) despite negative surgical margins or 2) incomplete biochemical response to salvage/adjuvant radiation. RP specimens were regraded independently by two genitourinary pathologists blinded to study aims or clinical outcomes. Additional blinding was performed by random inclusion of pGS6 control specimens from BF-free patients. Only upgrading identified independently by both pathologists was considered. Results Among 451 pGS6 patients identified, none had synchronous lymph node metastases and 43/451 (10%) suffered BF. Two patients (0.4%) developed metachronous metastasis during a 110-month median follow-up for BF patients. Both metastatic cases had Gleason pattern 4 on blinded RP review, as did 88% of cases with concern for micrometastasis versus 38% of control cases (P = 0.02). All BF patients (29/29) undergoing postoperative radiation had a complete biochemical response or Gleason pattern 4 on blinded RP review. Conclusions Unbiased pathologist review of archival RP specimens supports absent metastatic potential for contemporarily defined GS6 CaP. Reduced postoperative monitoring is appropriate for pGS6, but may require pathology review to confirm absent Gleason pattern 4.

561 Background: Pazopanib as single agent and bevacizumab plus interferon were approved for use in metastatic RCC (MRCC) based on their ability to modulate the vasculature and prolong progression free survival. VEGF levels rose unopposed while using VEGF tyrosine kinase inhibitors (TKI) without break. We hypothesized that adding a break as well as bevacizumab which removes VEGF could prolong PFS in MRCC pts. Methods: This phase I trial was conducted in VEGF treatment naïve MRCC pts. This trial utilized a unique regimen of alternating Pazopanib (day 1-28) with bevacizumab (on days 36 and 50) in a 10-week cycle. The study employed a classic 3+3 design for dose escalation (dose levels in table 1). Safety utilized CTCAE version 4.0 and response evaluation was done using RECIST 1.1 criteria. The primary endpoint of this phase I trial was to find the recommended phase 2 dose (RP2D) of this novel regimen. Key secondary endpoints included objective response rate (ORR), safety/ toxicity and pharmacokinetics. Phase I safety committee acknowledged the completion and approved reporting of Phase I portion of this study. Results: This phase I study was conducted at two academic centers. Twenty-five pts were enrolled in the phase I portion. Median age was 64 years and 68% were male patients. The Commonest adverse events (AE) included fatigue (64%), diarrhea (52%), hypertension (48%), nausea (36%), dysgeusia (36%), vomiting (24%) and proteinuria (28%). The commonest grade 3/4 AE of more than 5% frequency included hypertension (20%) and proteinuria (12%). The dose levels 1 and 4 were expanded due to one DLT each and RP2D was established at dose level 4. The ORR was 25% among evaluable pts who completed at least one cycle of therapy (n=20). The median PFS of the ITT cohort (n=25) was 20.9 months. Conclusions: These data demonstrate that this novel regimen could be safely tested in a phase II trial. The safety and efficacy data suggest that this novel regimen could be optimal for MRCC patients with favorable/intermediate risk. Clinical trial information: NCT01684397. [Table: see text]

Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma.Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity.Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies.Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Background The Kattan postoperative radical prostatectomy (RP) nomogram is used to predict biochemical recurrence-free progression (BCRFP) after RP. However, external validation among contemporary patients using modern outcome definitions is limited. Methods A total of 1,931 patients who underwent RP at Roswell Park Cancer Institute (RPCI) between 1993 and 2014 (median follow-up, 47 months; range, 0-244 months) were assessed for NCCN-defined biochemical failure (BF) and RPCI-defined treatment failure (TF). Actual rates of biochemical failure-free survival (BFS; defined as 1 - BF) and treatment failure-free survival (TFS; defined as 1 - TF) were compared with Kattan BCRFP nomogram predictions. Results The Kattan BCRFP nomogram predictions at 5 and 10 years were predictive of BFS (area under the receiver operating characteristic curve [AUC], 0.772) and TFS (AUC, 0.774). The Kattan BCRFP nomogram tended to underestimate BFS and TFS compared with actual outcomes. The Kattan 5-year BCRFP predictions consistently overestimated actual 5-year BFS outcomes among subgroups of high- and intermediate-risk patients with at least 5-year outcomes. Conclusions The Kattan BCRFP nomogram is a robust predictor of NCCN-defined BF in a large sample of patients with RP with substantial follow-up and modern, standardized failure definitions.

