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Background There is an ongoing need to develop prognostic biomarkers to improve the management of clear cell renal cell carcinoma (ccRCC). Objective To leverage enriched pathways in ccRCC to improve risk-stratification. Design, setting, and participants We retrospectively identified two complementary discovery cohorts of patients with ccRCC who underwent (1) radical nephrectomy (RNx) with inferior vena cava tumor thrombectomy (patients = 5, samples = 24) and (2) RNx for localized disease and developed recurrence versus no recurrence (n = 36). Patients with localized ccRCC (M0) in The Cancer Genome Atlas (TCGA, n = 386) were used for validation. Outcome measurements and statistical analysis A differential expression gene (DEG) analysis was performed on targeted RNA next-generation sequencing data from both discovery cohorts. Using TCGA for validation, Kaplan-Meier survival analysis and multivariable Cox proportional hazard testing were utilized to investigate the prognostic impact of DEGs, cell cycle proliferation (CCP), and a novel epithelial-mesenchymal transition (EMT) score on progression-free (PFS) and disease-specific (DSS) survival. Results and limitations In the discovery cohorts, we observed overexpression of WT1 and CCP genes in the tumor thrombus versus the primary tumor, as well as in patients with recurrence versus those without recurrence. A hallmark pathway analysis demonstrated enrichment of the EMT- and CCP-related pathways in patients with high WT1 expression in the TCGA (validation) ccRCC cohort. CCP and EMT scores were derived in the validation cohort, which was stratified into four risk groups using Youden Index cut points: CCPlow/EMTlow, CCPlow/EMThigh, CCPhigh/EMTlow, and CCPhigh/EMThigh. The CCPhigh/EMThigh risk group was associated with the worst PFS and DSS (both p Conclusions We demonstrate the synergistic prognostic impact of EMT in tumors with a high CCP score. Our novel EMT score has the potential to improve risk stratification and provide potential novel therapeutic targets. Patient summary Genes involved in epithelial-mesenchymal transition provides important prognostic information for patients with clear cell renal cell carcinoma.

ObjectiveTo evaluate the association of the MyProstateScore (MPS) urine test on the decision to undergo biopsy in men referred for prostate biopsy at a contemporary academic urology practice.MethodsMPS testing was offered as an alternative to immediate biopsy in men referred to the University of Michigan for prostate biopsy from October 2013 through October 2016. The primary endpoint was the decision to perform biopsy. The proportion of patients who underwent biopsy was calculated across MPS quintiles and compared to predicted risk scores from the Prostate Cancer Prevention Trial risk calculator (PCPTrc). Analyses were performed in the overall referral population and the intended-use population (PSA 3-10 ng/ml or PSA ResultsOf 248 patients, 134 (54%) proceeded to prostate biopsy. Clinical variables, PSA, and PCPTrc score did not significantly differ based on the decision to undergo biopsy, while MPS was significantly higher in biopsied patients (median 29 vs. 14, pConclusionIn a cohort of patients who underwent clinical MPS testing as an alternative to immediate prostate biopsy, 46% were able to avoid biopsy and increasing MPS was strongly associated with biopsy rates. These findings were robust to the use of mpMRI and consistent across pertinent subpopulations. Overall, these data suggest that the MPS assay may substantially reduce the number of men undergoing prostate needle biopsy.

The purpose of this review is to highlight the role of existing and promising urinary biomarkers for the detection and prognostication of prostate cancer (PCa). A number of novel urinary biomarkers have been introduced into the clinical space, which in combination with clinical variables, have demonstrated an increased ability to select patients for biopsy and identify men at risk of harboring clinically significant PCa. Though a number of assays require further validation, initial data is promising and forthcoming results will ultimately determine their clinical utility and commercial availability. For the past 30 years, first-line screening for PCa has relied on measurement of serum prostate-specific antigen (PSA) levels and the results from a digital rectal exam (DRE). A large body of evidence from the last 3 decades indicates that these screening methods are problematic, and often inadequate for detecting clinically significant PCa. Extensive efforts have recently been made to identify and commercialize novel PCa biomarkers for more effective detection of PCa, either alone or in combination with current screening methods. This review article highlights problems with current screening standards, and discusses 6 urinary biomarker assays in terms of their ability to detect and risk-stratify PCa: prostate cancer antigen 3 (PCA3), TMPRSS2-ERG, second chromosome locus associated with prostate-1 (SChLAP1), ExoDx, SelectMDx, and Michigan Prostate Score (MiPS).

