Faculty Bibliography

OBJECTIVE: To develop nomograms that predict the probability of overall PCa and clinically significant PCa (Gleason >/=7) on MRI targeted, and combined MRI-targeted and systematic, prostate biopsy. MATERIALS AND METHODS: From June 2012 to August 2014, MR-US fusion targeted prostate biopsy was performed on 464 men with suspicious regions identified on pre-biopsy 3T MRI along with systematic 12 core biopsy. Logistic regression modeling was used to evaluate predictors of overall and clinically significant PCa, and corresponding nomograms were generated for men who were not previously biopsied or had one or more prior negative biopsies. Models were created with 70% of a randomly selected training sample and bias-corrected using bootstrap resampling. The models were then validated with the remaining 30% testing sample pool. RESULTS: A total of 459 patients were included for analysis (median age 66 years, PSA 5.2 ng/ml, prostate volume 49 cc). Independent predictors of PCa on targeted and systematic prostate biopsy were PSA density, age, and MRI suspicion score. PCa probability nomograms were generated for each cohort using the predictors. Bias-corrected areas under the receiver-operating characteristic curves for overall and clinically significant PCa detection were 0.82 (0.78) and 0.91 (0.84) for men without prior biopsy and 0.76 (0.65) and 0.86 (0.87) for men with a prior negative biopsy in the training (testing) samples. CONCLUSION: PSA density, age, and MRI suspicion score predict prostate cancer on combined MRI-targeted and systematic biopsy. Our generated nomograms demonstrate high diagnostic accuracy and may further aid in the decision to perform biopsy in men with clinical suspicion of PCa.

OBJECTIVE: To provide insights into the role of mpMRI for predicting oncological control following two focal ablation (FA) templates for selective cases of prostate cancer (PCa). MATERIALS AND METHODS: 59 radical prostatectomies were performed between 2012 and 2016 on cases that fulfilled criteria for FA. The Gleason score (GS), extent of Gleason pattern (GP) 4, maximum linear cross sectional length (MLCSL) and location of tumor foci were recorded and related to scale on corresponding 3mm transverse slice prostate maps. Gleason pattern 4 extra-focal disease (GP4EFD) was defined as PCa with any GP 4 not detected by mpMRI and transrectal ultrasound systematic biopsy observed outside a specified ablation zone. The location of these GP4EFD relative to the MRI lesion (MRI-L) (contralateral or ipsilateral) was recorded and used to predict oncological control following a hypothetical margin and ipsilateral hemi-ablation templates. RESULTS: Overall, 15/59 (25.4%) of the prostate specimens had at least one GP4EFD. Of the total 20 GP4EFD, 7/20 (35%) were ipsilateral and 13/20 (65%) were contralateral to the MRI-L. Of the GP4EFD, 16/20 (80%), 2/20 (10%), and 2/20 (10%) were GS 3+4, GS 4+3, and GS 4+4, respectively. Of these GP4EFD, 10/20 (50%) exhibited a MLCSL < 5mm. Ablating only the MRI-L+10mm or performing a ipsilateral hemi-ablation would leave residual GP4 in 14/59 (23.7%) and 11/59 (18.6%) of cases, respectively. CONCLUSIONS: Since a significant proportion of candidates for FA based on mpMRI and systematic biopsy will have pre-existing GP4EFD outside ablation templates, active surveillance of the untreated prostate is mandatory.

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