To determine the oncologic impact of prospectively assigned tertiary pattern 4 in contemporary Gleason score (GS) 3 + 3 = 6 radical prostatectomy (RP) specimens.Oncologic outcomes were retrospectively reviewed for 720 consecutive patients from a single National Comprehensive Cancer Network (NCCN) center with at least 6 months follow-up after RP for GS3 + 3 = 6 (GS6, N = 222), GS6 with tertiary pattern 4 (GS6t4, N = 62), or GS3 + 4 = 7 (N = 436) prostate cancer, as prospectively graded since 2006 using the 2005 International Society of Urologic Pathologists criteria. Preoperative NCCN risk category, RP pathology, progression-free survival (PFS) and metastasis-free survival (MFS) were compared among the GS6, GS6t4, and GS3 + 4 = 7 groups using χ(2) , Kaplan-Meier, and log-rank analyses.The incidence of low NCCN preoperative risk classification for GS6t4 patients (63%) was less than that for GS6 patients (77%) while greater than that for GS3 + 4 = 7 patients (30%, P 0.001). GS6t4 patients had RP pathologic features which were intermediate in risk between that of GS6 and GS3 + 4 = 7 based on extraprostatic extension (27% vs. 6% vs. 31%, respectively, P 0.001) and mean percentage of prostate gland involvement (13% vs. 10% vs. 16%, respectively, P 0.001). With a mean overall follow-up of 42 months, PFS for GS6t4 patients (5-year 85%) was intermediate between that of GS6 (5-year 93%) and GS3 + 4 = 7 (5-year 76%) patients (P 0.001). The 5-year MFS rate was 100% for GS6 and GS6t4 patients compared to 97% for GS3 + 4 = 7 patients (P = 0.07).This study provides the longest follow-up to date for RP patients with prospectively assigned GS6t4 and supports a risk for adverse RP pathology and postoperative disease progression that is intermediate between GS6 and GS3 + 4 = 7. Whether a tertiary pattern 4 in GS6 disease increases the risk of metastasis is uncertain and requires longer term study. Given favorable oncologic outcomes, less stringent postoperative surveillance for both GS6 and GS6t4 patients may be warranted.

Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men.A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database.Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15 ng/dl with 95% of men having a PSA3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%).BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate 76:1135-1145, 2016. © 2016 Wiley Periodicals, Inc.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE • To determine oncological outcomes including early survival rates among unselected bladder urothelial carcinoma (BUC) patients treated with robotic-assisted radical cystectomy (RRC). PATIENTS AND METHODS • Clinicopathologic and survival data were prospectively gathered for 85 consecutive BUC patients treated with RRC. • The decision to undergo a robotic rather than open approach was made without regard to tumor volume or surgical candidacy. • Kaplan–Meier survival rates were determined and stratified by tumor stage and LN positivity, and multivariate analysis was performed to identify independent predictors of survival. RESULTS • Patients were relatively old (25% >80 years; median 73.5 years), with frequent comorbidities (46% with ASA class ≥3). Of these patients 28% had undergone previous pelvic radiation or pelvic surgery, and 20% had received neoadjuvant chemotherapy. • Extended pelvic lymphadenectomy was performed in 98% of patients, with on average 19.1 LN retrieved. • On final pathology, extravesical disease was common (36.5%). • Positive surgicalmargins were detected in five (6%) patients, all of whom had extravesical tumors with perineural and/or lymphovascular invasion, and most of whom were >80 years old. • At a mean postoperative interval of 18 months, 20 (24%) patients had developed recurrent disease, but only three (4%) patients had recurrence locally. Disease-free, cancer-specific and overall survival rates at 2 years were 74%, 85% and 79%, respectively. Patients with low-stage/LN(−) cancers had significantly better survival than extravesical/LN(−) or any-stage/LN(+) patients, with stage being the most important predictor on multivariate analysis. CONCLUSION • RRC can achieve adequately high LN yields with a low positive margin rate among unselected BUC patients. • Early survival outcomes are similar to those reported in contemporary open series, with an encouragingly low incidence of local recurrence, however long-term follow-up and head-to-head comparison with the open approach are still needed.

