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BACKGROUND: Prostate-specific antigen (PSA) occurs in different molecular forms in serum: free PSA (fPSA) and complexed PSA (cPSA), the sum of which corresponds to total PSA (tPSA). In addition to tPSA, percent fPSA is widely used in the detection of prostate cancer. Free PSA, approximately 28 kDa, is eliminated by glomerular filtration. Previous data showed that men with end-stage renal dysfunction requiring chronic dialysis have increased percent fPSA. In this study, we evaluated whether moderate-to-severe chronic renal dysfunction, but with no need for dialysis, also importantly affects percent fPSA. METHODS: The study group consisted of 101 men (median age 57 years, interquartile range 46-68) with chronic kidney disease and no diagnosis of prostate cancer. Their median glomerular filtration rate (GFR) was 23 mL/min/1.73 m(2) (interquartile range 16-33; range 8-83), determined by iohexol clearance. Controls included 5264 men (median age 57 years, interquartile range 54-62) attending a prostate cancer screening program with no diagnosis of prostate cancer during 8 years of follow-up. RESULTS: With adjustment for age, median fPSA levels and percent fPSA were significantly higher (P < 0.001) in patients with renal dysfunction, 0.45 microg/L and 47.2%, respectively, compared to controls, 0.29 microg/L and 29.9%, respectively. Regression analysis in the study group showed a significant association between GFR and percent fPSA (P = 0.036). CONCLUSIONS: The percent fPSA is importantly influenced by moderately impaired renal function in men with chronic kidney disease. For such men, use of the current clinical decision limits for percent fPSA could cause some men with prostate cancer to be misdiagnosed as having benign disease, and therefore fPSA should not be used to diagnose prostate cancer in these patients.
\n \n\n \n \nTesting for prostate-specific antigen (PSA) has profoundly affected the diagnosis and treatment of prostate cancer. PSA testing has enabled physicians to detect prostate tumours while they are still small, low-grade and localized. This very ability has, however, created controversy over whether we are now diagnosing and treating insignificant cancers. PSA testing has also transformed the monitoring of treatment response and detection of disease recurrence. Much current research is directed at establishing the most appropriate uses of PSA testing and at developing methods to improve on the conventional PSA test.
\n \n\n \n \nDue to its significant applicability for early detection, risk prediction and follow-up evaluation, prostate specific antigen (PSA) has revolutionized our ability to treat prostate cancer patients. With the prevalent use of PSA for early detection during the last two decades, disease characteristics have been altered towards early detected, localized tumors with a high chance of cure following local therapy. This advantage faces the risk of overdetection and overtreatment. In addition, PSA lacks both, sensitivity and specificity to accurately detect patients at risk of prostate cancer. Therefore, novel biomarkers are urgently needed to improve identification of men at risk of having the disease and to predict the natural behaviour of the tumor. Recent advances in the evaluation of high-throughput technologies have led to the discovery of novel candidate markers for prostate cancer. This article will briefly discuss current PSA-based strategies and review several novel biomarkers for prostate cancer, detectable in blood.
\n \n\n \n \nPURPOSE: The low molecular mass and short half-life of free (f) prostate specific antigen (PSA) implies elimination from blood by glomerular filtration. In addition, patients with terminal renal failure have increased fPSA in serum but there have been sparse data reported on the rates and pathways of elimination of PSA complexes and human kallikrein 2 (hK2). We studied glomerular filtration dependent elimination of fPSA and hK2 in patients with renal insufficiency undergoing successful renal transplantation. MATERIALS AND METHODS: We studied 14 patients with immediate onset of renal function after renal transplantation. Blood samples were obtained before and at regular intervals up to 160 hours after transplanted kidney reperfusion. Measurements of fPSA, total PSA and hK2 were performed with immunofluorometric assays and complexed PSA was determined by a chemiluminiscence assay. Glomerular filtration rates were monitored by analyzing serum creatinine and cystatin C. NONMEM, a multivariate pharmacokinetic approach, was used to determine the elimination rates of fPSA and hK2 after renal transplantation. RESULTS: Serum fPSA and hK2 but not PSA complexes, decreased rapidly after renal transplantation. Significant reductions in fPSA and hK2 were observed after only 16 and 8 hours, respectively. fPSA and hK2 showed similar elimination patterns, decreasing to 42% and 44% of their original levels compared to cystatin C, which was at 44% after 160 hours. The median half-lives of fPSA and hK2 were 17.4 and 11.5 hours, respectively. CONCLUSIONS: These results verify the hypothesis that fPSA and hK2 are eliminated from the blood circulation by glomerular filtration and severe renal failure influences the levels of the 2 proteins in serum.
