The Cancer of the Bladder Risk Assessment (COBRA) score: Estimating mortality after radical cystectomy.

BACKGROUND: Risk stratification of patients with urothelial carcinoma of the bladder (UCB) after cystectomy has important clinical and research implications. The authors assessed the relative effect of tumor stage and lymph node status on cancer-specific survival (CSS) after cystectomy and developed a simplified risk-assessment tool. METHODS: In total, 14,828 patients who underwent cystectomy with lymph node dissection for UCB were identified from the Surveillance, Epidemiology, and End Results database (1988-2011). The relative importance of tumor stage and lymph node status with regard to CSS was assessed using stratified Kaplan-Meier and Cox proportional-hazards analyses. The patients were split randomly into development and validation cohorts. Additional validation using overall survival was performed on 19,362 patients from the National Cancer Data Base. The Cancer of Bladder Risk Assessment (COBRA) tool was created using a Cox model incorporating age, tumor stage, and lymph node density. Performance was validated using observed versus expected survival plots and the Harrell concordance index. RESULTS: Patients with muscle invasive (T2), lymph node-positive disease had a survival curve similar to that in patients with extravesical (T3 and T4), lymph node-negative disease (2-year CSS, 67% and 70%, respectively). Each point increase in the COBRA score (range, 0-7) was associated with a 1.61-fold increase (95% confidence interval, 1.56-fold to 1.65-fold increase) in the risk of bladder cancer death in the development cohort. The model accurately stratified patients across risk levels in the development cohort and the 2 validation cohorts (C-index, 0.712, 0.705, and 0.68, respectively). CONCLUSIONS: The COBRA score offers a straightforward, validated risk-stratification tool that incorporates the relative contribution of tumor stage and lymph node involvement to patient prognosis after cystectomy for UCB. Cancer 2017;123:4574-4582. © 2017 American Cancer Society.

Extended followup and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer.

PURPOSE: Active surveillance to manage prostate cancer provides an alternative to immediate treatment in men with low risk prostate cancer. We report updated outcomes from a long-standing active surveillance cohort and factors associated with reclassification. MATERIALS AND METHODS: We retrospectively reviewed data on all men enrolled in the active surveillance cohort at our institution with at least 6 months of followup between 1990 and 2013. Surveillance consisted of quarterly prostate specific antigen testing, repeat imaging with transrectal ultrasound at provider discretion and periodic repeat prostate biopsies. Factors associated with repeat biopsy reclassification and local treatment were determined by multivariate Cox proportional hazards regression. We also analyzed the association of prostate specific antigen density and outcomes stratified by prostate size. RESULTS: A total of 810 men who consented to participate in the research cohort were followed on active surveillance for a median of 60 months. Of these men 556 (69%) met strict criteria for active surveillance. Five-year overall survival was 98%, treatment-free survival was 60% and biopsy reclassification-free survival was 40%. There were no prostate cancer related deaths. On multivariate analysis prostate specific antigen density was positively associated with the risk of biopsy reclassification and treatment while the number of biopsies and time between biopsies were inversely associated with the 2 outcomes (each p <0.01). When stratified by prostate volume, prostate specific antigen density remained significantly associated with biopsy reclassification for all strata but prostate specific antigen density was only significantly associated with treatment in men with a smaller prostate. CONCLUSIONS: Significant prostate cancer related morbidity and mortality remained rare at intermediate followup. Prostate specific antigen density was independently associated with biopsy reclassification and treatment while on active surveillance.

Diagnostic associations of gene expression signatures in prostate cancer tissue.

PURPOSE OF REVIEW: Over the past several years, multiple biomarkers designed to improve prostate cancer risk stratification have become commercially available, while others are still being developed. In this review, we focus on the evidence supporting recently reported biomarkers, with a focus on gene expression signatures. RECENT FINDINGS: Many recently developed biomarkers are able to improve upon traditional risk assessment at nearly all stages of disease. Prominent examples are reviewed in this article. ConfirmMDx uses gene methylation patterns to improve detection of clinically significant cancer following negative biopsy. Both the Prolaris and Oncotype DX Genomic Prostate Score tests can improve risk stratification following biopsy, especially among men who are eligible for active surveillance. Prolaris and the Decipher genomic classifier have been associated with risk of adverse outcome following prostatectomy, while Oncotype DX is being studied in this setting. Finally, recent reports of the association of androgen receptor-V7 in circulating tumor cells with resistance to enzalutamide and abiraterone raise the possibility of extending the use of genetic biomarkers to advanced disease. SUMMARY: With the development of multiple genetic expression panels in prostate cancer, careful study and validation of these tests and integration into clinical practice will be critical to realizing the potential of these tools.