Objective Robotic-assisted thoracoscopic transdiaphragmatic adrenalectomy (RATTA) represents a novel surgical approach for the management of adrenal pathology in patients with a history of extensive transperitoneal or retroperitoneal procedures. Methods Here we report the first described case of RATTA in a 56-year-old woman with metastatic renal cell carcinoma to the left adrenal gland and right lung. With the assistance of cardiothoracic surgery, this patient underwent robotic-assisted thoracoscopic pulmonary wedge resection and RATTA. In brief, after completion of the pulmonary wedge resection by thoracic surgery the diaphragm was incised starting at the left crus and extending laterally through the diaphragmatic muscle, exposing the retroperitoneal space and fat. The adrenal gland with mass was identified, dissected from surrounding structures, and extracted. The diaphragm was then closed using Ethibond suture with polytetrafluoroethylene felt pledgets. A 22-Fr chest tube was placed in the thoracic cavity. Results Operative and postoperative courses were uncomplicated. The patient was discharged on postoperative day 4. Pathology confirmed metastatic clear cell renal cell carcinoma in both the left adrenal and the right lung nodules with negative surgical margins. Conclusion The case described here highlights the surgical technique and ideal patient population in which RATTA serves as a feasible and safe alternative to conventional laparoscopic approaches in the treatment of adrenal pathologies.

INTRODUCTION AND OBJECTIVES:We conducted a phase II trial to evaluate combination therapy with BCG and Sunitinib for prevention of recurrence and progression of high-risk NMIBC with a primary endpoint of 3-month complete response (CR). We hypothesized that adding Sunitinib to BCG could increase the initial CR to therapy by synergistic inhibition of the VEGF pathway. We also measured urine levels of various biomarkers throughout treatment to identify trends that predict and/or explain a response to therapy.METHODS:Patients with high-grade clinical ≤T1N0M0 NMIBC who had not received BCG within 12 months of diagnosis were deemed eligible. Patients received a 6-week induction BCG course followed by 28 days of Sunitinib. CR was determined by biopsy and cytology. Urine samples were collected from patients before and after both BCG and Sunitinib. Urine biomarker levels were measured using a multiplexed bead assay for angiopoietin 2 (AP-2), fibroblast growth factor 2 (FGF-2), interleukin 8 (IL-8), and VEGF-A, -C,...

To evaluate whether incidental pathologic T3a (pT3a) upstaging after partial nephrectomy (PN) for clinical T1 disease results in inferior oncologic outcomes compared to pT1a-b disease.Retrospective chart review was completed at the University of Michigan and Moffitt Cancer Center to identify patients undergoing PN for clinical T1 masses between 1995 and 2015. A total of 1955 patients were identified, of which 95 had pT3a upstaging. Median follow-up was 38.2 months. Patients with pT3a disease were individually matched by clinicopathologic features with patients undergoing PN with pT1a-b disease in a 1:2 ratio. Kaplan-Meier analysis and univariate and multivariable Cox proportional hazards regression analysis were performed. Primary endpoint was recurrence-free survival (RFS). Secondary endpoints were all-cause mortality, cancer-specific survival (CSS), and rates of local and distant recurrence.Recurrence rates were significantly higher in pT3a disease compared to pT1a-b controls (P .01). In those patients with pT3a upstaging, 3- and 5-year RFS were 81% and 58%, compared to 86% and 75% in pT1a-b controls (P = .01). CSS at 3 and 5 years were 91% and 90% in pT3a disease and 100% and 97% in pT1a-b controls (P .01). All-cause mortality at 3 and 5 years were 82% and 71% in pT3a disease and 93% and 80% in pT1a-b controls (P = .04). Univariate and multivariable analysis of pT3a disease demonstrated no association between demographic or pathologic characteristics and RCC recurrence.Patients with pT3a upstaging following PN experience a significantly reduced RFS and CSS when compared to pT1 disease.

