Jonathan L. Silberstein

Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA

Urine TMPRSS2:ERG gene fusion could be used for stratification of patients at higher risk for prostate cancer. Old Gene Fusion, New Diagnostic Tricks The “PSA test” is a routine test for men over the age of 50 or for those at risk for prostate cancer. It measures the level of prostate-specific antigen (PSA) in the blood, and if that level is above a predefined cutoff, a biopsy is recommended for definitive diagnosis. This test is not perfect; benign conditions, such as an enlarged prostate, can contribute to high levels of PSA, resulting in a “false-positive” and subsequent overdiagnosis and overtreatment. Because of the high prevalence of prostate cancer (it is estimated that nearly 250,000 men will be diagnosed with the disease in 2011), it is clear that a more accurate test for prostate cancer is needed. Here, Tomlins et al. improve on the PSA test by taking a new twist on a known gene fusion, using it to stratify more than 1000 men in two multicenter cohorts based on risk for developing the disease. Recently, it was discovered that the fusion of two genes, the transmembrane protease, serine 2 (TMPRSS2) gene and the v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene, known as TMPRSS2:ERG, is overexpressed in more than 50% of PSA-screened prostate cancers. The protein product of this fusion cannot be detected in serum, so the authors decided to test for the presence of TMPRSS2:ERG mRNA in urine. First, they developed a clinical-grade, transcription-mediated amplification assay for quantifying fusion mRNA—this generated a TMPRSS2:ERG “score.” Urine TMPRSS2:ERG score was linked to the presence of cancer, tumor volume, and clinically significant cancer in patients. Then, the authors combined the TMPRSS2:ERG score with the level of prostate cancer antigen 3 (PCA3) in urine. TMPRSS2:ERG+PCA3 improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator, thus demonstrating clinical utility. Who said you can’t teach an old gene fusion new tricks? By combining the cancer-specific fusion TMPRSS2:ERG score with levels of PSA (in serum) and PCA3 (in urine), Tomlins and colleagues demonstrated more accurate, individualized stratification of men at high risk for developing clinically significant prostate cancer—an important step in streamlining diagnosis and treatment. Moreover, men with extremes of TMPRSS2:ERG+PCA3 had different risks of cancer on biopsy; in combination with other clinicopathological features, urine TMPRSS2:ERG+PCA3 might also inform the urgency of biopsy after PSA screening. More than 1,000,000 men undergo prostate biopsy each year in the United States, most for “elevated” serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.

Lymph Node–Positive Bladder Cancer Treated With Radical Cystectomy and Lymphadenectomy: Effect of the Level of Node Positivity

BACKGROUNDnThe extent of lymphadenectomy needed to optimize oncologic outcomes after radical cystectomy (RC) for patients with regionally advanced bladder cancer (BCa) is unclear.nnnOBJECTIVEnEvaluate the effect of the location of lymph node metastasis on recurrence-free survival (RFS) and cancer-specific survival (CSS) for patients undergoing RC with a mapping pelvic lymph node dissection (PLND).nnnDESIGN, SETTING, AND PARTICIPANTSnA study of 591 patients undergoing RC with mapping PLND was completed between 2000 and 2010. Median follow-up was 30 mo.nnnINTERVENTIONnRC with mapping PLND.nnnMEASUREMENTSnWe evaluated the impact of lymph node involvement by location on disease outcomes using the 2010 TNM staging system. Survival estimates were described using Kaplan-Meier methods. Gender, age, pathologic stage, histology, number of positive nodes, location of positive nodes, node density, use of perioperative chemotherapy, and grade were evaluated as predictors of RFS and CSS using multivariate Cox proportional hazard regression.nnnRESULTS AND LIMITATIONSnOverall, 114 patients (19%) had lymph node involvement, and 42 patients (7%) had pN3 disease. On multivariate analysis, the number of positive lymph nodes (one or two or more) was significantly associated with increased risk of cancer-specific death (hazard ratio [HR]: 1.9 [95% confidence interval (CI), 1.04-3.46], p=0.036; versus HR: 4.3 [95% CI, 2.25-8.34], p<0.0005). Positive lymph node location was not an independent predictor of RFS or CSS. Five-year RFS for pN3 patients undergoing RC with PLND was 25% (95% CI, 10-42). This finding was not statistically different from our pN1 and pN2 patients (38% [95% CI, 22-54] and 35% [95% CI, 11-60], respectively). This study is limited by the lack of prospective randomization and a control group.nnnCONCLUSIONSnThe outcome for patients with involved common iliac lymph nodes was similar to the outcome for patients with primary nodal basin disease. These data support inclusion of the common iliac lymph nodes (pN3) in the nodal staging system for BCa. Lymph node location was not an independent predictor of outcome, whereas the number of positive lymph nodes was an independent predictor of worse oncologic outcome (pN1, pN2). Further refinements of the TNM system to provide improved prognostication are warranted.

