Faculty Bibliography

PURPOSE/OBJECTIVE:While MRI-Ultrasound Fusion-targeted biopsy (MRF-TB) allows for improved detection of clinically significant prostate cancer (csPCa), concerning numbers of clinically significant disease are still missed. We hypothesize that a number of these are due to the learning curve associated with MRF-TB. We report results of repeat MRF-TB in men with continued suspicion for cancer and the institutional learning curve in detection of csPCa over time. MATERIALS AND METHODS/METHODS:Analysis of 1813 prostate biopsies in a prospectively acquired cohort of men presenting for prostate biopsy over a 4-year period. All men were offered pre-biopsy MRI and assigned a maximum Prostate Imaging - Reporting and Data System version 2 (PI-RADS) score. Biopsy outcomes of men with suspicious region of interest (ROI) were compared. The relationship between time and csPCa detection was analyzed. RESULTS:csPCa detection rate increased 26% over time in men with PI-RADS 4 and 5 (4/5) ROI. On repeat MRF-TB in men with continued suspicion for cancer, 53% of men with PI-RADS 4/5 ROI demonstrated clinically significant discordance from initial MRF-TB, compared to only 23% of men with PI-RADS 1/2 ROI. Significantly less csPCa were missed or under-graded in the most recent biopsies as compared to the earliest biopsies. CONCLUSION/CONCLUSIONS:High upgrade rates on repeat MRF-TB and increasing cancer detection rate over time demonstrate the significant learning curve associated with MRF-TB. Men with low risk or negative biopsies with persistent concerning ROI should be promptly re-biopsied. Improved targeting accuracy with operator experience can help decrease the number of missed csPCa.

Uroplakin (UP) tetraspanins and their associated proteins are major mammalian urothelial differentiation products that form unique 2D-crystals of 16-nm particles ("urothelial plaques") covering the apical urothelial surface. Although uroplakins are highly expressed only in mouse urothelium and are often referred to as being urothelium-specific, they are also expressed in several nonurothelial cell types in stomach, kidney, prostate, epididymis, testis/sperms and ovary/oocytes. In oocytes, uroplakins co-localize with CD9 on cell surface and multivesicular body-derived exosomes, and the cytoplasmic tail of UPIIIa undergoes a conserved fertilization-dependent, Fyn-mediated tyrosine-phosphorylation that also occurs in Xenopus laevis eggs. Uroplakin knockout and antibody blocking reduce mouse eggs' fertilization rate in in vitro fertilization assays, and UPII/IIIa double-knockout mice have a smaller litter size. Phylogenetic analyses showed that uroplakin sequences underwent significant mammal-specific changes. These results suggest that, by mediating signal transduction and modulating membrane stability that do not require 2D-crystal formation, uroplakins can perform conserved and more ancestral fertilization functions in mouse and frog eggs. Uroplakins acquired the ability to form 2D- crystalline plaques during mammalian divergence enabling them to perform additional functions, including umbrella cell enlargement and the formation of permeability and mechanical barriers, in order to protect/modify the apical surface of the modern-day mammalian urothelium.

OBJECTIVE:To provide insights into the long-term impact of radical retro-pubic prostatectomy (ORRP) on LUTS which are age and prostate dependent and adversely impact quality of life. METHODS:1,995 men undergoing ORRP enrolled in a prospective longitudinal outcomes study. The American Urological Association symptom index (AUASI) was self-administered before ORRP and at pre-determined time-points after surgery. A multivariate generalized linear model was used to evaluate the association of time since ORRP with AUASS. McNemar's test and paired sample t-tests were used to assess whether the proportion of men with clinically significant LUTS (CSLUTS) defined by an American Urological Association symptom score (AUASS) >7 or mean AUASS differed significantly between the time-dependent assessments, respectively. RESULTS:The 15 year mean adjusted AUASS was similar to baseline (7.00 vs. 6.85, p=0.66). Throughout the 15 years of follow-up, the proportion of men with CSLUTS was lower than baseline with the exception of the 3 month and 15 year assessments. Among men with baseline clinically insignificant LUTS (CILUTS), the mean adjusted AUASS at 15 years was significantly greater than baseline (6.09 vs. 3.19, p<0.001). Among men with baseline CSLUTS, ORRP led to a significant decrease in mean adjusted AUASS between baseline and 15 years (13.26 vs. 8.67, p<0.001). CONCLUSIONS:ORRP favorably affects the long-term natural history of LUTS. The long-term economic and quality of life benefits of ORRP on LUTS should inform the risks and benefits of RP for treatment of localized prostate cancer.