Objective To evaluate the outcome of patients after surgical resection of isolated retroperitoneal lymph node (RPLN) recurrence of renal cell carcinoma (RCC) using a multicentre international cohort. Patients and Methods In all, 50 patients were identified who underwent resection of isolated RPLN recurrence of RCC at four institutions after nephrectomy for pTanyNanyM0 disease. Progression-free (PFS) and cancer-specific survival (CSS) were estimated using the Kaplan–Meier method. Cox proportional hazards regression models were used to assess the association of clinicopathological characteristics with disease progression. Results The median (interquartile range, IQR) age at resection was 57.0 (50.0–62.5) years. The median (IQR) time to RPLN recurrence after nephrectomy was 12.6 (6.9–39.5) months, with no significant difference in median time to RPLN recurrence between patients with N+ disease at nephrectomy (10.7 [6.5–24.6] months) and those with Nx/pN0 disease at nephrectomy (13.7 [8.7–44.2] months) (P = 0.66). The median (IQR) size of the RPLN recurrence before resection was 2.6 (1.9–5) cm. The most common site for RPLN recurrence was within the interaortocaval region (34%). The median (IQR) follow-up after RPLN resection for patients alive at last follow-up was 28.0 (13.7–51.2) months. During follow-up, 26 patients developed RCC recurrence, at a median (IQR) of 9.9 (4.0–18.5) months after RPLN resection. Of those who developed a secondary recurrence, disease was again isolated to the retroperitoneum in seven patients. In all, 11 patients subsequently died, including 10 who died from disease. The median PFS after RPLN resection was 19.5 months, with a 3- and 5-year PFS of 40.5% and 35.4%, respectively. We also found that RPLN recurrence at ≤12 months after nephrectomy was associated with a significantly inferior median PFS (12.3 months) compared with RPLN recurrence at >12 months after nephrectomy (47.6 months; P = 0.003). Moreover, on multivariate analysis, a shorter time to recurrence remained associated with a significantly increased risk for subsequent disease progression (hazard ratio 3.51; P = 0.005). Conclusion Surgical resection of isolated RPLN recurrence from RCC may result in durable cancer control in appropriately selected patients. Recurrence at ≤12 months after nephrectomy was associated with a significantly increased risk of progression after resection, underscoring the importance of this variable for risk stratification. Thus, we recommend that, in the setting of isolated RPLN recurrence of RCC (in patients without precluding comorbidities), careful consideration with the patients and medical oncology colleagues be undertaken about the relative and individualised benefits of surgical resection, systemic therapy, and surveillance.

OBJECTIVE To evaluate whether incidental pathologic T3a (pT3a) upstaging after partial nephrectomy (PN) for clinical T1 disease results in inferior oncologic outcomes compared to pT1a-b disease. MATERIALS AND METHODS Retrospective chart review was completed at the University of Michigan and Moffitt Cancer Center to identify patients undergoing PN for clinical T1 masses between 1995 and 2015. A total of 1955 patients were identified, of which 95 had pT3a upstaging. Median follow-up was 38.2 months. Patients with pT3a disease were individually matched by clinicopathologic features with patients undergoing PN with pT1a-b disease in a 1:2 ratio. Kaplan-Meier analysis and univariate and multivariable Cox proportional hazards regression analysis were performed. Primary endpoint was recurrence-free survival (RFS). Secondary endpoints were all-cause mortality, cancer-specific survival (CSS), and rates of local and distant recurrence. RESULTS Recurrence rates were significantly higher in pT3a disease compared to pT1a-b controls (P

