Decision aids for localized prostate cancer treatment choice: Systematic review and meta-analysis.

Patients who are diagnosed with localized prostate cancer need to make critical treatment decisions that are sensitive to their values and preferences. The role of decision aids in facilitating these decisions is unknown. The authors conducted a systematic review of randomized trials of decision aids for localized prostate cancer. Teams of 2 reviewers independently identified, selected, and abstracted data from 14 eligible trials (n = 3377 men), of which 10 were conducted in North America. Of these, 11 trials compared decision aids with usual care, and 3 trials compared decision aids with other decision aids. Two trials suggested a modest positive impact on decisional regret. Results across studies varied widely for decisional conflict (4 studies), satisfaction with decision (2 studies), and knowledge (2 studies). No impact on treatment choices was observed (6 studies). In conclusion, scant evidence at high risk of bias suggests the variable impact of existing decision aids on a limited set of decisional processes and outcomes. Because current decision aids provide information but do not directly facilitate shared decision making, subsequent efforts would benefit from user-centered design of decision aids that promote shared decision making.

PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with prostate cancer.

BACKGROUND: Conventional systematic prostate biopsies (SBx) have multiple limitations, and magnetic resonance imaging (MRI)-ultrasound fusion targeting is increasingly applied (fusion biopsies [FBx]). In our previous studies, we have shown that loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in radical prostatectomy (RP) specimens predicts poor disease-specific survival, and in active surveillance (AS), PTEN loss in SBx predicts an adverse AS outcome, although SBx PTEN status does not correlate well with the corresponding RP status. Here, we have hypothesized that PTEN and erythroblast transformation-specific related gene (ERG) status in FBx correlate better with RP than they would in SBx. METHODS: A total of 106 men, who had undergone FBx and subsequent RP in a single center between June 2015 and May 2017 were included. Fifty-three of the men had concomitant or previous SBx's. All biopsy and RP specimens were collected, and tissue microarrays (TMA) were constructed from RP specimens. Immunohistochemical stainings for PTEN and ERG expression were conducted on biopsies and RP TMAs and results were compared by using Fisher's exact test. RESULTS: The immunohistochemical predictive power of FBx, determined by the concordance of biopsy PTEN and ERG status with RP, is superior to SBx (77.6% vs 66.7% in PTEN, 92.4% vs 66.6% in ERG). FBx was superior to SBx in correlation with RP Gleason Grade Groups and MRI prostate imaging reporting and data system scores. CONCLUSION: FBx grading correlates with RP histology and MRI findings and predicts the biomarker status in the RP specimens more accurately than SBx. A longer follow-up is needed to evaluate if this translates to better prediction of disease outcomes, especially in AS and radiation therapy where prostatectomy specimens are not available for prognostication.

The Impact of Nocturia on Mortality: A Systematic Review and Meta-Analysis.

PURPOSE: Nocturia (waking from sleep at night to void) is a common cause of sleep disruption associated with increased comorbidity and impaired quality of life. However, its impact on mortality remains unclear. We performed a systematic review and meta-analysis to evaluate the association of nocturia with mortality as a prognostic factor and a causal risk factor. MATERIALS AND METHODS: We searched PubMed®, Scopus®, CINAHL® (Cumulative Index of Nursing and Allied Health Literature) and major conference abstracts up to December 31, 2018. Random effects meta-analyses were done to address the adjusted RR of mortality in people with nocturia. Meta-regression was performed to explore potential determinants of heterogeneity, including the risk of bias. We applied the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) framework to rate the quality of evidence for nocturia as a prognostic risk factor for mortality and separately as a cause of mortality. RESULTS: Of the 5,230 identified reports 11 observational studies proved eligible for inclusion. To assess nocturia 10 studies used symptom questionnaires and 1 used frequency-volume charts. Nocturia was defined as 2 or more episodes per night in 6 studies (55%) and as 3 or more episodes per night in 5 (45%). Pooled estimates demonstrated a RR of 1.27 (95% CI 1.16-1.40, I2=48%) with an absolute 1.6% and 4.0% 5-year mortality difference in individuals 60 and 75 years old, respectively. The pooled estimates of relative risk did not differ significantly across varying age, gender, followup, nocturia case definition, risk of bias or study region. We rated the quality of evidence for nocturia as a prognostic factor as moderate and as a cause of mortality as very low. CONCLUSIONS: Nocturia is probably associated with an approximately 1.3-fold increased risk of death.

