Urine Exosomes for Non-Invasive Assessment of Gene Expression and Mutations of Prostate Cancer.

PURPOSE: The analysis of exosome/microvesicle (extracellular vesicles (EVs)) and the RNA packaged within them (exoRNA) has the potential to provide a non-invasive platform to detect and monitor disease related gene expression potentially in lieu of more invasive procedures such as biopsy. However, few studies have tested the diagnostic potential of EV analysis in humans. EXPERIMENTAL DESIGN: The ability of EV analysis to accurately reflect prostate tissue mRNA expression was examined by comparing urinary EV TMPRSS2:ERG exoRNA from pre-radical prostatectomy (RP) patients versus corresponding RP tissue in 21 patients. To examine the differential expression of TMPRSS2:ERG across patient groups a random urine sample was taken without prostate massage from a cohort of 207 men including prostate biopsy negative (Bx Neg, n = 39), prostate biopsy positive (Bx Pos, n = 47), post-radical prostatectomy (post-RP, n = 37), un-biopsied healthy age-matched men (No Bx, n = 44), and young male controls (Cont, n = 40). The use of EVs was also examined as a potential platform to non-invasively differentiate Bx Pos versus Bx Neg patients via the detection of known prostate cancer genes TMPRSS2:ERG, BIRC5, ERG, PCA3 and TMPRSS2. RESULTS: In this technical pilot study urinary EVs had a sensitivity: 81% (13/16), specificity: 80% (4/5) and an overall accuracy: 81% (17/21) for non-invasive detection of TMPRSS2:ERG versus RP tissue. The rate of TMPRSS2:ERG exoRNA detection was found to increase with age and the expression level correlated with Bx Pos status. Receiver operator characteristic analyses demonstrated that various cancer-related genes could differentiate Bx Pos from Bx Neg patients using exoRNA isolated from urinary EVs: BIRC5 (AUC 0.674 (CI:0.560-0.788), ERG (AUC 0.785 (CI:0.680-0.890), PCA3 (AUC 0.681 (CI:0.567-0.795), TMPRSS2:ERG (AUC 0.744 (CI:0.600-0.888), and TMPRSS2 (AUC 0.637 (CI:0.519-0.754). CONCLUSION: This pilot study suggests that urinary EVs have the potential to be used as a platform to non-invasively differentiate patients with prostate cancer with very good accuracy. Larger studies are needed to confirm the potential for clinical utility.

Findings of routine apical margin biopsy during robot-assisted radical prostatectomy.

INTRODUCTION: Intraoperative biopsy of the apical margin during radical prostatectomy has been recommended as a way to reduce the positive margin rate at this location. However, the enhanced visibility of the apex during robot-assisted radical prostatectomy (RARP) may obviate this need, allowing for the preservation of maximal urethral length. We assessed pathologic findings of routine apical margin biopsy intraoperative frozen section (IFS) during RARP. PATIENTS AND METHODS: The Columbia University Robotic Database was retrospectively reviewed to identify men who underwent RARP with biopsy of the apical soft tissue (urethroprostatic junction). Both IFS and permanent section samples were analyzed. The clinical characteristics associated with IFS and permanent section histological findings were assessed. RESULTS: In total, 335 men underwent RARP with apical biopsy from December 2007 to August 2011. Of these, 329 had IFS available for analysis. Median age and prostate-specific antigen level were 60 years (range, 42-78 years) and 5.2 ng/mL (interquartile range, 4.1-6.9 ng/mL), respectively. Of the 329 apical IFS cases, cancer was detected in 9 patients (2.7%), benign prostatic glands in 135 (41%), and nonprostatic tissue in 185 (56.3%). On permanent section, cancer was seen in 9 patients (2.7%), benign prostatic glands in 125 (38%), and nonprostatic tissue in 195 (59.3%). False-positive and false-negative rates of detecting cancer on IFS were 33% (3/9) and 1% (3/320), respectively. The overall positive surgical margin rate was 11%. CONCLUSIONS: Cancer is rarely detected by IFS analysis of routine biopsy of the apical margin during RARP. Although routine IFS may not be beneficial for all patients, selective utilization of IFS may be useful in directing apical dissection in men with apical tumors, allowing for the preservation of maximal urethral length.

Diagnostic radiation exposure during surveillance in patients with pT1a renal cell carcinoma.

OBJECTIVE: To determine the pattern of postoperative radiographic surveillance in patients with pT1a renal cell carcinoma (RCC) at a tertiary care hospital. METHODS: An institutionally approved urologic oncology database was used to retrospectively identify patients who underwent partial or radical nephrectomy for pT1a RCC from 1990 to 2010 at a tertiary care center. Baseline characteristics were reviewed, and postoperative imaging for the indication of RCC surveillance was recorded. Radiation exposure was calculated using the effective dose according to imaging modality. Relative risks of the development of solid malignancies and leukemia were calculated from the dose of radiation exposure. RCC recurrence, defined as radiologic evidence of local recurrence or distant metastases, was noted. RESULTS: A total of 1708 patients had undergone partial or radical nephrectomy for a renal mass. Of these, 315 patients had pT1a RCC with postsurgical follow-up, and 252 (80%) of these patients were exposed to ionizing radiation during postoperative surveillance. Mean radiation doses in years 1, 2 to 5, and ≥6 after surgery were 11.4, 47.0, and 13.8 mSv, respectively. Relative risks of radiation-induced solid cancers and leukemia were 1.05 and 1.12, respectively. There were 8 (2.5%) total recurrences. CONCLUSION: During the past 20 years, 80% of patients undergoing surgery for pT1a RCC were monitored with radiation-based imaging during postoperative surveillance. Given the low rate of cancer recurrence in this population, expanded efforts in counseling physicians regarding the risk of ionizing radiation in imaging should be encouraged.