\n \n\n \n \nPURPOSE: We evaluated the significance of focal prostate cancer found in sextant biopsies in men participating in a biennial prostate specific antigen (PSA) based screening program. MATERIALS AND METHODS: In 1995, 10000 men 50 to 65 years old were randomized to biennial screening with PSA testing. Sextant biopsies were recommended when total PSA was 3 ng/ml or greater at screening rounds 1 and 2, and 2.54 ng/ml or greater at subsequent screening rounds. Focal cancer was defined as total a core cancer length of less than 3 mm in the biopsy specimen. Low volume cancer was defined as a total tumor volume of less than 0.5 cm in the radical retropubic prostatectomy specimen. RESULTS: The number of men who underwent biopsy and the number of cancers detected in the 5 possible sets of biopsies were 1725 and 402, 706 and 124, 307 and 36, 103 and 9, and 13 and 0, respectively. The risk of detecting focal cancer was 7.9%, 10.2%, 7.5%, 5.8% and 0%, respectively, but the relative ratio (focal-to-all cancers) increased 34%, 58%, 64%, 67% and, not applicable, respectively. In men with a total core cancer length of less than 10 mm there was no correlation between core cancer length and total tumor volume, as measured in the prostatectomy specimen. Two-thirds of men with a total core cancer length of less than 3 mm had a tumor volume of greater than 0.5 cm, while the risk of low volume cancer was less than 5% only in men with a total core cancer length of greater than 10 mm. CONCLUSIONS: In a repeat PSA based screening program sextant biopsies are of little or no value for predicting tumor volume.
\n \n\n \n \nOBJECTIVE: To study the follow-up of men with elevated prostate-specific antigen (PSA) (>3 ng/ml) after one benign set of sextant biopsies. From the G\u00f6teborg branch of the European Randomised Study of Screening for Prostate Cancer (ERSPC). METHOD: 456 men with one set of benign sextant biopsies were followed every second year for 4 years with PSA determinations. In cases of elevated PSA, transrectal ultrasound (TRUS) guided sextant biopsies were suggested. Digital rectal examination (DRE), prostate volume, PSA, PSA density (PSAD) and the ratio between free and total PSA (PSA F/T) were recorded. RESULTS: Complete data were available for 322 men. 3 groups were identified. In 84/322 (26%) men cancer was found (\"cancer\" group). 182/322 (56%) had benign biopsies (\"benign\" group) and 56/322 (17%) had normalised PSA (\"normalised PSA\" group). Median prostate volumes were 36, 46, and 33 cc respectively in the three groups. DRE and/or TRUS were abnormal in only 30% of the men in all groups. Cancer was not found in any prostate >70 cc volume. In prostates of <20 cc either cancer was found or PSA was normalised. The \"normalised PSA\" group had initial PSA, PSAD and PSA F/T similar to cancer, normalising during follow-up. CONCLUSIONS: Patients with one negative sextant biopsy still have a high likelihood of cancer, especially men with persistently elevated PSA and small prostates (<20 cc) while the majority of men with large prostates (>70 cc) have PSA elevation due to benign prostate hyperplasia (BPH) and not to cancer.
