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We previously found no significant differences in mortality between men who underwent surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long-term mortality. From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation. We extended follow-up through August 2014 for our primary outcome, all-cause mortality, and the main secondary outcome, prostate-cancer mortality. We describe disease progression, treatments received, and patient-reported outcomes through January 2010 (original follow-up). During 19.5 years of follow-up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], -1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) assigned to observation (absolute difference in risk, 4.0 percentage points; 95% CI, -0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associated with lower all-cause mortality than observation among men with intermediate-risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 25.6) but not among those with low-risk disease (absolute difference, 0.7 percentage points; 95% CI, -10.5 to 11.8) or high-risk disease (absolute difference, 2.3 percentage points; 95% CI, -11.5 to 16.1) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate-specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease-related or treatment-related limitations in activities of daily living were greater with surgery than with observation through 2 years. After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veterans Affairs and others; PIVOT ClinicalTrials.gov number, NCT00007644 .).

Over 700 men were assigned to radical prostatectomy or observation after receiving a diagnosis of prostate cancer, usually on the basis of elevated PSA levels. After a median of 10 years, between-group differences in all-cause and prostate-cancer mortality were not significant. The treatment of early-stage prostate cancer remains controversial, especially for tumors detected by means of prostate-specific antigen (PSA) testing. 1 Systematic reviews have provided inadequate information for assessing the comparative effectiveness of treatments and any associated harms. 2 Although the lifetime risk of receiving a diagnosis of prostate cancer is about 17%, the risk of dying from the disease is approximately 3%, suggesting that conservative management may be appropriate for many men. 3 , 4 Two randomized trials compared radical prostatectomy with observation but were conducted before PSA testing became widespread. 5 , 6 One study failed to show a significant difference in overall mortality after . . .

Dutasteride, an inhibitor of 5α-reductase in the prostate, was tested in a large, randomized trial to determine its ability to prevent prostate cancer. Over the 4 years of the trial, dutasteride, as compared with placebo, reduced the relative risk of biopsy-detected prostate cancer by 23%. The reduction was limited mainly to tumors with Gleason scores of 5 or 6; by year 4, there were 12 tumors with Gleason scores of 8 to 10 in the dutasteride group but only 1 in the placebo group. Dutasteride, an inhibitor of 5α-reductase in the prostate, reduced the relative risk of biopsy-detected prostate cancer by 23%; however, the reduction was limited mainly to tumors with Gleason scores of 5 or 6. The 5α-reductase inhibitors that are used to treat benign prostatic hyperplasia block the conversion of testosterone to dihydrotestosterone and may reduce the risk of prostate cancer. 1 The results of the Prostate Cancer Prevention Trial showed that finasteride, as compared with placebo, reduced the risk of prostate cancer by 25%, but among the tumors that were detected, there was a 27% increase in the number of those that had Gleason scores of 7 to 10. 2 (The Gleason score is the sum of the two most common histologic patterns or grades in a prostate tumor, each of which is graded on a . . .

Although prostate-specific antigen (PSA) screening has improved the detection of prostate cancer, allowing for stage migration to less advanced disease, the precise mortality benefit of early detection is unclear. This is in part due to a discrepancy between the two large randomized controlled trials comparing PSA screening to usual care. The European Randomized Study of Screening for Prostate Cancer (ERSPC) found a survival benefit to screening, while the United States Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial did not. Furthermore, the benefit of immediate surgical intervention for screen-detected prostate cancer is unclear, as the results superficially differ between the two large randomized controlled trials comparing prostatectomy to observation. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) found no survival benefit for prostatectomy in PSA screened U.S. men, while the Scandinavian Prostate Cancer Group Study Number Four (SPCG-4) found a survival benefit for prostatectomy in clinically diagnosed prostate cancer. As a result of the controversy surrounding PSA screening and subsequent prostate cancer treatment, guidelines vary widely by organization.

SummaryBackgroundBCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. MethodsIn this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10 11 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FindingsBetween Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3–4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. InterpretationIntravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FundingFKD Therapies Oy.