Objective To report and analyze the outcomes of endoscopic inguinal lymph node dissection (E-ILND), inclusive of video endoscopic ILND (VEIL) and robotic-assisted ILND (RAIL) approaches, in the largest reported series to date. Materials and Methods We retrospectively identified men with penile cancer who underwent E-ILND. Nodal resection volume, perioperative parameters, and postoperative complications were assessed and analyzed. A subset analysis of complications by tumor and operative characteristics was performed to determine the impact of these variables on complication rates. Results A total of 34 E-ILND, comprising 7 VEIL and 27 RAIL limbs, were performed. Median nodal yield was 10.0 (interquartile range [IQR] 6.0-12.5) in all E-ILND limbs and 8.0 (IQR 13.0-23.0) in RAIL limbs. Median length of stay was 1 day (range 1-3) following E-ILND and RAIL procedures. The saphenous vein was spared in 57% (4/7) of VEIL and 100% (27/27) of RAIL limbs. Postoperative complications occurred in 33% (6/18) of E-ILND, including 21% (3/14) of RAIL patients. Median follow-up was 5.5 months (IQR 3.0-10.8), during which time 3 patients developed regional or distant metastases at a median duration of 1.7 months (IQR 0.9-3.9). Conclusion E-ILND is feasible from a technical standpoint, and our results demonstrate that lymph node counts are comparable with an open approach. Importantly, E-ILND has the potential to reduce complication rates and time to convalescence when compared with open ILND.

We report a multicenter international cohort representing what is to our knowledge the largest surgical experience with managing isolated retroperitoneal nodal recurrence of renal cell carcinoma, a unique subset of locoregional disease, yet to be described in detail.Patients with isolated nodal recurrence of pTanyN+M0 disease after nephrectomy were identified by retrospective chart review at 3 independent institutions. Progression-free survival was estimated by the Kaplan-Meier method and used to compare survival outcomes between primary T(1-2)N(any)M0 and T3N(any)M0 tumors as well as clear cell and nonclear cell histology renal cell carcinoma.A total of 22 patients met study inclusion criteria. Median time to local postoperative recurrence was 31.5 months (IQR 12.9-43.3). After resection of isolated nodal recurrence 10 patients (46%) had a secondary recurrence at a median of 11.2 months (IQR 8.1-18.4), of whom 2 (9%) died of the disease. Overall median progression-free survival was 12.7 months, including 24.8 months for T(1-2)N(any)M0 tumors, 9.9 months for T3N(any)M0 tumors, and 13.4 and 17.6 months for clear and nonclear cell renal cell carcinoma, respectively.Surgical resection represents the best curative option for patients who present with isolated retroperitoneal lymph node recurrence of renal cell carcinoma. Durable postoperative progression-free survival is attainable in many patients regardless of histology or clinical TNM stage. In addition, our cohort showed a lower renal cell carcinoma related mortality rate than in previous series of local metastasis. As such, all patients free of precluding comorbidities should be considered candidates for complete surgical resection performed by an experienced genitourinary surgeon.

Nephron-sparing surgery is the accepted standard of care for the small renal mass, and minimally invasive techniques have increasingly gained recognition. Robotic-assisted transperitoneal partial nephrectomy (RATPN) has been well described but there are few reports assessing the retroperitoneal approach. Therefore, we present our initial experience with robotic-assisted retroperitoneal partial nephrectomy (RARPN). We identified 14 patients from a single-surgeon IRB-approved database who underwent RARPN for suspected renal cell carcinoma. Our results showed a mean pathologic tumor size of 2.6 cm (SD = 0.9) and a median R.E.N.A.L. nephrometry score of 8. Mean estimated blood loss was 178 cc (SD = 182) and mean warm ischemia time was 28.9 min (SD = 8.9). There were no intra-operative or post-operative complications and mean length of stay was 2.9 days (SD = 1.6). At an average of 4-month follow-up, the mean decrease in renal function was 7.3 %. RARPN is an effective alternative to RATPN and can be safely and successfully applied to selected patients with tumors amenable to nephron preservation.

While radical cystectomy (RC) with pelvic lymph node dissection (PLND) represents the accepted gold standard for the treatment of muscle-invasive bladder cancer, this treatment approach is associated with significant morbidity. As such, bladder preservation strategies are often utilized in patients who are either deemed medically unfit due to significant comorbidities or whom decline management with RC and PLND secondary to its associated morbidity. In a select group of patients, meeting strict criteria, bladder preservation approaches may be employed with curative intent. Trimodal therapy, consisting of complete transurethral resection of bladder tumor (TURBT), chemotherapy, and radiation therapy has demonstrated durable oncologic control and long-term survival in a number of studies. The review presented here provides a description of trimodal therapy and the role of TURBT in bladder preservation for patients with muscle-invasive bladder cancer.