\n \n\n \n \nBACKGROUND: Measurement of human kallikrein 2 (hK2) has improved early detection and staging of prostate cancer. However, reported concentrations of hK2 among currently used assays have not been standardized in any way. We compared two hK2 assays and five different recombinant hK2 variants (rhK2) and suggest a common calibrator as an important step and putative reference substance in hK2 assay standardization. METHODS: We measured 146 sera by two hK2 assays, using assay-specific calibrators to assess the difference between the two assays. Serial dilutions of five rhK2 preparations were measured repeatedly, with one preparation assigned as calibrator and the others as unknowns to define which variant provided the closest match between the two assays. This rhK2 variant was used to recalibrate both assays. We measured hK2 concentrations in the same 146 patients to evaluate the change in the difference. RESULTS: Use of assay-specific calibrators for comparison of the two assays yielded a Deming regression equation of: y = 0.789 (95% confidence interval, 0.674-0.922)x + 0.014 (0.004-0.025) micro g/L; R(2) = 0.667. Analysis of five rhK2 variants revealed that the enterokinase (ek)-rhK2 form provided the best match between both assays. Using the ek-rhK2 as a common calibrator, we observed a change in the slope of the regression curve to: y = 1.106 (0.872-1.340)x + 0.006 (-0.002 to 0.016) micro g/L; R(2) = 0.648, suggesting an increase in the mean estimate of agreement between the two assays. CONCLUSION: Calibration with a common calibrator substantially increased agreement between the assays. The ek-rhK2 variant provided the best performance of all tested rhK2 variants and should undergo mass spectrometry and amino acid analysis for exact mass determination and value assignment to evaluate its potential as a reference material for immunoassays for hK2.
\n \n\n \n \nQuantitative RT-PCR (QRT-PCR) enables the sensitive and specific detection of mRNA with a small copy number. We used the QRT-PCR method and dual-label analysis of amplification products for the detection of prostate-specific antigen (PSA) mRNA. The QRT-PCR assay employed a PSA-like internal standard (IS) mRNA, which was used to quantify the PSA mRNA copies and to control the variations during the whole assay procedure from the RNA extraction to the detection of QRT-PCR amplification products by hybridization assay. After co-amplification, the PSA and IS products were detected in a microplate using Eu3+ chelate-labeled PSA and Tb3+ chelate-labeled IS hybridization probes. The detection probes allowed the simultaneous and dual-label detection of PSA and IS products in the same microtiter well. Compared to the single-label assay, the dual-label detection improved the within- and between-assay CV% from 21.7 to 7.5 and from 36.0 to 30.3, respectively. The between- and within-assay variation of the dual-label assay was further studied using PSA-producing LNCaP cells. The cells were found to express 980 +/- 170 (mean +/- SD) copies of PSA-mRNA with the within-assay CV% of 17.7 and 890 +/- 220 (mean +/- SD) copies of PSA-mRNA with the between-assay CV% of 25.0. The methodology developed may help in future studies to obtain reliable quantification of PSA mRNA generated by circulating prostate cancer cells.
\n \n\n \n \nBACKGROUND: The purpose of this study was to validate the use of whole-blood samples in the determination of circulating forms of prostate-specific antigen (PSA). METHODS: Blood samples of hospitalized prostate cancer and benign prostatic hyperplasia patients were collected and processed to generate whole-blood and serum samples. Three different rapid two-site immunoassays were developed to measure the concentrations of total PSA (PSA-T), free PSA (PSA-F), and PSA-alpha(1)-antichymotrypsin complex (PSA-ACT) to detect in vitro changes in whole-blood samples immediately after venipuncture. The possible influence of muscle movement on the release of PSA from prostate gland was studied in healthy men by measuring the rapid in vitro whole-blood kinetics of PSA forms before and after 15 min of physical exercise on a stationary bicycle. RESULTS: Rapid PSA-T, PSA-F, and PSA-ACT assays were designed using a 10-min sample incubation. No significant changes were detected in the concentrations of PSA-T, PSA-F, and PSA-ACT from the earliest time point of 12-16 min compared with measurements performed up to 4 h after venipuncture. Physical exercise did not influence the concentrations of the circulating forms of PSA. Hematocrit-corrected whole-blood values of PSA-T and PSA-F forms were comparable to the respective serum values. Calculation of the percentage of PSA-F (PSA F/T ratio x 100) was similar irrespective of the sample format used, i.e., whole blood or serum. CONCLUSIONS: We found that immunodetectable PSA forms are likely at steady state immediately after venipuncture, thus enabling the use of anticoagulated whole-blood samples in near-patient settings for point-of-care testing, whereas determinations of PSA (e.g., PSA-T, PSA-F, or PSA-ACT) performed within the time frame of the office visit would provide results equivalent to conventional analyses performed in serum.