Age and baseline quality of life at radical prostatectomy--who has the most to lose?

PURPOSE: Although younger men have better health related quality of life scores after radical prostatectomy, many have higher baseline function with more to lose than older men. We examined the impact of age on sexual and urinary function and bother during the first 2 years after radical prostatectomy. MATERIALS AND METHODS: Participants enrolled in CaPSURE™ reported sexual and urinary scores before and after radical prostatectomy using UCLA-PCI. Repeated measures mixed models were used to compare the change in health related quality of life with time between men who were younger (age 60 years or less) and older (age greater than 60 years). Logistic regression models were used to assess associations between age and clinically meaningful health related quality of life decreases (worsening). Models were adjusted for clinical characteristics. RESULTS: Of 1,806 patients younger men reported higher sexual and urinary function scores at each time point and higher sexual function decrease rates at 1 year than older men (81% vs 75%, p<0.01). Younger men also had higher sexual bother decrease rates 1 year (74% vs 61%, p<0.01) and 2 years (62% vs 56%, p=0.02) after radical prostatectomy. On multivariate analysis age was associated with changes in sexual function and bother from baseline through 2 years (each p<0.01). Younger men had higher adjusted odds of sexual function decreases at 1 year (OR 1.15/5 years, 95% CI 1.01-1.30, p=0.03) but not at 2 years. Younger age was associated with lower odds of worsening sexual bother at 2 years (OR 0.79/5 years, 95% CI 0.67-0.94, p<0.01). Urinary function and bother decrease rates were similar by age. Secondary analyses of the age/health related quality of life interaction showed that men were at greater risk for health related quality of life decreases if baseline scores were above average regardless of age. CONCLUSIONS: Younger men reported higher sexual and urinary function overall, and experienced greater decreases in sexual function immediately after radical prostatectomy than older men. While the 2 groups experienced similar relative sexual function decreases at 2 years, younger men had worse interim decreases at 1 year. Providers should consider these findings when discussing treatment timing, particularly with younger men diagnosed with early stage, low grade disease.

Meaningful end points and outcomes in men on active surveillance for early-stage prostate cancer.

PURPOSE OF REVIEW: Active surveillance is a management strategy for early-stage prostate cancer designed to balance early detection of aggressive disease and overtreatment of indolent disease. We evaluate recently reported outcomes and discuss the potentially most important endpoints for such an approach. RECENT FINDINGS: The past 2 years have seen the publication of two trials of watchful waiting versus immediate treatment and updates of multiple active surveillance cohorts for men with early-stage prostate cancer. The watchful waiting trials demonstrated a small potential mortality benefit to immediate treatment when applied to all risk levels (6% absolute difference at 15 years), emphasizing the importance of a risk-adapted strategy. In reported active surveillance cohorts, prostate cancer death and metastasis remain rare events. Intermediate outcomes such as progression to treatment and upgrading/upstaging on final disease appear consistent among cohorts, but must be interpreted with caution when compared with historical controls of immediate treatment because of potential selection bias. SUMMARY: The safety of active surveillance has been reinforced by recent reports. Accumulation of additional data on men with intermediate risk cancer and development and validation of new biomarkers of risk will allow refined and, likely, expanded use of this approach.

Single cell transcriptomic analysis of prostate cancer cells.