The effect of fibrin clot inhibitors on the immunomodulatory efficacy of Bacillus Calmette-Guérin therapy for non-muscle-invasive bladder cancer.

OBJECTIVE: To determine if there is a difference in clinical outcomes among non-muscle-invasive bladder cancer patients taking fibrin clot-inhibiting (FCI) medications (aspirin, clopidogrel, or warfarin) while receiving Bacillus Calmette-Guérin (BCG) therapy compared with their counterparts not taking anticoagulation. MATERIALS AND METHODS: Our Investigational Review Board-approved database was queried for patients who received an induction course of BCG from 2001 to 2011. The analysis included 224 patients with a minimum of 3 months of follow-up. Recurrence-free survival (RFS), cystectomy-free survival, overall survival, and disease-specific survival were analyzed using the Kaplan-Meier method stratified by FCI status. Logistic regression was used to predict the initial response rate to BCG and progression by FCI status. RESULTS: Of the 224 patients analyzed, 68, 19, and 23 patients were taking aspirin, clopidogrel and warfarin, respectively, at BCG induction. No specific FCI was associated with differences in cystectomy-free survival, overall survival, disease-specific survival, or the likelihood of progression at recurrence. Neither warfarin nor clopidogrel affected RFS. Patients taking aspirin trended toward increased RFS, although this was not statistically significant (P = .058). Multivariate analysis showed aspirin use was associated with an increased initial response to BCG (odds ratio, 2.41; P = .031) CONCLUSION: Contrary to the postulated inhibitory molecular effect of FCI on BCG-binding activity, this study did not substantiate a significant impact on BCG efficacy of the concomitant use of these medications during BCG induction. The observation that aspirin use potentiates an increased initial response to BCG may warrant further analysis.

Is there a difference in laterality during robot-assisted radical prostatectomy? Assessment of lymph node yield and neurovascular bundle dissection.

BACKGROUND AND PURPOSE: The da Vinci Surgical System (dVSS) has been reported to eliminate innate hand dominance of the surgeon. There are no studies to date, however, that specifically address whether the dVSS has its own inherent "handedness" resulting from the fixed left-right preference of specific instrument docking and assistant positioning. We identified the pelvic lymph node (LN) and neurovascular bundle (NVB) dissections as well as positive surgical margin rates as procedure points during robot-assisted radical prostatectomy (RARP) that could be influenced by laterality and sought to illustrate left-right consistency. PATIENTS AND METHODS: Patients who underwent RARP by a single right-handed surgeon (KKB) between 2008 and 2010 were identified. Surgeon instrument preference and port placement were consistent across all cases. Pathologic LN yield was stratified by the intended limits of dissection (limited or extended) and laterality. In addition, fascial widths (FW) were prospectively measured for 93 consecutive patients, a narrower FW indicating a more precise intended NVB dissection. The pathologists were blinded to intended dissections. RESULTS: A total of 340 limited, 11 bilateral extended, 11 right extended, and 5 left extended LN dissections were performed. For patients undergoing limited LN dissection, the mean LN yield was greater on the right compared with the left (3.26 vs 2.76, P=0.010). This difference was not seen in the extended LN dissection (P=0.96). Average FW was narrower on the right surgical margin compared with the left (1.99 vs 2.64 mm, P<0.001). CONCLUSIONS: Our findings suggest that a greater number of LNs and a closer NVB dissection are achieved on the right compared with the left using the dVSS during RARP. This can be attributed to surgeon handedness, robotic instrument laterality, or assistant instrument laterality. Surgeon awareness of these potential differences is important for the preoperative planning before RARP.

Single institutional experience with nephron-sparing surgery for pathologic stage T3bNxM0 renal cell carcinoma confined to the renal vein.

OBJECTIVE: To assess our institution's experience with the management of pathologic stage T3bNxM0 renal cell carcinoma with tumor thrombus confined to the renal vein treated with nephron-sparing surgery (NSS). METHODS: Of the 492 patients who have undergone NSS at Columbia University from 1998 to 2009, 8 patients were found to have stage T3bNxM0 renal cell carcinoma (RCC) on final pathology. Records were reviewed for indication for NSS, imaging studies, perioperative management, surgical details, pathology, and both functional and disease-specific outcomes. Postoperative renal function was estimated by most recent glomerular filtration rate using Modification of Diet in Renal Disease formula. Recurrence of RCC was monitored using serial axial imaging. RESULTS: The 8 patients were presumed to be clinical stage T1aN0M0 RCC before surgery; however, tumor thrombus was identified in the renal vein intraoperatively and on final pathology in 4, and 4 cases, respectively, corresponding to stage T3bNxM0 RCC by current American Joint Committee on Cancer-Tumor-Necrosis-Metastasis 2002 criteria. After a median follow-up of 19.8 months, the patients experienced a mean decrease in estimated glomerular filtration rate of 27.1%. One patient developed new-onset renal failure, defined as an estimated glomerular filtration rate below 30 mL/min/1.73 m(2). Clean surgical margins were obtained in 7 patients. Carcinoma was identified at the parenchymal margin in 1 patient. No patients have evidence of recurrence of RCC by serial axial imaging. CONCLUSIONS: NSS does not seem to have had a negative impact on a small series of patients with pathologic stage T3bNxM0 RCC limited to the renal vein and may be a feasible option when the clinical situation indicates a need for preservation of renal function.