\n \n\n \n \nBACKGROUND: Our recently reported finding of rapid bi-exponential elimination of free prostate-specific antigen (PSA) after radical retropubic prostatectomy in patients with moderately elevated PSA levels, which contrasted a very slow, linear elimination of PSA complexed to alpha-1-antichymotrypsin (ACT), prompted us to study whether these elimination rates were applicable for patients selected for castration treatment with very high pretreatment concentrations of PSA in serum. In addition, serum concentrations of hK2, the activator of proPSA, were measured. METHODS: Pretreatment serum was obtained from 21 previously untreated prostate cancer patients due for hormonal treatment with a GnRH-analog. Samples were also collected during treatment up to a minimum of 24 weeks at 2-week intervals and analyzed with immunofluorometric assays for free PSA (PSA-F), PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), total PSA (PSA-T), and human kallikrein 2 (hK2). For pharmaco-kinetic analysis the serum concentrations of hK2 and PSA forms for each patient were plotted against time both before and after logarithmic transformation and the half-lives were calculated as ln2/k. RESULTS: Median pretreatment serum concentrations were 322 ng/ml (range, 1.9-2210) for PSA-T, 27.8 ng/ml (range, 1.14-259) for PSA-F, and 207 ng/ml (range, 0.8-2080) for PSA-ACT. All patients had castrate levels of serum testosterone (< 2.5 nmol/l) in less than 21 days after initiation of GnRH-analog treatment. It was possible to evaluate data from 19/21 patients which showed an exponential decrease of all PSA concentrations in serum, with mean half-lives of 12.9 days (range, 7.3-30) for PSA-T, 15.5 days (range, 7.7-37.5) for PSA-F, and 12.3 days (range, 6.6-30) for PSA-ACT. Median pretreatment percent free PSA (PSA-F/PSA-T) was 12% compared to 18% at nadir. The median pretreatment level of hK2 was 3.5 ng/ml (range, 0.29-30.3). There was an exponential decrease in hK2 concentrations in serum after initiation of hormonal treatment with a mean half-life of 18.7 days (range, 7.5-37.5). CONCLUSIONS: For the majority of patients with hormonally treated prostate cancer the serum concentrations of PSA-T, PSA-F, PSA-ACT, and hK2 decreased slowly in parallel and mono-exponentially after initiation of treatment. Mean half-lives were between 12 and 19 days.
\n \n\n \n \nBACKGROUND: Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear. OBJECTIVE: Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men. DESIGN, SETTING, AND PARTICIPANTS: This study used a nested case-control design based on the Malm\u00f6 Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005. MEASUREMENTS: We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer. RESULTS AND LIMITATIONS: Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p<0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage\u2265T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage\u2265T3, metastasis, Gleason score\u22658, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group. CONCLUSIONS: Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malm\u00f6, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline.
\n \n\n \n \nOBJECTIVES: Prostate specific antigen (PSA) is a widely used and clinically valuable marker for prostate disease. In order to enable the development of new PSA assays and progress the understanding of the biology of PSA we have analyzed PSA in seminal plasma. DESIGN AND METHODS: PSA in seminal plasma from men attending a fertility clinic and healthy controls was analyzed using SDS-PAGE, Western blotting and mass spectrometry. RESULTS: Using mass spectrometry, different forms of PSA could be identified in 1-9 bands seen on SDS-PAGE analysis of the respective sample. However, a majority of these molecular forms of PSA were not observed on Western blots. Enzymatic activity of PSA isoforms was demonstrated by sequencing data in zymogram gels. Multivariate analysis of clinical data revealed well-separated patient groups. CONCLUSIONS: We demonstrated that PSA in seminal plasma occurs in several isoforms, yet not all were detectable using an antibody based clinical routine method. The heterogeneity of PSA expression might be of clinical significance, by an improved patient phenotyping.