The Impact of Nocturia on Falls and Fractures: A Systematic Review and Meta-Analysis.

PURPOSE: Although nocturia is associated with various comorbidities, its impact on falls and fractures remains unclear. We performed a systematic review and meta-analysis to evaluate the association between nocturia and falls and fractures as a prognostic and as a causal risk factor. MATERIALS AND METHODS: We searched PubMed®, Scopus®, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and abstracts of major urological meetings up to December 31, 2018. We conducted random effects meta-analyses of adjusted relative risks of falls and fractures. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for nocturia as a prognostic and causal factor of falls and fractures. RESULTS: Among 5,230 potential reports 9 observational longitudinal studies provided data on the association between nocturia and falls or fractures (1 for both, 4 for falls, 4 for fractures). Pooled estimates demonstrated a risk ratio of 1.20 (95% CI 1.05-1.37, I2=51.7%, annual risk difference 7.5% among the elderly) for association between nocturia and falls and 1.32 (95% CI 0.99-1.76, I2=57.5%, annual risk difference 1.2%) for association between nocturia and fractures. Subgroup analyses showed no significant effect modification by age, gender, followup time, nocturia case definition or risk of bias. We rated the quality of evidence for nocturia as a prognostic factor as moderate for falls and low for fractures, and as very low as a cause of falls/fractures. CONCLUSIONS: Nocturia is probably associated with an approximately 1.2-fold increased risk of falls and possibly an approximately 1.3-fold increased risk of fractures.

Rectal E. coli above ciprofloxacin ECOFF associate with infectious complications following prostate biopsy.

Transrectal prostate biopsies carry the risk of infection. By using non-selective culture plates, instead of commonly used ciprofloxacin (CIP)-containing plates, we analyzed the association between Escherichia coli CIP minimal inhibitory concentration (MIC) and post-biopsy infectious complications. A pre-biopsy rectal swab was taken from 207 consecutive men, scheduled for transrectal 12-core prostate biopsy with CIP 750 mg as the mostly used prophylaxis. CIP MIC of rectal Gram-negative bacilli was determined from a chromogenic agar. Rectal E. coli were categorized to resistant (R) and intermediate (I) isolates together (R + I, MIC > 0.25 mg/l) and to sensitive (S, MIC ≤ 0.25 mg/l) using EUCAST clinical breakpoints. In addition, epidemiological cutoff (ECOFF R, MIC > 0.064 mg/l) was used for categorization. Eighteen (8.7%) men showed CIP R + I E. coli by the EUCAST breakpoints and 41 (19.8%) using the ECOFF R criteria. During follow-up, 15 (7.2%) men had infectious symptoms, of which 9 (4.3%) were culture-confirmed infections. Only 4 (26.7%) of these 15 patients showed R + I E. coli in the rectal swab according to EUCAST, but 10 (66.7%) using the ECOFF cutoff. Rectal E. coli CIP R + I by the EUCAST clinical breakpoints associated with infectious complications with OR 5.7 (95% CI 1.5-21.8, P = 0.005) and ECOFF R E. coli by OR 10.7 (95% CI 3.0-37.6, P < 0.001). Men carrying rectal E. coli with moderately lowered CIP susceptibility (MIC > ECOFF 0.064 mg/l) were identified and, interestingly, they showed a high risk of developing infectious symptoms after the biopsy. This explains why some men develop infectious complications despite appropriate antibiotics before prostatic biopsies. TRIAL REGISTRATION: NCT02140502.

