K. Clint Cary

Biomarkers in prostate cancer surveillance and screening: Past, present, and future

The use of biomarkers for prostate cancer (PCa) screening, detection, and prognostication have revolutionized the diagnosis and management of the disease. Current clinical practice has been driven largely by the utilization of prostate-specific antigen (PSA). The lack of specificity of PSA for PCa has led to both unnecessary biopsies and overdiagnosis of indolent cancers. The recent controversial recommendation by the United States Preventive Services Task Force against PCa screening has highlighted the need for novel clinically useful biomarkers. We review the literature on PCa biomarkers in serum, urine, and tissue. While these markers show promise, none seems poised to replace PSA, but rather may augment it. Further validation and consideration of how these novel markers improve clinical outcome is necessary. The discovery of new genetic markers shows promise in stratifying men with aggressive PCa.

Predictors of pathologic progression on biopsy among men on active surveillance for localized prostate cancer: the value of the pattern of surveillance biopsies.

BACKGROUND A better understanding of the independent predictors of disease progression for prostate cancer (PCa) patients is needed to improve the selection of ideal candidates for active surveillance (AS) and refine the surveillance regimen. OBJECTIVE To examine the association of clinical and pathologic characteristics, as well as patterns of surveillance biopsy results, with the risk of progression in men on AS. DESIGN, SETTING, AND PARTICIPANTS The retrospective study consisted of men with PCa who were on AS in the prospectively maintained University of California, San Francisco, institutional database from 1996 to 2011. Strict criteria for AS were prostate-specific antigen (PSA) ≤10 ng/ml, clinical stage T1 or T2, biopsy Gleason grade 6, <33% positive cores, and <50% tumor in any single core. Men were then categorized based on results of their confirmatory surveillance biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Disease progression was defined as an increase in Gleason grade and/or biopsy volume beyond prespecified cut points. Serial biopsy patterns over the course of surveillance were stratified by confirmatory biopsy findings: negative, positive without progression, and positive with progression. Multivariable logistic regression models were used to evaluate predictors of progression during AS. RESULTS AND LIMITATIONS A total of 465 men met inclusion criteria (median follow-up: 51 mo). Of these men, 23% had negative confirmatory biopsies. Only 3% of the men (1 of 30) progressed by the fourth surveillance biopsy following a biopsy pattern of negative confirmatory and negative third biopsy findings. Negative confirmatory biopsy and lower PSA density (both p<0.01) were independently associated with decreased odds of biopsy progression at 3 yr. The main limitation of this study is its observational nature. CONCLUSIONS The patterns of surveillance biopsy results yield additional important information in AS. Negative confirmatory biopsy and PSA density are important independent predictors of progression on AS and may be used to better counsel men opting for AS.

Contemporary bladder cancer: variant histology may be a significant driver of disease.

OBJECTIVES To evaluate pathologic and survival outcomes among patients with variant histology (VH) urothelial carcinoma of the bladder. METHODS A retrospective review of an institutional database was performed to identify all patients who underwent radical cystectomy with curative intent for urothelial carcinoma between 2008 and June 2013. VH was assigned by genitourinary pathologists. Descriptive statistics comparing clinicopathologic outcomes were performed using the Pearson chi-square test and analysis of variance. Survival was evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression. RESULTS In total, 624 patients were identified. Overall, 26% (n = 162) had VH, with the most common being squamous differentiation (n = 68), micropapillary variant (MPV, n = 28), plasmacytoid variant (PCV, n = 25), and sarcomatoid variant (n = 15); 64% of MPV and 72% of PCV had positive lymph nodes. Compared with 8% of patients with a non VH, 44% of those with VH were categorized as pT4 (P<0.001). MPV and PCV were independently associated with twice the risk of all-cause mortality compared with nonvariant, when adjusting for demographics, American Society of Anesthesiologists class, transurethral resection of bladder tumor stage, cystectomy stage, positive lymph nodes, and reception of chemotherapy (odds ratio = 2.20, 95% CI: 1.28-3.78; P = 0.004; odds ratio = 2.42, 95% CI: 1.33-4.42; P = 0.004, respectively). There was no difference in risk of mortality associated with squamous differentiation or sarcomatoid variant (P>0.05 each). CONCLUSIONS MPV and PCV are associated with increased risk of mortality. Improved recognition of VH will enable larger cohorts of study and better prognostic understanding of the significance of specific VH involvement.