\n \n\n \n \nBACKGROUND: The urokinase plasminogen activator (uPA) system is involved in tissue remodelling processes and is up-regulated in many types of malignancies. We investigated whether serum levels of different forms of soluble uPA receptor (suPAR) are associated with survival and in particular with prostate cancer and cardiovascular disease mortality. METHODS: Using time-resolved fluorescence immunoassays, we measured intact suPAR [suPAR(I-III)] and intact plus cleaved suPAR [suPAR(I-III) + suPAR(II-III)] and thus calculated the amount of suPAR(II-III) in serum samples from 375 men participating in a prostate cancer screening trial. A total of 312 men were free of prostate cancer and 63 men had prostate cancer diagnosed at the time of screening. The cohort was followed for 15 years. We assessed survival using Kaplan-Meier estimation and Cox proportional hazards regression. RESULTS: The mean age at blood sampling was 64 years. In total, 152 men died during follow-up. SuPAR(I-III) and suPAR(II-III) were significantly positively associated with mortality (P = 0.001 and P < 0.0001, respectively). In a Cox regression model adjusting for age and prostate cancer status, an increase in suPAR(I-III) and suPAR(II-III) by 1-unit (ln-scale) was associated with a hazard ratio (HR) of 2.26 [95% confidence interval (CI) 1.17-4.35] and 2.53 (95% CI 1.56-4.10), respectively. There was a trend towards an increased risk of death from prostate cancer in screening-detected prostate cancer patients with increased values of either suPAR form. However, this difference was not significant and the association disappeared after adjusting for age, tumour stage, tumour grade and prostate-specific antigen. Being in the highest quartile of any of the suPAR forms was associated with a highly significant increased risk of cardiovascular death, with HR adjusted for age of 3.27 (95% CI 1.38-7.73) for suPAR(I-III) quartile 4 versus quartile 1. Conclusions.\u2002 High concentrations of serum suPAR(I-III) and suPAR(II-III) were associated with poor overall survival. The association was particularly strong for death from cardiovascular disease. No similar association was found for prostate cancer after adjustment for other prognostic factors.
\n \n\n \n \nOBJECTIVE: To study the effects of early versus delayed oxytocin augmentation on the obstetrical and neonatal outcome in nulliparous women with spontaneous but prolonged labour. DESIGN: Randomised controlled study. SETTING: Two delivery units in Sweden. POPULATION: Healthy nulliparous women with normal pregnancies, spontaneous onset of active labour, a cervical dilatation of 4-9 cm and no progress in cervical dilatation for 2 hours and for an additional hour if amniotomy was performed due to slow progress. METHODS: Women (n = 630) were randomly allocated either to labour augmentation by oxytocin infusion (early oxytocin group) or to postponement of oxytocin augmentation for another 3 hours (expectant group). MAIN OUTCOME MEASURE: Mode of delivery (spontaneous vaginal or instrumental vaginal delivery or caesarean section) and time from randomisation to delivery. RESULTS: The caesarean section rate was 29 of 314 (9%) in the early oxytocin group and 34 of 316 (11%) in the expectant group (OR 0.8, 95% CI 0.5-1.4), and instrumental vaginal delivery 54 of 314 (17%) in the early oxytocin versus 38 of 316 (12%) in the expectant group (OR 1.5, 95% CI 0.97-2.4). Early initiation of oxytocin resulted in a mean decrease of 85 minutes in the randomisation to delivery interval. CONCLUSION: Early administration of oxytocin did not change the rate of caesarean section or instrumental vaginal delivery but shortened labour duration significantly in women with a 2-hour arrest in cervical dilatation. No other clear benefits or harms were seen between early and delayed administration of oxytocin.