BACKGROUND: The ability to interrogate circulating tumor cells (CTC) and disseminated tumor cells (DTC) is restricted by the small number detected and isolated (typically <10). To determine if a commercially available technology could provide a transcriptomic profile of a single prostate cancer (PCa) cell, we clonally selected and cultured a single passage of cell cycle synchronized C4-2B PCa cells. Ten sets of single, 5-, or 10-cells were isolated using a micromanipulator under direct visualization with an inverted microscope. Additionally, two groups of 10 individual DTC, each isolated from bone marrow of 2 patients with metastatic PCa were obtained. RNA was amplified using the WT-Ovation™ One-Direct Amplification System. The amplified material was hybridized on a 44K Whole Human Gene Expression Microarray. A high stringency threshold, a mean Alexa Fluor® 3 signal intensity above 300, was used for gene detection. Relative expression levels were validated for select genes using real-time PCR (RT-qPCR). RESULTS: Using this approach, 22,410, 20,423, and 17,009 probes were positive on the arrays from 10-cell pools, 5-cell pools, and single-cells, respectively. The sensitivity and specificity of gene detection on the single-cell analyses were 0.739 and 0.972 respectively when compared to 10-cell pools, and 0.814 and 0.979 respectively when compared to 5-cell pools, demonstrating a low false positive rate. Among 10,000 randomly selected pairs of genes, the Pearson correlation coefficient was 0.875 between the single-cell and 5-cell pools and 0.783 between the single-cell and 10-cell pools. As expected, abundant transcripts in the 5- and 10-cell samples were detected by RT-qPCR in the single-cell isolates, while lower abundance messages were not. Using the same stringency, 16,039 probes were positive on the patient single-cell arrays. Cluster analysis showed that all 10 DTC grouped together within each patient. CONCLUSIONS: A transcriptomic profile can be reliably obtained from a single cell using commercially available technology. As expected, fewer amplified genes are detected from a single-cell sample than from pooled-cell samples, however this method can be used to reliably obtain a transcriptomic profile from DTC isolated from the bone marrow of patients with PCa.

Combined partial cystectomy and cesarean delivery in a pregnant female with bladder pheochromocytoma.

We report the first known case of concurrent partial cystectomy and cesarean delivery in a pregnant female with bladder pheochromocytoma. A 28-year-old G4P2 female presented at 28 weeks gestation with labile blood pressures requiring three antihypertensive medications. Urinary catecholamines were elevated, and a subsequent MRI showed a 2.6 cm x 3.2 cm bladder wall mass. She underwent combined cesarian section and partial cystectomy at 37 weeks. Fluid resuscitation and vasopressors were required in the immediate postoperative period. While bladder pheochromocytoma with pregnancy is a rare occurrence, concurrent delivery and removal of the bladder tumor can be performed safely.

Ductal adenocarcinoma of the prostate: increased mortality risk and decreased serum prostate specific antigen.

PURPOSE: The clinical significance of ductal prostatic carcinoma is not well-defined. In a population based cancer registry we identified a large group of patients with ductal carcinoma to characterize the impact of the ductal subtype on presentation and survival in men with prostate cancer. MATERIALS AND METHODS: We used a national cancer registry to identify incident cases of ductal and acinar adenocarcinoma from 1996 to 2006. We analyzed clinicopathological variables and performed Cox multivariate survival analysis. Prostate specific antigen values were available for 2004 to 2006 and used to assess differences in Gleason grade and serum prostate specific antigen between ductal and acinar cancer cases at diagnosis. RESULTS: We identified 442,881 acinar and 371 ductal cases. Ductal cases were more likely to present with distant disease (12% vs 4%, p <0.001) and be poorly differentiated (50% vs 32%, p <0.001). Ductal histology was associated with a 30% decrease in geometric mean prostate specific antigen (adjusted coefficient 0.7, 95% CI 0.6-0.8) and more than 2-fold increased odds of prostate specific antigen less than 4.0 ng/ml (OR 2.4, 95% CI 1.4-4.0) independent of other clinicopathological variables. In men with nondistant disease at diagnosis ductal histology was associated with 2.2-fold (CI 1.4-3.5) increased disease specific mortality. CONCLUSIONS: In what is to our knowledge the largest series of this histological subtype ductal cancer cases were more likely to present with advanced stage cancer and lower prostate specific antigen, suggesting that timely disease detection is a significant challenge. Also, men with locoregional disease were more likely to die of the disease.

Monoscopic versus stereoscopic photography in screening for clinically significant macular edema.