Reverse Stage Shift at a Tertiary Care Center: Escalating Risk in Men Undergoing Radical Prostatectomy

The objective of this study was to evaluate changes in clinical and pathologic characteristics of prostate cancer in patients who underwent surgery at a large tertiary care center in the context of increased use of active surveillance (AS) and minimally invasive surgery (MIS).

Trends in Partial and Radical Nephrectomy: An Analysis of Case Logs from Certifying Urologists

PURPOSEnSurgical treatment options for renal masses include radical vs partial nephrectomy and the open vs laparoscopic approach. Using American Board of Urology (ABU) case log data, we investigated contemporary trends in these treatment options, and how surgeon and practice characteristics may influence these trends.nnnMATERIALS AND METHODSnAnnualized case log data for nephrectomy were obtained from the ABU for all urologists certifying or recertifying from 2002 to 2010. We evaluated trends in nephrectomy use. Logistic regression was used to evaluate surgeon and practice characteristics as predictors of partial and laparoscopic procedures.nnnRESULTSnFrom the 3,852 case logs submitted by nonpediatric urologists we analyzed a total of 48,384 nephrectomies. From 2002 to 2010 the proportion of annual nephrectomies performed as open radical nephrectomy gradually decreased from 54% to 29%. During the same period, there was a moderate gradual increase in laparoscopic radical nephrectomies (from 30% to 39%). The proportion of open partial nephrectomies remained stable at 15%, while laparoscopic partial nephrectomy increased from 2% to 17%. On multivariable analysis the use of partial nephrectomy and laparoscopy was predicted by urologist annual nephrectomy volume, initial or recertification status, subspecialty, practice area size and geographic region.nnnCONCLUSIONSnSince 2002, the use of laparoscopic nephrectomy and partial nephrectomy has increased. However, the diffusion of these techniques is not uniform. Initial certification, higher surgical volume, and practicing in areas with more than 1,000,000 population and in the Northeast region were associated with greater use of laparoscopy and partial nephrectomy. Factors that affect the adoption of these techniques require further research.

Pelvic Lymph Node Dissection for Patients with Elevated Risk of Lymph Node Invasion During Radical Prostatectomy: Comparison of Open, Laparoscopic and Robot-Assisted Procedures

BACKGROUND AND PURPOSEnPublished outcomes of pelvic lymph node dissection (PLND) during robot-assisted laparoscopic prostatectomy (RALP) demonstrate significant variability. The purpose of the study was to compare PLND outcomes in patients at risk for lymph node involvement (LNI) who were undergoing radical prostatectomy (RP) by different surgeons and surgical approaches.nnnPATIENTS AND METHODSnInstitutional policy initiated on January 1, 2010, mandated that all patients undergoing RP receive a standardized PLND with inclusion of the hypogastric region when predicted risk of LNI was ≥ 2%. We analyzed the outcomes of consecutive patients meeting these criteria from January 1 to September 1, 2010 by surgeons and surgical approach. All patients underwent RP; surgical approach (open radical retropubic [ORP], laparoscopic [LRP], RALP) was selected by the consulting surgeon. Differences in lymph node yield (LNY) between surgeons and surgical approaches were compared using multivariable linear regression with adjustment for clinical stage, biopsy Gleason grade, prostate-specific antigen (PSA) level, and age.nnnRESULTSnOf 330 patients (126 ORP, 78 LRP, 126 RALP), 323 (98%) underwent PLND. There were no significant differences in characteristics between approaches, but the nomogram probability of LNI was slightly greater for ORP than RALP (P=0.04). LNY was high (18 nodes) by all approaches; more nodes were removed by ORP and LRP (median 20, 19, respectively) than RALP (16) after adjusting for stage, grade, PSA level, and age (P=0.015). Rates of LNI were high (14%) with no difference between approaches when adjusted for nomogram probability of LNI (P=0.15). Variation in median LNY among individual surgeons was considerable for all three approaches (11-28) (P=0.005) and was much greater than the variability by approach.nnnCONCLUSIONSnPLND, including hypogastric nodal packet, can be performed by any surgical approach, with slightly different yields but similar pathologic outcomes. Individual surgeon commitment to PLND may be more important than approach.