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.

Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo(a)pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O⁶-methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents.

BACKGROUND:There is no consensus regarding how to assess oncological control following focal ablation of prostate cancer. OBJECTIVE:To assess quality of life and in-field recurrence following focal laser ablation (FLA). DESIGN, SETTING, AND PARTICIPANTS/METHODS:Of 34 men participating in a prospective outcomes study following FLA, 32 underwent prostate-specific antigen (PSA) testing and magnetic resonance imaging (MRI) at 6 mo and 2 yr. All underwent assessment of urinary and sexual function at 1 yr. INTERVENTION/METHODS:FLA and MRI-targeted biopsy of the ablation zone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/UNASSIGNED:The American Urological Association Symptom Score and the Sexual Health Inventory for Men at baseline and 12 mo were compared using a two-sided Wilcoxon signed-rank test with a significance level of p=0.05. The percentage of positive and negative in-field biopsies was calculated for suspicious and nonsuspicious post-ablation MRI scans. RESULTS AND LIMITATIONS/CONCLUSIONS:FLA was associated with no adverse impact on urinary or sexual function. For men with suspicious MRI (MRI+) findings, in-field disease recurrence of intermediate and low risk disease was detected in 75% and 25% of cases, respectively. For men with nonsuspicious MRI (MRI-) findings, in-field disease recurrence of intermediate- and low-risk disease was detected in 22.4% and 50% of cases, respectively. The change in PSA from baseline did not discriminate cases with MRI- findings with and without cancer at 2 yr. CONCLUSIONS:MRI reliably identifies in-field recurrence of only intermediate-risk prostate cancer at 2 yr after FLA. A biopsy of the ablation zone must be performed for MRI+ findings. The decision to perform an ablation-zone biopsy for men with MRI- scans should be influenced by whether detection of low-risk disease would influence management. PATIENT SUMMARY/UNASSIGNED:Our study provides compelling evidence that men should undergo interval magnetic resonance imaging to assess the probability of intermediate-risk disease in the ablation zone following focal laser ablation of localized prostate cancer.

Background/UNASSIGNED:Active surveillance (AS) is the most rapidly expanding management option for favorable-risk prostate cancer (PCa). Early studies suggested substantial decrements in utility (quality of life weights) from disease-related anxiety. Our objective was to determine utilities for contemporary AS patients using different instruments. Methods/UNASSIGNED:We performed a systematic review of PubMed, PMC and OVID for utility measurements in modern AS patients. We then examined utilities among 37 men on AS participating in focus groups between 2015-2016 using the generic EurQol five dimensions questionnaire (EQ-5D-3L) and Patient Oriented Prostate Utility Scale (PORPUS), a PCa-specific instrument. Results/UNASSIGNED:The systematic review found previous studies with utilities for PCa treatment and historical watchful waiting populations, but none specifically in contemporary AS. In our AS population, the mean EQ-5D-3L score was 0.90±0.16 (median, 1.00; range, 0.21-1.00) and PORPUS was 0.98±0.03 (median, 0.99; range, 0.84-1.00). The Spearman correlation between the EQ-5D-3L and PORPUS was 0.87 (P<0.0001), and 38% of patients had a difference >0.1 between instruments. Conclusions/UNASSIGNED:Most contemporary AS patients had high utility scores suggesting that they perceive themselves in good health without a major decrement in quality of life from the disease. However, some patients had substantial differences in utility measured with generic versus disease-specific instruments. Further study is warranted into the optimal instrument for utility assessment in contemporary AS patients.