Faculty Bibliography

PURPOSE/OBJECTIVE:To examine the time dependent rates of urinary continence (UC) following open retropubic radical prostatectomy (ORRP). MATERIALS AND METHODS/METHODS:1,995 men undergoing RP were enrolled in a prospective, longitudinal outcomes study. The University of California, Los Angeles-Prostate Cancer Index Urinary Function Index (UCLA-PCI-UFS) was administered at baseline, 3, 6, 12, 24, 96, 120, and 180 months post-ORRP. Urinary continence was defined by <1 pad in 24 hours. Two multiple regression models were used to evaluate the association of time since ORRP with UCLA-PCI-UFI score and UC. RESULTS:The decrease in UC rates between baseline and 15 years (99.6% vs. 87.2%, p<0.001) and 2 and 15 years (95.3% vs. 87.2%, p=0.021) were statistically significant. UC rates were consistently higher in the younger group at all time points. CONCLUSION/CONCLUSIONS:A significant decrease in UC rates was observed between baseline to 2 years and 2 to 15 years for the entire cohort. UC rates for age-matched men in the general population followed longitudinally for 15 years are comparable to our study population suggesting that while ORRP causes primarily sphincteric urinary incontinence, it may be protective for subsequent BPH mediated urinary incontinence.

E-cigarette smoke delivers stimulant nicotine as aerosol without tobacco or the burning process. It contains neither carcinogenic incomplete combustion byproducts nor tobacco nitrosamines, the nicotine nitrosation products. E-cigarettes are promoted as safe and have gained significant popularity. In this study, instead of detecting nitrosamines, we directly measured DNA damage induced by nitrosamines in different organs of E-cigarette smoke-exposed mice. We found mutagenic O6-methyldeoxyguanosines and γ-hydroxy-1,N2 -propano-deoxyguanosines in the lung, bladder, and heart. DNA-repair activity and repair proteins XPC and OGG1/2 are significantly reduced in the lung. We found that nicotine and its metabolite, nicotine-derived nitrosamine ketone, can induce the same effects and enhance mutational susceptibility and tumorigenic transformation of cultured human bronchial epithelial and urothelial cells. These results indicate that nicotine nitrosation occurs in vivo in mice and that E-cigarette smoke is carcinogenic to the murine lung and bladder and harmful to the murine heart. It is therefore possible that E-cigarette smoke may contribute to lung and bladder cancer, as well as heart disease, in humans.

OBJECTIVE:To understand the informational needs during active surveillance (AS) for prostate cancer from the perspectives of patients and providers. METHODS:We conducted seven focus groups with 37 AS patients in two urban clinical settings, and 24 semi-structured interviews with a national sample of providers. Transcripts were analyzed using applied thematic analysis, and themes were organized using descriptive matrix analyses. RESULTS:We identified six themes related to informational needs during AS: 1) more information on prostate cancer (biopsy features, prognosis), 2) more information on active surveillance (difference from watchful waiting, testing protocol), 3) more information on alternative management options (complementary medicine, lifestyle modification), 4) greater variety of resources (multiple formats, targeting different audiences), 5) more social support and interaction, and 6) verified integrity of information (trusted, multidisciplinary and secure). CONCLUSIONS:Patients and providers described numerous drawbacks to existing prostate cancer resources and a variety of unmet needs including information on prognosis, AS testing protocols, and lifestyle modification. They also expressed a need for different types of resources, including interaction and unbiased information. PRACTICAL IMPLICATIONS/CONCLUSIONS:These results are useful to inform the design of future resources for men undergoing AS.

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.

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.

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.

PURPOSE:Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. METHODS AND MATERIALS:Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). RESULTS:Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non-prostate cancer) did not differ (5% relative reduction, P=.48). CONCLUSIONS:LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

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.

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