The Finnish prostate cancer screening trial: analyses on the screening failures.

Prostate cancer (PC) screening with prostate-specific antigen (PSA) has been shown to decrease PC mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). However, in the Finnish trial, which is the largest component of the ERSPC, no statistically significant mortality reduction was observed. We investigated which had the largest impact on PC deaths in the screening arm: non-participation, interval cancers or PSA threshold. The screening (SA) and control (CA) arms comprised altogether 80,144 men. Men in the SA were screened at four-year intervals and referred to biopsy if the PSA concentration was ≥ 4.0 ng/ml, or 3.0-3.99 ng/ml with a free/total PSA ratio ≤ 16%. The median follow-up was 15.0 years. A counterfactual exclusion method was applied to estimate the effect of three subgroups in the SA: the non-participants, the screen-negative men with PSA ≥ 3.0 ng/ml and a subsequent PC diagnosis, and the men with interval PCs. The absolute risk of PC death was 0.76% in the SA and 0.85% in the CA; the observed hazard ratio (HR) was 0.89 (95% confidence interval (CI) 0.76-1.04). After correcting for non-attendance, the HR was 0.78 (0.64-0.96); predicted effect for a hypothetical PSA threshold of 3.0 ng/ml the HR was 0.88 (0.74-1.04) and after eliminating the effect of interval cancers the HR was 0.88 (0.74-1.04). Non-participating men in the SA had a high risk of PC death and a large impact on PC mortality. A hypothetical lower PSA threshold and elimination of interval cancers would have had a less pronounced effect on the screening impact.

Safety and long-term results of endoscopic transanal resection in treating rectal adenomas: 15 years' experience.

BACKGROUND: Endoscopic transanal resection (ETAR) is a scarcely used technique to treat large or sessile rectal adenomas not amenable to polypectomy. The purpose of this study was to evaluate safety and long-term results of ETAR in treating rectal adenomas in three hospitals over 15 years. METHODS: Patients who underwent ETAR during 1996-2010 were retrospectively analyzed with respect to patient, adenoma, and operative characteristics, earlier operations, complications, follow-up time, recurrence rates, recurrence treatment, and cancer incidence. RESULTS: Ninety-two patients underwent a total 111 ETARs to treat rectal adenoma. The mean age of patients was 71 years, and the median ASA class 3. Twenty-eight patients previously had received other treatments for rectal adenoma. Incidental carcinoma was found in eight patients. Sixty-seven adenomas were treated with only one ETAR and 17 with two or three ETARs. Sixty-seven patients did not have a recurrence, whereas 14 patients had an adenoma recurrence and 3 patients developed invasive carcinoma during a mean follow-up of 30 months. Complications occurred in 14 patients; all were minor, except for one explorative laparotomy without findings. No mortalities or conversions to open surgery occurred. CONCLUSIONS: ETAR is a minimally invasive and safe technique with inexpensive instrumentation to treat rectal adenomas that are not amenable to polypectomy. Adenoma recurrence rate was 15% and cancer incidence 3% in follow-up.

Associations of PTEN and ERG with Magnetic Resonance Imaging Visibility and Assessment of Non-organ-confined Pathology and Biochemical Recurrence After Radical Prostatectomy.