Context Over the previous2 decades, there have been numerous advancements in the diagnostic evaluation, therapeutic management, and postoperative assessment of genitourinary malignancies. Objective To present a review of current and novel imaging modalities and their utility in the assessment of therapeutic response in the systemic management of renal, testicular, and prostate cancers. Evidence acquisition A PubMed/Medline search of the current published literature inclusive of prospective and retrospective original research, systematic reviews, and meta-analyses was conducted evaluating imaging modalities for renal cell carcinoma, prostate cancer, and testicular cancer. All relevant literature was individually reviewed and summarized to provide a concise description of the currently available imaging modalities and their efficacy in assessing treatment response of the genitourinary malignancies targeted in this review. Evidence synthesis Conventional imaging techniques play a pivotal role in predicting the treatment response of genitourinary malignancies and have, therefore, been incorporated into clinical guidelines. Advancements in imaging technology have led to increased utilization for prognostication of a genitourinary cancer’s response to therapy. Conclusions A good understanding of current recommended imaging techniques to evaluate treatment response in genitourinary malignancies is of paramount importance for today’s clinician, who faces increasing treatment modalities. Patient summary In this review, we summarize available imaging modalities in the evaluation of treatment response in kidney, prostate, or testicular tumors. We believe that a good understanding of current imaging modalities is of paramount importance for healthcare providers treating these cancers.

To evaluate whether varying degrees of seminomatous elements in the primary orchiectomy specimen would be predictive of patient morbidity during post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) since the desmoplastic reaction with seminoma is associated with increased intraoperative complexity.We retrospectively identified 127 patients who underwent PC-RPLND for residual retroperitoneal masses. Clinicodemographic, intraoperative, and 30 day postoperative outcomes were compared for patients with pure seminoma (SEM), mixed germ cell tumors (GCT) containing seminoma elements (NS+SEM), and tumors with no seminoma elements (NS). Multivariate logistic regression was used to determine independent predictors of intraoperative and postoperative 30 day complications.We excluded 19 patients who received chemotherapy prior to orchiectomy, 2 patients with primary extragonadal GCT, and 3 patients who underwent re-do RPLND, leaving 103 patients for analysis. Fourteen patients (13.6%) had SEM, 18 (17.5%) had NS+SEM, and 71 (68.9%) had only NS elements. SEM patients were older (p = 0.03), had more intraoperative blood loss (p = 0.03), and were more likely to have residual seminomatous components in their post-chemotherapy lymph node (LN) histology (p = 0.01). Percent seminoma in the orchiectomy specimen was an independent predictor of estimated blood loss1.5 liters (odds ratio: 1.04, 95% confidence interval: 1.01-1.07; p = 0.013) after adjusting for age, stage, IGCCC risk category, preop chemotherapy, number and largest LN removed, need for vascular or adjacent organ resection (including nephrectomy), and LN histology.Higher percentage of seminoma in the orchiectomy specimen is associated with increased estimated blood loss during PC-RPLND. Percent seminoma, therefore, may be a useful prognostic tool for appropriate pre-surgical planning prior to PC-RPLND.

Aloe-emodin (1,8-dihydroy-3-[hydroxymethyl]-anthraquione) purified from Aloe vera leaves has been reported to have antitumor activity. The objectives of our research were to determine how aloe-emodin regulates the cell cycle, cell proliferation and protein kinase C (PKC) during glioma growth and development. To establish the cell cycle effects of aloe-emodin on brain cells [transformed glia cell line (SVG) and human glioma U-373MG cell line (U-373MG)], cells were treated with either dimethylsulfoxide (DMSO; control) or aloe-emodin (40 microM). Results from flow cytometry demonstrated that aloe-emodin delayed the number of cells entering and exiting DNA synthesis (S) phase in both SVG and U-373MG cells indicating that aloe-emodin may inhibit S phase progression. Assessment of cell viability demonstrated that SVG and U-373MG glioma cell were highly sensitive to aloe-emodin. The aloe-emodin-induced decreased proliferation was sustained at 48-96 h. A PKC activity assay was quantified to establish the role of PKC in aloe-emodin's mode of action. Exposure of SVG and U-373MG glioma cells to aloe-emodin suppressed PKC activity and reduced the protein content of most of the PKC isozymes. We determined that cancer growth inhibition by aloe-emodin was due to apoptosis (i.e., programmed cell death). Taken together, these results support the hypothesis that aloe-emodin represents a novel antitumor chemotherapeutic drug.