The purpose of the study was to determine whether monoscopic photography could serve as an accurate tool when used to screen for clinically significant macular edema. In a masked randomized fashion, two readers evaluated monoscopic and stereoscopic retinal photographs of 100 eyes. The photographs were evaluated first individually for probable clinically significant macular edema based on the Early Treatment Diabetic Retinopathy Study criteria and then as stereoscopic pairs. Graders were evaluated for sensitivity and specificity individually and in combination. Individually, reader one had a sensitivity of 0.93 and a specificity of 0.77, and reader two had a sensitivity of 0.88 and a specificity of 0.94. In combination, the readers had a sensitivity of 0.91 and a specificity of 0.86. They correlated on 0.76 of the stereoscopic readings and 0.92 of the monoscopic readings. These results indicate that the use of monoscopic retinal photography may be an accurate screening tool for clinically significant macular edema.

Immediate versus delayed radical prostatectomy: updated outcomes following active surveillance of prostate cancer.

BACKGROUND: Biopsy progression on active surveillance (AS) for prostate cancer (PCa) often reflects failure of the initial biopsy to detect cancer present at enrollment. The risks for delayed treatment among men who progress on AS are not well defined. OBJECTIVE: To report outcomes for men who underwent surgery after AS compared to men who underwent immediate surgery and the influence of selection bias on this outcome. DESIGN, SETTING, AND PARTICIPANTS: AS-eligible (ASE) men who underwent radical prostatectomy (RP) after a median of 20 mo of AS were compared to ASE men who underwent RP within 6 mo of diagnosis. A subset of men on AS who underwent RP after upgrade to Gleason 3+4 was compared to matched controls with similar pretreatment biopsy features who underwent immediate RP. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: Rates of adverse pathology (upstaging, positive surgical margin, or Gleason upgrading) were examined. Logistic regression was used to determine associations between treatment subgroup and adverse pathology. RESULTS AND LIMITATIONS: Of 157 ASE men who underwent delayed RP after AS, 54 were upgraded to Gleason 3+4 before surgery. ASE men who underwent immediate RP had lower probability of adverse pathology than ASE men who underwent delayed RP (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.21-0.55). The rate of adverse pathology did not differ between immediate and delayed RP patients matched for pretreatment characteristics (HR 0.79, 95% CI 0.27-2.28). The observational design of this study is its main limitation. CONCLUSIONS: When compared to men with similar pretreatment biopsy features, those who underwent delayed RP were not at higher risk of adverse pathology. PATIENT SUMMARY: The oncologic safety of delayed treatment when indicated for men enrolled in active surveillance for prostate cancer is important. We found that men who underwent delayed surgery had similar outcomes to men who underwent immediate prostatectomy.

Persistence of urothelial carcinoma of the bladder risk among former smokers: results from a contemporary, prospective cohort study.

OBJECTIVES: Cigarette smoking is a known risk factor for urothelial carcinoma (UC) of the bladder. However, the persistence of an increased risk for UC following smoking cessation is not well established. We assessed the risk of UC among former smokers using a recent, prospective cohort with a high proportion of former smokers. MATERIALS AND METHODS: Study participants were members of the VITamins And Lifestyle cohort (VITAL), a group of 77,719 men and women between the ages of 50 and 76 years from western Washington State. Smoking history and other risk factors were obtained at the time of recruitment. The primary outcome was a new diagnosis of UC (n =385), as determined through linkage to a population-based cancer registry. RESULTS AND LIMITATIONS: The cohort included 8% current and 44% former smokers, and among the UC cases, 15% were current and 60% former smokers. Both the current and former smoker had an increased risk of UC compared with never smokers (hazard ratio [HRs]: 3.81; 95% confidence intervals [CI] 2.71-5.35 and 2.0; 95% CI 1.55-2.58, respectively). Among former smokers, the risk of UC increased with the pack-years smoked and decreased with the years since quitting. When both the measures of smoking were considered together, the risk of UC was similar for long-term quitters and recent quitters for a given level of pack-years. For example, for those with pack-years of 22.5-37.5, the HR of UC was 1.91 (95% CI 1.17-3.11) for the distant quitters (≥ 23.5 y before baseline) and HR = 1.92 (95% CI 1.26-2.94) among the recent quitters. Limitations include the small number of cases at the extremes of smoking history and errors in self-reported smoking history. CONCLUSIONS: The risk of bladder cancer in former smokers remains elevated>32 years after quitting, even among those with moderate smoking histories. This argues that a history of smoking confers a lifelong increased risk of UC.