BACKGROUND: Diagnosing clinically significant prostate cancer (PCa) is challenging, but may be facilitated by biomarkers and multiparametric magnetic resonance imaging (MRI). OBJECTIVE: To determine the association between biomarkers phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) with visible and invisible PCa lesions in MRI, and to predict biochemical recurrence (BCR) and non-organ-confined (non-OC) PCa by integrating clinical, MRI, and biomarker-related data. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of a population-based cohort of men with PCa, who underwent preoperative MRI followed by radical prostatectomy (RP) during 2014-2015 in Helsinki University Hospital (n = 346), was conducted. A tissue microarray corresponding to the MRI-visible and MRI-invisible lesions in RP specimens was constructed and stained for PTEN and ERG. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations of PTEN and ERG with MRI-visible and MRI-invisible lesions were examined (Pearson's χ2 test), and predictions of non-OC disease together with clinical and MRI parameters were determined (area under the receiver operating characteristic curve and logistic regression analyses). BCR prediction was analyzed by Kaplan-Meier and Cox proportional hazard analyses. RESULTS AND LIMITATIONS: Patients with MRI-invisible lesions (n = 35) had less PTEN loss and ERG-positive expression compared with patients (n = 90) with MRI-visible lesions (17.2% vs 43.3% [p = 0.006]; 8.6% vs 20.0% [p = 0.125]). Patients with invisible lesions had better, but not statistically significantly improved, BCR-free survival probability in Kaplan-Meier analyses (p = 0.055). Rates of BCR (5.7% vs 21.1%; p = 0.039), extraprostatic extension (11.4% vs 44.6%; p < 0.001), seminal vesicle invasion (0% vs 21.1%; p = 0.003), and lymph node metastasis (0% vs 12.2%; p = 0.033) differed between the groups in favor of patients with MRI-invisible lesions. Biomarkers had no independent role in predicting non-OC disease or BCR. The short follow-up period was a limitation. CONCLUSIONS: PTEN loss, BCR, and non-OC RP findings were more often encountered with MRI-visible lesions. PATIENT SUMMARY: Magnetic resonance imaging (MRI) of the prostate misses some cancer lesions. MRI-invisible lesions seem to be less aggressive than MRI-visible lesions.

Fast prostate retrieval in robot-assisted laparoscopic prostatectomy for next-generation biobanking.

Robotic-assisted laparoscopic radical prostatectomy (RALP) has become the most widespread treatment for organ-confined prostate cancer. Here, we describe a fast specimen retrieval technique for RALP to obtain high-quality tissue specimen with minimal warm ischemia time for next-generation biobanking. Here, we show that using fast retrieval technique, short warm ischemia times can be achieved while not increasing the surgical time. Patients undergoing RALP with written informed consent participated in Helsinki Urological Bank study. Previously operated RALP patients and those, who were not willing to participate in the study, served as a control group. The study consisted of 1685 patients, 684 in fast retrieval and 1001 in control group. We developed a novel fast retrieval technique in which fascia is opened for camera port according to the prostate size and a running suture is placed and tightened against the camera port in the beginning of the operation. Immediately after prostate is freed from attachments, suture is loosened and the prostate is extirpated inside the endoscopic bag through the camera port fascial opening, then the fascial suture is again tightened against the camera port and the RALP procedure is completed. The mean warm ischemia times in fast retrieval group were 20 min 18 s and 22 min 30 s, respectively, in patients without and with lymphadenectomy. The mean console and surgery times with and without lymphadenectomy were similar in both groups. There were no technique-related complications associated with Fast Retrieval procedure. Tissue integrity test results for the RNA and DNA quality showed good quality for the specimen. Fast retrieval technique can easily and safely be utilized to maximize usefulness of RALP tissue specimen in downstream biobank applications.

Prostate MRI added to CAPRA, MSKCC and Partin cancer nomograms significantly enhances the prediction of adverse findings and biochemical recurrence after radical prostatectomy.