A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons

Radical prostatectomy provides local‐regional control of prostate cancer and is the most common treatment for prostate cancer in the United States. Over the past decade there has been a shift in the surgical approach used to treat this disease, moving from open retropubic approach to robot‐assisted laparoscopic prostatectomy. While robotic prostatectomy has been demonstrated to result in less blood loss, fewer transfusions and shorter hospital duration, it has never been demonstrated in a meaningful prospective manner to result in improved or even equivalent oncological outcomes. Prior attempts to address this question have been hampered by methodological issues with study design, differences in case mix, or differences in surgical learning curve between surgeons. In this retrospective study we compared the oncological outcomes of open radical prostatectomy and robotic prostatectomy limiting our analysis to expert surgeons in their respective surgical approaches. Importantly, the patient cohort contained a majority of patients with intermediate‐ and high‐risk features and all surgeons attempted to adhere to strict oncological principles, including performing complete pelvic lymph node dissections in almost all of the patients in the study. The results demonstrate that oncological outcomes show no significant difference with respect to surgical approach, even for patients with higher risk features, and that there is more variation between individual surgeons than between surgical approaches.

Renal Function and Oncologic Outcomes of Parenchymal Sparing Ureteral Resection Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

PURPOSEnWe compared renal function and oncologic outcomes of parenchymal sparing ureteral resection with radical nephroureterectomy for the treatment of upper tract urothelial carcinoma confined to the ureter.nnnMATERIALS AND METHODSnReview of a large institutional database identified 367 patients treated for primary upper tract urothelial carcinoma with radical nephroureterectomy or parenchymal sparing ureteral resection from 1994 to 2009. Patients with known renal pelvis tumors, muscle invasive urothelial carcinoma, prior cystectomy, contralateral upper tract urothelial carcinoma, metastatic disease or chemotherapy were excluded, leaving 120 patients for analysis. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation. Recurrence-free, cancer specific and overall survival were estimated using Kaplan-Meier analysis.nnnRESULTSnRadical nephroureterectomy was performed in 87 patients and parenchymal sparing ureteral resection in 33. Median age at surgery was 73 years in the radical nephroureterectomy group (IQR 64-76) vs 70 years (IQR 59-77) in the parenchymal sparing ureteral resection group (p = 0.5). The radical nephroureterectomy and parenchymal sparing ureteral resection cohorts had several disparate clinicopathological variables including preoperative hydronephrosis (80% vs 45%, p = 0.0006), stage (pT3 or greater 26% vs 9%, p = 0.01) and baseline estimated glomerular filtration rate (51 vs 63 ml/minute/1.73 m(2), p = 0.009). Patients who underwent radical nephroureterectomy experienced a significantly greater decrease in estimated glomerular filtration rate after surgery (median -7 vs 0 ml/minute/1.73 m(2), p <0.001). Median followup was 4.2 years. Of the patients 79 experienced cancer recurrence and 44 died (28 of upper tract urothelial carcinoma). There were no obvious differences in the rates of recurrence, cancer specific death or overall death by procedure type. However, due to the limited number of events we cannot exclude the possibility that there are large differences in oncologic outcomes by procedure type.nnnCONCLUSIONSnParenchymal sparing ureteral resection is associated with superior postoperative renal function. However, the impact on cancer control cannot be determined conclusively due to the small sample size and putative selection bias.