Background The relationship between psychological stress and interstitial cystitis/bladder pain syndrome (IC/BPS) has been well described. Even though there is some overlapping of symptoms between overactive bladder (OAB) and IC/BPS, there have been very few studies that specifically investigated the relationship between psychological stress and urinary symptoms in OAB patients who do not have pelvic pain. Here we examined the relationship between psychological stress levels and the severity of overactive bladder (OAB) symptoms. Methods Patients diagnosed with OAB (n=51), IC/BPS (n=27), and age-matched healthy controls (n=30) participated in a case control study that inquired about their psychological stress levels using the perceived stress scale (PSS). PSS reported by the three patient groups were compared. Among OAB patients, their responses on the PSS was correlated to OAB symptoms using the following questionnaires: 1) international consultation on incontinence – urinary incontinence (ICIQ-UI), 2) international consultation on incontinence – overactive bladder (ICIQ-OAB), 3) OAB-q short form, 4) urogenital distress inventory (UDI-6), 5) incontinence impact questionnaire (IIQ-7), 6) urgency severity scale (USS), 7) numeric rating scales of urgency symptom, and 8) frequency symptom. Spearman’s correlation tests were performed to examine the relationship between psychological stress levels and the severity of OAB symptoms. Results OAB patients reported psychological stress levels that were as high as IC/BPS patients (median 17.0 versus 18.0, p=0.818, Wilcoxon sum rank test), and significantly higher than healthy controls (17.0, versus 7.5, p=0.001). Among OAB patients, there was a positive correlation between perceived stress levels and urinary incontinence symptoms (ICIQ-UI, Spearman’s correlation coefficient=0.39, p=0.007), and impacts on quality of life (UDI-6, IIQ-7, OAB-q quality of life subscale; Spearman’s correlation coefficient=0.32, 0.31, 0.39, and p=0.028, 0.005, 0.029, respectively). No significant correlation was observed between perceived stress levels and urgency or frequency symptoms (ICIQ-OAB, USS, numeric ratings of urgency and frequency). Conclusions OAB patients reported psychological stress levels that were as high as IC/BPS patients, and significantly higher than healthy controls. There was a positive correlation between perceived stress levels and urinary incontinence symptoms, and its impacts on quality of life among OAB patients.

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus ( P = 9.42 × 10 −13 ; heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13–1.41; homozygote OR: 1.58, 95% c.i.: 1.40–1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 × 10 −11 ; rs6983267 P = 6.62 × 10 −10 ). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

BackgroundNocturia (voids arising from sleep) is a ubiquitous phenomenon reflecting many diverse conditions but whether it has significance in its own right remains uncertain. We examined whether nocturia was an independent risk factor for mortalityMethodsThese were observational analyses employing primarily North American and European participants and included 7343 men, aged 50–75 years participating in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial. Cox proportional hazards models were used to test the association between baseline nocturia (voiding ≥3 times per night) and all-cause mortality. Potential confounding variables included: age; race; region of origin; treatment group; self-reported coronary artery disease, diabetes mellitus, hypertension, and peripheral vascular disease; smoking; alcohol use; prostate volume; and diuretics. Self-reported sleep quality, as measured with the Medical Outcomes Study sleep scale, was entered as a final step in the model.ResultsNocturia was associated with increased mortality risk (hazard ratio [HR] = 1.72; 95% CI 1.15–2.55) independent from demographics and medical comorbidities. Inclusion of disturbed sleep in the model reduced the magnitude of the association (HR = 1.43; 95% CI 0.93–2.19).ConclusionsAlthough the findings are limited to men, half of whom ingested dutasteride, the interruption of sleep by nocturia may have long-term impact on health and may warrant targeted intervention.

Background Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer. Methods In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m 2 ) men with localized prostate cancer, aged 43–72 years, were randomized (1:1) with permuted blocks to 4–6 weeks of customized isocaloric PR diets (0.8 g protein/kg lean body mass) or their usual diet. Biomarkers influencing cancer biology, including serum IGF-1 and its binding proteins were measured longitudinally. Results Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration. Conclusion These findings demonstrate that protein restriction without calorie restriction does not reduce serum IGF-1 concentration or increase IGFBP-1 and IGFBP-3 in men with localized prostate cancer. Further research is needed to identify dietary interventions for safely and effectively reducing IGF-1 in this patient group.