BACKGROUND: To determine the added value of preoperative prostate multiparametric MRI (mpMRI) supplementary to clinical variables and their role in predicting post prostatectomy adverse findings and biochemically recurrent cancer (BCR). METHODS: All consecutive patients treated at HUS Helsinki University Hospital with robot assisted radical prostatectomy (RALP) between 2014 and 2015 were included in the analysis. The mpMRI data, clinical variables, histopathological characteristics, and follow-up information were collected. Study end-points were adverse RALP findings: extraprostatic extension, seminal vesicle invasion, lymph node involvement, and BCR. The Memorial Sloan Kettering Cancer Center (MSKCC) nomogram, Cancer of the Prostate Risk Assessment (CAPRA) score and the Partin score were combined with any adverse findings at mpMRI. Predictive accuracy for adverse RALP findings by the regression models was estimated before and after the addition of MRI results. Logistic regression, area under curve (AUC), decision curve analyses, Kaplan-Meier survival curves and Cox proportional hazard models were used. RESULTS: Preoperative mpMRI data from 387 patients were available for analysis. Clinical variables alone, MSKCC nomogram or Partin tables were outperformed by models with mpMRI for the prediction of any adverse finding at RP. AUC for clinical parameters versus clinical parameters and mpMRI variables were 0.77 versus 0.82 for any adverse finding. For MSKCC nomogram versus MSKCC nomogram and mpMRI variables the AUCs were 0.71 and 0.78 for any adverse finding. For Partin tables versus Partin tables and mpMRI variables the AUCs were 0.62 and 0.73 for any adverse finding. In survival analysis, mpMRI-projected adverse RP findings stratify CAPRA and MSKCC high-risk patients into groups with distinct probability for BCR. CONCLUSIONS: Preoperative mpMRI improves the predictive value of commonly used clinical variables for pathological stage at RP and time to BCR. mpMRI is available for risk stratification prebiopsy, and should be considered as additional source of information to the standard predictive nomograms.

Decision Aids for Prostate Cancer Screening Choice: A Systematic Review and Meta-analysis.

IMPORTANCE: US guidelines recommend that physicians engage in shared decision-making with men considering prostate cancer screening. OBJECTIVE: To estimate the association of decision aids with decisional outcomes in prostate cancer screening. DATA SOURCES: MEDLINE, Embase, PsycINFO, CINAHL, and Cochrane CENTRAL were searched from inception through June 19, 2018. STUDY SELECTION: Randomized trials comparing decision aids for prostate cancer screening with usual care. DATA EXTRACTION AND SYNTHESIS: Independent duplicate assessment of eligibility and risk of bias, rating of quality of the decision aids, random-effects meta-analysis, and Grading of Recommendations, Assessment, Development and Evaluations rating of the quality of evidence. MAIN OUTCOMES AND MEASURES: Knowledge, decisional conflict, screening discussion, and screening choice. RESULTS: Of 19 eligible trials (12 781 men), 9 adequately concealed allocation and 8 blinded outcome assessment. Of 12 decision aids with available information, only 4 reported the likelihood of a true-negative test result, and 3 presented the likelihood of false-negative test results or the next step if the screening test result was negative. Decision aids are possibly associated with improvement in knowledge (risk ratio, 1.38; 95% CI, 1.09-1.73; I2 = 67%; risk difference, 12.1; low quality), are probably associated with a small decrease in decisional conflict (mean difference on a 100-point scale, -4.19; 95% CI, -7.06 to -1.33; I2 = 75%; moderate quality), and are possibly not associated with whether physicians and patients discuss prostate cancer screening (risk ratio, 1.12; 95% CI, 0.90-1.39; I2 = 60%; low quality) or with men's decision to undergo prostate cancer screening (risk ratio, 0.95; 95% CI, 0.88-1.03; I2 = 36%; low quality). CONCLUSIONS AND RELEVANCE: The results of this study provide moderate-quality evidence that decision aids compared with usual care are associated with a small decrease in decisional conflict and low-quality evidence that they are associated with an increase in knowledge but not with whether physicians and patients discussed prostate cancer screening or with screening choice. Results suggest that further progress in facilitating effective shared decision-making may require decision aids that not only provide education to patients but are specifically targeted to promote shared decision-making in the patient-physician encounter.