National trends in the utilization of robotic-assisted radical cystectomy: an analysis using the Nationwide Inpatient Sample.

OBJECTIVES To determine temporal and regional trends in utilization of robotic-assisted radical cystectomy (RARC) in the United States and to explore factors associated with utilization of robotic assistance. MATERIALS AND METHODS Using 2009 to 2011 data from the Nationwide Inpatient Sample, we identified radical cystectomy cases that were performed using either open or robotic assistance and applied Nationwide Inpatient Sample discharge weights to determine national incidence. Univariable and multivariable logistic regressions were performed to assess regional trends and characteristics associated with having RARC. Descriptive analysis was performed using the chi-square test, the Student t test, and the Mann-Whitney U test. RESULTS Of the 29,719 radical cystectomy patients, 3,733 were RARC (12.6%). Although there was no change in the proportion of RARC performed annually (P = 0.702). Length of stay was 1 day longer for open cystectomy than RARC (P<0.001). On multivariate regression, patients whose primary payer was Medicaid were less likely than private insurance patients to undergo RARC (odds ratio = 0.60, P = 0.074). Additionally, patients in the south were at 50% reduced odds of undergoing RARC (odds ratio = 0.49, P = 0.044). Median hospital costs were

Impact of androgen deprivation therapy on mental and emotional well-being in men with prostate cancer: Analysis from the CaPSURE™ registry

5,000 greater for RARC (P<0.001). CONCLUSIONS Regional variation in utilization should be monitored to ensure equal access to new technology and to assess potential overuse of new technology. Although RARC is associated with higher median hospital costs, further studies to assess its benefits are warranted.

Limited ability of existing nomograms to predict outcomes in men undergoing active surveillance for prostate cancer.

PURPOSE While androgen deprivation therapy can delay cancer progression and reduce tumor burden, its use can be limited by adverse side effects. We evaluated the effect of androgen deprivation therapy on mental and emotional well-being in men with nonmetastatic prostate cancer. MATERIALS AND METHODS Participants were enrolled in the national CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry, and treated with radical prostatectomy, external beam radiation therapy or brachytherapy with no androgen deprivation therapy (local); local with androgen deprivation therapy (combination); or primary androgen deprivation therapy. Emotional quality of life was evaluated by SF-36® social function, role emotional, vitality and mental health subscales before and up to 24 months after treatment. Subscales were assessed as continuous scores and as clinically meaningful declines of at least half a standard deviation since pretreatment. Associations between treatment and quality of life changes over time were evaluated with mixed modeling. Quality of life declines were evaluated with logistic regression. RESULTS Among 3,068 men the combination and primary androgen deprivation therapy groups were older, single, with less education and higher clinical CAPRA (Cancer of the Prostate Risk Assessment) score risk than the local group (all values p <0.01). Androgen deprivation therapy exposure was associated with significant changes with time in adjusted role emotional (-8.4 points, p = 0.01) and vitality (-9.2 points, p = 0.02) scores. Treatment group was not associated with any clinically meaningful quality of life declines. A potential limitation is the observational nature of the study. CONCLUSIONS Use of androgen deprivation therapy was associated with changes in mental and emotional well-being but did not result in clinically meaningful declines at 24 months. Patients must be counseled on possible quality of life changes related to androgen deprivation therapy as well as interventions to attenuate these effects before receiving treatment for prostate cancer.

Plasmacytoid variant urothelial bladder cancer: Is it time to update the treatment paradigm?

To assess the ability of current nomograms to predict disease progression at repeat biopsy or at delayed radical prostatectomy (RP) in a prospectively accrued cohort of patients managed by active surveillance (AS).

Original articlePlasmacytoid variant urothelial bladder cancer: Is it time to update the treatment paradigm?