\n \n\n \n \nTo improve the sensitivity of antibody microarray assays, we developed ENSAM (Europium Nanoparticles for Signal enhancement of Antibody Microarrays). ENSAM is based on two nanomaterials. The first is polystyrene nanoparticles incorporated with europium chelate (beta-diketone) and coated with streptavidin. The multiple fluorophores incorporated into each nanoparticle should increase signal obtained from a single binding event. The second nanomaterial is array surfaces of nanoporous silicon, which creates high capacity for antibody adsorption. Two antibody microarray assays were compared: ENSAM and use of streptavidin labeled with a nine-dentate europium chelate. Analyzing biotinylated prostate-specific antigen (PSA) spiked into human female serum, ENSAM yielded a 10-fold signal enhancement compared to the streptavidin-europium chelate. Similarly, we observed around 1 order of magnitude greater sensitivity for the ENSAM assay (limit of detection < or = 0.14 ng/mL, dynamic range > 10(5)) compared to the streptavidin-europium chelate assay (limit of detection < or = 0.7 ng/mL, dynamic range > 10(4)). Analysis of a titration series showed strong linearity of ENSAM ( R2 = 0.99 by linear regression). This work demonstrates the novel utility of nanoparticles with time-resolved fluorescence for signal enhancement of antibody microarrays, requiring as low as 100-200 zmol biotinylated PSA per microarray spot. In addition, proof of principle was shown for analyzing PSA in plasma obtained from patients undergoing clinical PSA-testing.
\n \n\n \n \nIn this study we characterize a novel gene on human chromosome 9 and its translation product, PC3-secreted microprotein (PSMP). The gene contains three exons that encode a protein of 139 amino acid residues, including a predicted signal peptide of 36 residues. The molecule is homologous to beta-microseminoprotein (MSP), a protein of unknown function, secreted at high concentration by the prostate gland. These two proteins have only 23% sequence identity, but their common origin is revealed by a preserved pattern of Cys residues. In contrast to MSP, which shows poor conservation between species, PSMP is very conserved. High transcript levels were detected in the prostate cancer cell line PC-3. Antiserum raised against PSMP detected a protein with an apparent molecular mass of 18 kDa in culture medium conditioned by PC-3 cells, but in cell lysates the antiserum also recognized a molecular species of 16 kDa, suggesting that PSMP undergoes post-translational modification. Xenografted PC-3 cell tumors in athymic nude mice showed strong staining for both PSMP protein and mRNA. Studies on human prostate cancer specimens showed immunohistochemical staining of both tumor and benign glandular cells. Our results suggest that PSMP is an important protein with significance in prostate cancer.
\n \n\n \n \nOBJECTIVES: Randomized controlled trials are currently conducted to assess whether the mortality from prostate cancer is reduced by early detection with the use of prostate-specific antigen (PSA) measurements in serum. To be effective, such a program should be able to reduce the absolute number of men diagnosed with metastatic prostate cancer (for which no cure is available). The aim of the present report is to evaluate whether PSA-based screening reduces the risk of being diagnosed with metastatic prostate cancer. METHODS: A population-based, prospective, randomized, controlled screening trial for prostate cancer started in 1995 (the G\u00f6teborg branch of the European Randomized Study of Screening for Prostate Cancer [ERSPC]). Ten thousand, randomly selected men aged 50-66 yr were invited for biennial PSA testing, with 10,000 men serving as passive controls for whom diagnosis of metastatic prostate cancer was monitored by using the Swedish Cancer Registry. RESULTS: After a follow-up of 10 yr, the risk of being diagnosed with metastatic prostate cancer was reduced by 48.9%-that is, decreasing from 47 cases in the control group to 24 cases in the group randomized to PSA-based screening (p=0.0084). However, the risk of being diagnosed with prostate cancer increased 1.8-fold with PSA-based screening. CONCLUSIONS: Biennial PSA screening reduces the risk of being diagnosed with metastatic prostate cancer, the first prerequisite for achieving decreased cancer mortality in younger men. This putative benefit is balanced by a 1.8-fold increased risk for diagnosis of prostate cancer.
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