Initiation of robot-assisted radical prostatectomies in Finland: Impact on centralization and quality of care.

Objective The aim of this study was to analyze the impact of introduction of robot-assisted prostate surgery and its quality measures in Finland from 2008 to 2012. Materials and methods Registry data were collected for time trends and national distribution of prostate cancer surgery in Finland, while preoperative, operative and follow-up data were collected for quality measures. Results The number and proportion of robot-assisted laparoscopic radical prostatectomies (RALPs) increased rapidly and they accounted for 68% of all radical prostatectomies in 2012. The number of centers performing prostatectomies diminished from 25 to 20 at the expense of low-volume centers. In total, 1996 patients were operated on in the four RALP centers in 2008-2012. As anticipated, the learning curve was uniform between the centers, as were mean blood loss (212 ml), hospitalization (1.8 days) and catheterization times (10.6 days). At 3 and 12 months, 49.4% and 71.2% of patients, respectively, were totally continent (no pads). After unilateral nerve-sparing surgery, 9.9% and 5.1% had partial or normal erection at 3 months postoperatively and 14.8% and 20.4% at 12 months, respectively. If bilateral nerve sparing was done, the figures were 13.0% and 13.5% at 3 months and 14.6% and 34.9% at 12 months. Clavien-Dindo grade 3, 4 or 5 complications were seen in 0.3%, 0.3% and 0.1% of patients, respectively. Limitations of the study include non-standardized collection of outcome parameters. Conclusions This report shows that the main impact of adoption of RALP on a national level was rapid spontaneous centralization of prostate cancer surgery. The main advantages of minimally invasive prostatectomy, i.e. low blood loss and short hospitalization, are easily achieved, while continuous effort is necessary for improvements in surgical outcomes.

Incidence and Remission of Nocturia: A Systematic Review and Meta-analysis.

CONTEXT: Although vital for decision-making about management, the natural history of nocturia remains uncertain. A systematic review would clarify the issue, but because natural history reviews are uncommon it would require methodological innovations. OBJECTIVE: To estimate the incidence and remission of nocturia, and refine methods for meta-analyses assessing natural history. EVIDENCE ACQUISITION: We conducted a comprehensive search of PubMed, Scopus, and Cumulative Index of Nursing and Allied Health Literature databases and abstracts of major urologic meetings as far as August 31, 2015. Random effects meta-analyses addressed incidence/remission rates of nocturia; meta-regression explored potential determinants of heterogeneity. Studies were categorized as either low or high risk of bias using a novel instrument specifically designed for longitudinal symptom studies aimed at the general population. EVIDENCE SYNTHESIS: Of 4165 potentially relevant reports, 16 proved eligible. Pooled estimates from 13 studies (114 964 person-years of follow-up) demonstrated that annual incidence was strongly associated with age: 0.4% (0-0.8%) for adults aged < 40 yr; 2.8% (1.9-3.7%) for adults aged 40-59 yr; and 11.5% (9.1-14.0%) for adults aged ≥ 60 yr. Of those with nocturia, each year 12.1% (9.5-14.7%) experienced remission. CONCLUSIONS: The available evidence suggests that nocturia onset is strongly associated with age, with much higher rates in those over 60 yr; remission occurs in approximately 12% each year. These estimates can aid with management decisions and counseling related to nocturia. PATIENT SUMMARY: We reviewed all previous studies of progression of night-time urination (nocturia). We found that in any given year 0.4% of adults aged < 40 yr, 3% of adults aged 40-59 yr, and 12% of adults aged ≥ 60 yr will develop nocturia, while overall 12% of those with nocturia will improve. These findings may be helpful in making decisions about coping with or treating nocturia.

Expression of the E3 SUMO-1 ligases PIASx and PIAS1 during spermatogenesis in the rat.