Intraoperative Mannitol Use Does Not Improve Long-term Renal Function Outcomes After Minimally Invasive Partial Nephrectomy

OBJECTIVEnTo evaluate intravenous mannitol during minimally invasive partial nephrectomy (PN) by comparing the renal function outcomes of the patients who received it versus those who did not.nnnMETHODSnOf 285 consecutive elective minimally invasive PN cases from February 2005 to July 2010, 164 patients (58%) were treated with mannitol. We compared the renal function recovery using a multivariate generalized estimating equation linear model of estimated glomerular filtration rate (eGFR) controlling for nephrometry complexity, preoperative eGFR, American Society of Anesthesiologists score, ischemia time, estimated blood loss, age, and sex. Sensitivity analyses were performed to adjust for cold ischemia and individual surgeon differences corrected for year of surgery.nnnRESULTSnOf the 285 patients who underwent minimally invasive treatment, 164 received mannitol and 121 did not. Those who received mannitol had a better preoperative eGFR (median 72 vs 69 mL/min/m(2), P = .046), less complex nephrometry scores (P = 0.051), and were less likely to have an American Society of Anesthesiologists score of ≥ 3 (42% vs 54%, P = .005). Renal function recovery was similar in both groups (estimated effect of mannitol -0.7 mL/min/m(2), 95% confidence interval -3.6-2.2, P = .6). At no point in the postoperative period did mannitol make a significant difference in the eGFR according to the generalized estimating equation model after adjusting for multiple potential renal function confounders.nnnCONCLUSIONnMannitol use did not influence renal function recovery within 6 months of minimally invasive PN as measured by the eGFR in our analysis. An appropriately designed prospective study of mannitol is being conducted to validate its use during PN.

Surgical Practice Patterns for Male Urinary Incontinence: Analysis of Case Logs from Certifying American Urologists

PURPOSEnSeveral options exist for the surgical correction of male stress urinary incontinence including periurethral bulking agents, artificial urinary sphincters and the recently introduced male urethral slings. We investigated contemporary trends in the use of these treatments.nnnMATERIALS AND METHODSnAnnualized case log data for incontinence surgeries from certifying and recertifying urologists were obtained from the ABU (American Board of Urology), ranging from 2004 to 2010. Chi-square tests and logistic regression models were used to evaluate the association between surgeon characteristics (type of certification, annual volume, practice type and practice location) and the use of incontinence procedures.nnnRESULTSnAmong the 2,036 nonpediatric case logs examined the number of incontinence treatments reported for certification has steadily increased over time from 1,936 to 3,366 treatments per year from 2004 to 2010 (p = 0.008). Nearly a fifth of urologists reported placing at least 1 sling. The proportion of endoscopic procedures decreased from 80% of all incontinence procedures in 2004 to 60% in 2010, but they remained the exclusive incontinence procedure performed by 49% of urologists. A urologists increased use of endoscopic treatments was associated with a decreased likelihood of performing a sling procedure (OR 0.5, p <0.0005). Artificial urinary sphincter use remained stable, accounting for 12% of procedures.nnnCONCLUSIONSnIncontinence procedures are on the rise. Urethral slings have been widely adopted and account for the largest increase among treatment modalities. Endoscopic treatments continue to be commonly performed and may represent overuse in the face of improved techniques. Further research is required to validate these trends.

Urinary Diversion Practice Patterns Among Certifying American Urologists

PURPOSEnWe investigated trends in urinary diversion use and surgeon characteristics in the performance of incontinent and continent urinary diversion using American Board of Urology data.nnnMATERIALS AND METHODSnAnnualized case log data for urinary diversion were obtained from the American Board of Urology for urologists who certified or recertified from 2002 to 2010. We evaluated the association between surgeon characteristics and the performance of any urinary diversion or the type of urinary diversion.nnnRESULTSnOf the 5,096 certifying or recertifying urologist case logs examined 1,868 (37%) urologists performed any urinary diversion. The median number of urinary diversions was 4 per year (IQR 2, 6) and 222 urologists (4%) performed 10 or more per year. On multivariate analysis younger urologists, those self-identified as oncologists or female urologists, those who certified in more recent years and those in larger practice areas or outside the Northeast region of the United States were more likely to perform any urinary diversion. Only 9% of the total cohort (471 urologists) performed any continent urinary diversion. The likelihood of performing any continent urinary diversion increased with the number of urinary diversions (p <0.0001). As urinary diversion volume increased, the proportion representing continent urinary diversion also increased (p <0.0005). Surgeons in private practice settings and those in the Northeast were less likely to perform continent urinary diversion.nnnCONCLUSIONSnFew urologists perform any urinary diversion. Continent urinary diversion is most frequently done by high volume surgeons. The type of urinary diversion that a patient receives may depend in part on surgeon characteristics.