5068Background: High CD8+ tumor infiltrating lymphocytes (TILs) are associated with improved survival in many solid tumors. However, its prognostic value in prostate cancer (PCa) is unclear. Method...

PurposeGleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management.Materials and methodsMembers of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes.ResultsThe Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes.ConclusionsThe definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening.

Current guidelines for metastatic renal cell carcinoma (mRCC) do not recommend routine brain imaging as part of the surveillance protocol unless central nervous system (CNS) symptoms or abnormal laboratory values suggest brain involvement. We hypothesized that strict adherence to these guidelines will delay diagnosis and management of RCC brain metastases. Retrospective review of our IRB-approved kidney cancer database examined a consecutive series of subjects from 1995 to 2012. We identified all mRCC patients with radiographic evidence of renal cell brain metastasis (RCCBM). RCCBM patients were divided into two cohorts: CNS symptoms present at RCCBM diagnosis and those without symptoms present at diagnosis. Fifty-two patients within our database met criteria; CNS symptoms were present at RCCBM diagnosis in 73 % (36) of patients. Median size of RCCBM on presentation was smaller in the asymptomatic verses the symptomatic cohort (0.83 vs. 1.7 cm, p = 0.003). Multivariate analysis demonstrated presence of CNS symptoms and female gender as a survival advantage (p < 0.05) while poor performance status, history of tobacco abuse and coexistence of lung metastasis were poor indicators for survival (p < 0.05). Patients with pulmonary metastases and a history of tobacco abuse are more likely to harbor RCCBM and perhaps in the absence of CNS symptoms these subjects should have routine brain surveillance incorporated into the RCC follow up. Overall, the current urologic guidelines may be missing a subset of metastatic RCC patients who could potentially benefit from early radiation or neurosurgical intervention. This may result in improved overall survival.

Smoking is the best established modifiable risk factor for renal cell carcinoma. However, the risks of individual renal cell carcinoma histological subtypes are unknown. Therefore, we investigated the relationship between smoking and renal cell carcinoma subtype.Cigarette smoking data were prospectively collected from 816 consecutive patients with nonfamilial renal cell carcinoma (705) or benign pathology (111) undergoing nephrectomy at a single National Comprehensive Cancer Network® cancer center, and were retrospectively tested for an association with histological diagnosis on univariable and propensity adjusted analyses.Smoking was reported by 51% of patients, including 21% active smokers and 30% former smokers. Active smoking was more common with clear cell (23%) or papillary (26%) renal cell carcinoma than benign histology (14%, p0.05 each), yet strikingly less common with chromophobe renal cell carcinoma (6%, p0.05 vs clear cell or papillary). Any smoking history (active or former) was also relatively uncommon with chromophobe (26%) vs clear cell (53%, p = 0.003) or papillary (58%, p = 0.001) histology. Smoking extent based on mean pack-years was significantly greater with clear cell (15.3 mean pack-years) or papillary (15.2 mean pack-years) renal cell carcinoma but not chromophobe renal cell carcinoma (9.4 mean pack-years) compared to benign histology (9.4 mean pack-years, p ≤0.05, p0.05, p = 1.0, respectively). On propensity analyses adjusting for multiple variables, clear cell (OR 2.2, p0.05) and papillary (OR 2.4, p0.05) histologies but not chromophobe histology remained independently associated with active smoking.Traditional understanding of smoking as a renal cell carcinoma risk factor applies to clear cell and papillary renal cell carcinoma but not the chromophobe subtype. These findings underscore distinct carcinogenic mechanisms underlying the various renal cell carcinoma subtypes.