PIASx and PIAS1, two members of the conserved protein inhibitor of activated STAT (PIAS) family, are able to interact with and modulate activities of several distinct nuclear proteins, including androgen receptor (AR). PIASx and PIAS1 also function as E3-type ligases in small ubiquitin-related modifier 1 modifications. To gain better insight into the physiological roles of PIASx and PIAS1 in vivo, their cell-type specific expression and regulation were analyzed during testicular development and spermatogenesis in the rat. The expression of both PIASx and PIAS1 was low or undetectable in newborn rats. PIASx mRNA started to accumulate after day 20 of postnatal life, whereas expression of PIAS1 mRNA increased around day 30 after birth. In the adult rat testis, both PIASx and PIAS1 mRNA were present in Sertoli cells and in germ cells in the seminiferous epithelium at all stages. However, PIASx mRNA was more abundant in spermatocytes than in other cell types, whereas higher levels of PIAS1 mRNA were detected in late spermatocytes and round spermatids than in early spermatocytes. Since PIASx and PIAS1 accumulate in developing male germ cells, their regulatory functions are not only restricted to AR in Sertoli cells, but they also participate in molecular processes during meiosis.

Prostate cancer mortality in the Finnish randomized screening trial.

BACKGROUND: Prostate cancer (PC) screening with prostate-specific antigen (PSA) has been shown to decrease PC mortality by the European Randomized Study of Screening for Prostate Cancer (ERSPC). We evaluated mortality results in the Finnish Prostate Cancer Screening Trial, the largest component of ERSPC. The primary endpoint was PC-specific mortality. METHODS: A total of 80 144 men were identified from the population registry and randomized to either a screening arm (SA) or a control arm (CA). Men in the SA were invited to serum PSA determination up to three times with a 4-year interval between each scan and referred to biopsy if the PSA concentration was greater than or equal to 4.0 ng/mL or 3.0 to 3.99 ng/mL with a free/total PSA ratio less than or equal to 16%. Men in the CA received usual care. The analysis covers follow-up to 12 years from randomization for all men. Hazard ratios (HRs) were estimated for incidence and mortality using Cox proportional hazard model. All statistical tests were two-sided. RESULTS: PC incidence was 8.8 per 1000 person-years in the SA and 6.6 in the CA (HR = 1.34, 95% confidence interval [CI] = 1.27 to 1.40). The incidence of advanced PC was lower in the SA vs CA arm (1.2 vs 1.6, respectively; HR = 0.73, 95% CI = 0.64 to 0.82; P < .001). For PC mortality, no statistically significant difference was observed between the SA and CA (HR = 0.85, 95% CI = 0.69 to 1.04) (with intention-to-screen analysis). To avoid one PC death, we needed to invite 1199 men to screening and to detect 25 PCs. We observed no difference in all-cause mortality between trial arms. CONCLUSIONS: At 12 years, a relatively conservative screening protocol produced a small, non-statistically significant PC-specific mortality reduction in the Finnish trial, at the cost of moderate overdiagnosis.

GC-rich elements flanking the transcription start site govern strong activation on the SNURF gene.

To study the regulation of the murine small nuclear RING finger protein SNURF (RNF4) gene, approximately 0.7 kb of its TATA-less promoter was isolated. This fragment conferred strong activation in reporter gene assays, yielding > or = 30% of the activity of the SV40 virus promoter/enhancer construct. Interestingly, the short region from -38 to +36 flanking the transcription start site was sufficient for potent basal promoter activity in various mammalian cell lines. Mutation of the conserved GC box at +9 abolished nuclear protein binding to the proximal promoter and severely compromised promoter activity, suggesting that this element is critical for the assembly of the transcription apparatus to regulate SNURF gene expression. Furthermore, our results show that the Wilms' tumor 1 gene product is one of the potential activators of the SNURF gene.

Reduced circulating androgen bioactivity in patients with prostate cancer.