OBJECTIVES Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC. MATERIALS AND METHODS A retrospective analysis of the Indiana University Bladder Cancer Database between January 2008 and June 2013 was performed comparing 30 patients with PCV UC at cystectomy to 278 patients with nonvariant (NV) UC at cystectomy who underwent surgery for muscle-invasive disease. Multivariable logistic regression was used to assess precystectomy variables associated with non-organ-confined disease at cystectomy and Cox regression analysis to assess variables associated with mortality. RESULTS Patients with PCV UC who were diagnosed with a higher stage at cystectomy (73% pT3-4 vs. 40%, P = 0.001) were more likely to have lymph node involvement (70% vs. 25%, P<0.001), and positive surgical margins were found in 40% of patients with PCV UC vs. 10% of patients with NV UC (P<0.001). Median overall survival and disease-specific survival were 19 and 22 months for PCV, respectively. Median overall survival and disease-specific survival had not been reached for NV at 68 months (P<0.001). Presence of PCV UC on transurethral resection of bladder tumor was associated with non-organ-confined disease (odds ratio = 4.02; 95% CI: 1.06-15.22; P = 0.040), and PCV at cystectomy was associated with increased adjusted risk of mortality (hazard ratio = 2.1; 95% CI: 1.2-3.8; P = 0.016). CONCLUSIONS PCV is an aggressive UC variant, predicting non-organ-confined disease and poor survival. Differentiating between non-muscle- and muscle-invasive disease in patients with PCV UC seems less important than the aggressive nature of this disease. Instead, any evidence of PCV on transurethral resection of bladder tumor may warrant aggressive therapy.

Plasmacytoid bladder cancer: Variant histology with aggressive behavior and a new mode of invasion along fascial planes

OBJECTIVES Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC. MATERIALS AND METHODS A retrospective analysis of the Indiana University Bladder Cancer Database between January 2008 and June 2013 was performed comparing 30 patients with PCV UC at cystectomy to 278 patients with nonvariant (NV) UC at cystectomy who underwent surgery for muscle-invasive disease. Multivariable logistic regression was used to assess precystectomy variables associated with non-organ-confined disease at cystectomy and Cox regression analysis to assess variables associated with mortality. RESULTS Patients with PCV UC who were diagnosed with a higher stage at cystectomy (73% pT3-4 vs. 40%, P = 0.001) were more likely to have lymph node involvement (70% vs. 25%, P<0.001), and positive surgical margins were found in 40% of patients with PCV UC vs. 10% of patients with NV UC (P<0.001). Median overall survival and disease-specific survival were 19 and 22 months for PCV, respectively. Median overall survival and disease-specific survival had not been reached for NV at 68 months (P<0.001). Presence of PCV UC on transurethral resection of bladder tumor was associated with non-organ-confined disease (odds ratio = 4.02; 95% CI: 1.06-15.22; P = 0.040), and PCV at cystectomy was associated with increased adjusted risk of mortality (hazard ratio = 2.1; 95% CI: 1.2-3.8; P = 0.016). CONCLUSIONS PCV is an aggressive UC variant, predicting non-organ-confined disease and poor survival. Differentiating between non-muscle- and muscle-invasive disease in patients with PCV UC seems less important than the aggressive nature of this disease. Instead, any evidence of PCV on transurethral resection of bladder tumor may warrant aggressive therapy.

Management of stage I testicular germ cell tumours

OBJECTIVE To examine differences in disease progression and nature of tumor invasion that may lead to more accurate expectations of tumor behavior and improved management options for plasmacytoid variant (PCV) histology urothelial bladder cancer patients. METHODS Using the Indiana University Bladder Cancer Database, we conducted a retrospective analysis of patients undergoing radical cystectomy from 2008 to June 2013 to identify patients with PCV, micropapillary variant (MPV), or nonvariant (NV) histology and either positive ureteral margins (+UM), paravesical surgical margins (+PSM), or lymph node (+LN) involvement. Pearsons chi-squared test and analysis of variance were used for descriptive analysis. RESULTS Of 510 patients who met inclusion criteria, 30 had +UM on final pathology. The incidence of +UM in NV patients was 17 of 457 (3.7%), in MPV 5 of 28 (17.9%), and in PCV 8 of 25 (32.0%) (P <.001). Carcinoma in situ on the luminal margin was noted for all cases, except in 5 of the 8 PCV patients with +UM, in whom retrograde longitudinal invasion along the subserosal and adventitia was noted. +PSM and +LN were significantly higher for both PCV (28.0%, 72.0%) and MPV (10.7%, 64.3%) than NV (2.6%, 18.6%, P <.001, each). CONCLUSION PCV exhibits a unique pattern of spread along the ureter. This proposes a new mode of invasion along the fascial sheath. The incidence of +PSM and +LN liken PCV to the known aggressive MPV, and in conjunction with the increased incidence of +UM, may lead to a paradigm shift, with surgeons and pathologists being more vigilant with surgical margins.