378 Background: Post-chemotherapy retroperitoneal lymph node dissections (PC-RPLND) performed at high-volume centers are safe and comparable in risk to primary RPLNDs. The desmoplastic reaction encountered during PC-RPLND in patients with seminoma components increases the complexity of surgical dissection. We examined whether the presence of seminoma at diagnosis was associated with more adverse events in the perioperative setting. Methods: A single institution review board approved retrospective review identified 108 patients undergoing PC−RPLND from 1992 to 2012. All patients had received at least first-line cisplatin-based induction chemotherapy. Of these, 11 patients undergoing redo PC-RPLNDs were excluded from analysis. Patients were divided into two groups; those with any seminoma element in their orchiectomy or retroperitoneal specimens and those without seminoma elements. We performed independent t-tests and Chi-squared analysis of the data. Results: Of 97 patients undergoing PC-RPLND, 33 had seminoma components in their diagnostic specimens. Using the Clavien classification system to stratify post-operative complications, the percentage of seminomatous elements (less than 50% compared to more than 50%) within the primary tumor did not correlate with a higher incidence of complications; even when examining only major complications (p=0.673). There was a trend towards higher nephrectomy rate for tumors with seminoma elements compared to those without (27% vs. 8.5%, p = .058). The nephrectomy rate did show a dependence on the pathologic size of the residual mass regardless of histology (31% for more than 10 cm, 6.8% for 5 to 10 cm, 0% for 0 to 5 cm p = 0.021). There was also a trend towards blood loss greater than one liter for patients with seminoma elements compared to those without (63% vs. 43%, p = 0.078), while the transfusion rate was similar between the two groups (p=0.785). Post−operative length of stay was independent of a patient’s histology (p=0.94). Conclusions: PC-RPLND remains a safe and necessary therapeutic procedure. The presence of seminoma germ cell elements in our patient cohort did not result in a more complicated perioperative course surrounding PC-RPLND.

238 Background: Limited derived benefit from definitive treatment has been observed with respect to prostate cancer−specific mortality (PCSM) in those low−risk disease and only small absolute risk reductions in both overall PCSM and incidence of metastasis have been demonstrated. Thus, active surveillance (AS) strategies have been adopted to monitor for disease progression with intent for intervention at time of disease reclassification. Yet, the timing and frequency of surveillance remain without evidence-based standardization. We assessed the relationship between the frequency of surveillance prostate biopsies and the oncologic outcomes in those patients with low−risk prostate cancer (CaP) managed by AS. Methods: An IRB approved retrospective chart review identified 114 patients placed on AS for their CaP between November of 1997 and November of 2000. Of those, 96 patients meet study inclusion criteria mandating a Gleason sum of < 7, tumor presence in < 4 sextets, involvement of

170 Background: Prostate cancer (CaP) has exhibited a downward stage migration during the PSA era. Approximately 70% of those newly diagnosed with CaP, harbor tumors of low-risk. Such tumors often prove to be of low-volume and of clinical insignificance at time of radical prostatectomy (RP), suggesting over treatment and excessive exposure to the morbidity associated with definitive management. Over the last decade, active surveillance (AS) strategies have become a more accepted practice when addressing low-risk tumors. We present the long-term oncologic outcomes of patients placed on AS. Methods: An IRB approved retrospective chart review identified 114 patients placed on AS for their CaP between November of 1997 and November of 2000. Of those, 96 patients meet study inclusion criteria mandating a Gleason sum of < 7, tumor presence in < 4 sextets, and involvement of