BACKGROUND: Previous studies on immunoreactive androgen levels in serum have revealed equivocal associations with the risk of prostate cancer (CaP). The aim of this study was to compare serum biological androgen activity between men with newly diagnosed CaP and age-matched men with benign prostatic hyperplasia (BPH). METHODS: Caucasian men with newly diagnosed, untreated CaP (n = 101) and age-matched patients with BPH (n = 103) were investigated. Serum androgen bioactivity (ABA) levels were measured using a recently developed recombinant cell bioassay. RESULTS: In comparison to men with BPH, CaP patients with Gleason score >or=8 (n = 16) had lower serum ABA (P < 0.05), and patients with Gleason score or=8 (P = 0.07) displayed suppressed ABA levels in relation to serum testosterone. As the entire group, men with CaP (n = 101) had significantly lower serum ABA than age-matched men with BPH (n = 103): median 3.0 nM (range, 0.8-6.4 nM) versus 3.2 nM (range, 0.8-7.9 nM) testosterone equivalents, respectively (P < 0.005). By contrast, serum immunoreactive testosterone and SHBG concentrations and free androgen indices did not differ significantly between the two groups. CONCLUSIONS: Patients with CaP have lower serum ABA than controls with BPH, and men with low or high Gleason score display suppressed circulating ABA-to-testosterone ratio. These features may reflect interaction between variables such as the degree of tumor differentiation and tumor volume with androgen metabolism.

Identification of a short PIASx gene promoter that directs male germ cell-specific transcription in vivo.

PIASx gene encodes two SUMO E3 ligases that are highly expressed in the testis. We have isolated and analyzed the promoter of the murine PIASx gene. Electrophoretic mobility shift assays with testicular nuclear extracts showed that the proximal promoter forms a major DNA-protein complex containing Sp1, Sp2, and Sp3 transcription factors. Reporter gene assays in cultured cells indicated that a fragment comprising nucleotides from -168 to +76 relative to transcription start site is sufficient for basal promoter activity in cultured cells, but these in vitro assays failed to reveal clear differences in promoter activity between testis- and non-testis-derived cell lines. Interestingly, however, the proximal promoter encompasses the elements necessary for a testis-specific transcription in vivo, as it directed beta-galactosidase expression exclusively to male germ cells in transgenic mice. In conclusion, we have characterized the minimal PIASx promoter that can be used for highly specific targeting of transgene expression to male germ cells.

Down-regulation of estrogen receptor beta and transcriptional coregulator SNURF/RNF4 in testicular germ cell cancer.

OBJECTIVE: The role of estrogens and androgens in the etiology and progression of testicular germ cell cancer is poorly understood. To gain insight into the role of sex steroid action in testicular tumorigenesis, we have measured mRNAs encoding estrogen receptor beta (ERbeta), androgen receptor (AR), and their coregulators SNURF/RNF4, PIASx, and PIAS1 in testicular germ cell tumors. METHODS: We used real-time quantitative reverse transcription-PCR assay to compare the steroid receptor and coregulator mRNA levels in 12 matched samples of testicular tumors and adjacent normal tissues (seminomas n=8, nonseminomas n=4). In addition, ERbeta and SNURF/RNF4 protein immunoreactivity was analyzed from paraffin-embedded normal testis and tumor specimens. RESULTS: ERbeta mRNA levels were down-regulated by 59% in seminomas (p=0.017), and those of AR and SNURF/RNF4 mRNAs were decreased by 75% and 67%, respectively, in seminomas and teratocarcinomas compared to paired normal samples (p=0.034 for both, Wilcoxon signed rank test), whereas the PIASx and PIAS1 mRNA were unaltered. ERbeta and SNURF/RNF4 were also clearly down-regulated at the protein level in testicular tumors. CONCLUSIONS: Expression of ERbeta and SNURF/RNF4 was significantly lower in cancerous than in noncancerous testis tissue. Down-regulation of the ERbeta and the coregulator SNURF/RNF4 genes may play a role in testicular tumorigenesis.