Faculty Bibliography

OBJECTIVE: To determine if multiparametric MRI (mpMRI) identifies significant apical disease, thereby informing decisions regarding preservation of the membranous urethra. MATERIALS AND METHODS: Men undergoing radical prostatectomy between January 2012 and June 2016 who underwent a 12-core transrectal-ultrasound guided systematic biopsy, preoperative 3-T MRI, and sectioning of the prostate specimen with tumor foci mapping were extracted from a single surgeon's prospective longitudinal outcomes database. Apical systematic biopsy vs. mpMRI lesion were compared for predicting aggressive tumor in the prostatic apex defined as Prostate Cancer Grade Group >1. RESULTS: Of the 100 men who met eligibility criteria, 43 (43%) exhibited aggressive prostate cancer in the distal 5mm of the apex. A Likert score > 2 in the apical one-third of the prostate was found to be more reliable than any cancer found on apical systematic biopsy at detecting aggressive cancer in the apex. On multivariate regression that included Likert score in the apex, age, PSA, prostate size, and presence of any cancer on apical biopsy, only Likert score (p=.005) and PSA (p=.025) were significant and independent predictors of aggressive cancer in the distal apex. CONCLUSION: MRI is superior to systematic biopsy at identifying aggressive prostate cancer within the distal prostatic apex and may be useful for planning the extent of apical preservation during prostatectomy.

A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy number changes in those populations, and measures of the proportion of cells with clonal copy number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathological measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant since primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions.

The challenge to the urology community is to reduce the risks of screening and treatment by reducing the number of men undergoing unnecessary biopsy and whole-gland curative treatment of low-risk disease. There is compelling evidence that focal ablation of prostate cancer is truly minimally invasive and offers major functional advantages over whole-gland treatment.

BACKGROUND:An increasing proportion of prostate cancer is being managed conservatively. However, there are no randomized trials or consensus regarding the optimal follow-up strategy. OBJECTIVE:To compare life expectancy and quality of life between watchful waiting (WW) versus different strategies of active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS/METHODS:A Markov model was created for US men starting at age 50, diagnosed with localized prostate cancer who chose conservative management by WW or AS using different testing protocols (prostate-specific antigen every 3-6 mo, biopsy every 1-5 yr, or magnetic resonance imaging based). Transition probabilities and utilities were obtained from the literature. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:Primary outcomes were life years and quality-adjusted life years (QALYs). Secondary outcomes include radical treatment, metastasis, and prostate cancer death. RESULTS AND LIMITATIONS/CONCLUSIONS:All AS strategies yielded more life years compared with WW. Lifetime risks of prostate cancer death and metastasis were, respectively, 5.42% and 6.40% with AS versus 8.72% and 10.30% with WW. AS yielded more QALYs than WW except in cohorts age >65 yr at diagnosis, or when treatment-related complications were long term. The preferred follow-up strategy was also sensitive to whether people value short-term over long-term benefits (time preference). Depending on the AS protocol, 30-41% underwent radical treatment within 10 yr. Extending the surveillance biopsy interval from 1 to 5 yr reduced life years slightly, with a 0.26 difference in QALYs. CONCLUSIONS:AS extends life more than WW, particularly for men with higher-risk features, but this is partly offset by the decrement in quality of life since many men eventually receive treatment. PATIENT SUMMARY/UNASSIGNED:More intensive active surveillance protocols extend life more than watchful waiting, but this is partly offset by decrements in quality of life from subsequent treatment.

Approximately 100,000 radical prostatectomies (RP) are performed annually in the US with the intent to cure clinically localized prostate cancer. Oncological control following RP is assessed by monitoring serum PSA levels. By consensus, a PSA exceeding 0.2 ng/mL is considered the threshold for a biochemical recurrence (BCR) following RP (3). BCR often predates radiographic and clinical evidence of disease recurrence by many years (4-6)

Objectives: Nocturia is a multifactorial condition with numerous comorbidities. The efficacy of SER120 after controlling for placebo effect was investigated in a subset of patients with nocturia due to nocturnal polyuria (NP) with concomitant overactive bladder (OAB) in two randomized, placebo-controlled trials. Methods: Two phase 3 trials enrolled patients >=50 years old who had experienced >=2 nocturia episodes for >=6 months. Patients were randomized 1:1:1 to SER120 1.66 mcg, 0.83 mcg or placebo for a 12-week treatment period after a 2-week placebo-controlled run-in period to control for placebo effect. Placebo responder patients (achieving 50% decrease in nocturic episodes/night from baseline or a mean < 1.8 nocturic episodes/night) during the run-in period were excluded from the analysis. Placebo non-responders (mITT population) with OAB and NP were pooled for analysis. The co-primary efficacy endpoints were mean change from baseline in nocturic episodes/night and percentage of patients with 50% reduction in nocturic episodes/night (responding patients). Secondary efficacy endpoints included change in time from bedtime to first nocturic episode and percent of nights >=1 nocturic episodes/night. Meaningful clinical improvement in health-related quality of life (HRQoL) was also assessed in one trial using a newly validated patient reported outcome (PRO) in-strument called Impact of Night-time Urination (INTU). Results: Study patients (n=207) with nocturia due to OAB and NP (mean age 68.3+/-9.9 years, 60.9% female, 78.3% Caucasian) showed significant results for both doses in both co-primary endpoints following treatment with SER120 compared to placebo. The reduction in mean nocturic episodes/night for the 1.66 mcg dose was 2 times that of placebo (-1.4 vs.-0.7, p=0.0010) and for the 0.83 mcg dose almost 2 times that of placebo (-1.3 vs.-0.7, p=0.0076). The percentage of responding patients for the 1.66 mcg dose was > 3 times greater than placebo (36.5% vs. 10.9%, p=0.0007) and for the 0.83 mcg dose was >2.5 times that of placebo (29% vs. 10.9%, p=0.0096). Secondary efficacy endpoints also showed significant results. Time from bedtime to first nocturic void showed an increase from baseline for SER120 of 72 minutes (1.66 mcg, p=0.0136) and 84 minutes (0.83 mcg, p=0.0036) vs 30 minutes for placebo. The percentage of nights with >=1 episode/night showed an increase from baseline for SER120 of 28.18% (1.66 mcg, p=0.0161) and 26.86% (0.83 mcg, p=0.0269) vs. 11.79% for placebo. The PRO instrument also showed significant improvements on HRQoL for both SER120 doses compared to placebo. The reduction in total impact score was-12.1 (1.66 mcg, p=0.0056),-10.4 (0.83 mcg, p=0.0244) and-2.1 (placebo). Two patients at the 1.66 mcg dose who were on systemic steroids had serum sodium >=125 mmol/L. No patients at the 0.83 mcg dose had serum sodium >=125 mmol/L. Conclusions: SER120 at doses of 1.66 and 0.83 mcg is effective for the treatment of patients with nocturia due to NP with concomitant OAB. The results of the PRO (INTU) instrument demonstrated that SER120 has a clinical meaningful benefit and statistically significant improvement on HRQoL. SER120 was shown to be safe and well tolerated in this patient population