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1.  Can one blood draw replace transrectal ultrasonography-estimated prostate volume to predict prostate cancer risk? 
BJU international  2013;112(5):602-609.
OBJECTIVE
To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting.
SUBJECTS AND METHODS
The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (≥ 3ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam (n=2914) and Göteborg (n=740).
A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome.
RESULTS
The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Göteborg.
Adding digital rectal examination (DRE) or DRE plus transrectal ultrasonography (TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high grade cancer.
There was a strong correlation between the blood measurements and TRUS-estimated prostate volume (Spearman’s correlation 0.60 in Rotterdam and 0.57 in Göteborg).
CONCLUSIONS
In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to-day clinical practice.
Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches.
doi:10.1111/j.1464-410X.2012.11690.x
PMCID: PMC3675187  PMID: 23448270
prostate cancer; transrectal ultrasonography; kallikreins; prostate-specific antigen
2.  Mortality results from the Göteborg Randomised Prostate Cancer Screening Trial 
The lancet oncology  2010;11(8):725-732.
Summary
Background
Prostate cancer is one of the leading causes of death from malignant disease among men in the Western world. One strategy to decrease the risk of dying from this disease is screening with Prostate-Specific Antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate.
Methods
In December 1994, 20 000 men born 1930 to 1944, randomly sampled from the Population Register, were computer randomised in a 1:1 ratio to a screening group invited for biennial PSA testing or to a control group not invited. In each arm, 48 men were excluded from analysis due to either death or emigration before randomization date or prevalent prostate cancer. The primary endpoint was prostate cancer specific mortality analyzed according to the intention-to-screen principle. Men in the screening group were invited up to the upper age limit (median 69, range 67–71 years) and only men with elevated PSA were offered additional tests such as digital rectal examination and prostate biopsies. The study is still ongoing inviting men who have not yet reached the upper age limit. This is the first planned report on cumulative prostate cancer incidence and mortality calculated up to Dec 31 2008. This study is registered [as an International Standard Randomised Controlled Trial], number [ISRCTN49127736].
Findings
Among men randomised to screening 7578/9952 (76%) attended at least once (attendees). During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer resulting in a cumulative incidence of prostate cancer of 12.7% in the screening arm and 8.2% in the control arm (hazard ratio 1.64; 95% confidence interval [CI] 1.50–1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17–0.64%), from 0.90% in the control group to 0.50% in the screening group. The incidence rate ratio for death from prostate cancer was 0.56 (95% CI 0.39–0.82; p=0.002) in the screening compared to the control group. The incidence rate ratio of attendees compared to the control group was 0.44 (95% CI 0.28–0.68; p=0.0002). Overall, 293 men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death.
Interpretation
The benefit of prostate cancer screening compares favourably to other cancer screening programs and in this study prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over diagnosis is substantial and the number needed to treat is at least as high as in breast cancer screening.
Funding
The Swedish Cancer Society, the Swedish Research Council and the National Cancer Institute.
doi:10.1016/S1470-2045(10)70146-7
PMCID: PMC4089887  PMID: 20598634
3.  Influence of blood prostate specific antigen levels at age 60 on benefits and harms of prostate cancer screening: population based cohort study 
Objective To determine the relative risks of prostate cancer incidence, metastasis, and mortality associated with screening by serum prostate specific antigen (PSA) levels at age 60.
Design Population based cohort study.
Setting General male population of Sweden taking part in a screening trial in Gothenburg or participating in a cardiovascular study, the Malmö Preventive Project.
Participants The screened group consisted of 1756 men aged 57.5-62.5 participating in the screening arm of the Gothenburg randomized prostate cancer screening trial since 1995. The unscreened group consisted of 1162 men, born in 1921, participating in the Malmö Preventive Project, with PSA levels measured retrospectively in stored blood samples from 1981.
Intervention PSA screening versus no screening.
Main outcome measures Incidence rate ratios for the effect of screening on prostate cancer diagnosis, metastasis, and death by PSA levels at age 60.
Results The distribution of PSA levels was similar between the two cohorts. Differences in benefits by baseline PSA levels were large. Among men with baseline levels measured, 71.7% (1646/2295) had a PSA level <2 ng/mL. For men aged 60 with PSA level <2 ng/mL, there was an increase in incidence of 767 cases per 10 000 without a decrease in prostate cancer mortality. For men with PSA levels ≥2 ng/mL, the reduction in cancer mortality was large, with only 23 men needing to be screened and six diagnosed to avoid one prostate cancer death by 15 years.
Conclusions The ratio of benefits to harms of PSA screening varies noticeably with blood PSA levels at age 60. For men with a PSA level <1 ng/mL at age 60, no further screening is recommended. Continuing to screen men with PSA levels >2 ng/mL at age 60 is beneficial, with the number needed to screen and treat being extremely favourable. Screening men with a PSA level of 1-2 ng/mL is an individual decision to be based on a discussion between patient and doctor.
doi:10.1136/bmj.g2296
PMCID: PMC3968958  PMID: 24682399
4.  Effects of surgeon variability on oncologic and functional outcomes in a population-based setting 
BMC Urology  2014;14:25.
Background
Oncologic and functional outcomes after radical prostatectomy (RP) can vary between surgeons to a greater extent than is expected by chance. We sought to examine the effects of surgeon variation on functional and oncologic outcomes for patients undergoing RP for prostate cancer in a European center.
Methods
The study comprised 1,280 men who underwent open retropubic RP performed by one of nine surgeons at an academic institution in Sweden between 2001 and 2008. Potency and continence outcomes were measured preoperatively and 18 months postoperatively by patient-administered questionnaires. Biochemical recurrence (BCR) was defined as a prostate-specific antigen (PSA) value > 0.2 ng/mL with at least one confirmatory rise. Multivariable random effect models were used to evaluate heterogeneity between surgeons, adjusting for case mix (age, PSA, pathological stage and grade), year of surgery, and surgical experience.
Results
Of 679 men potent at baseline, 647 provided data at 18 months with 122 (19%) reporting potency. We found no evidence for heterogeneity of potency outcomes between surgeons (P = 1). The continence rate for patients at 18 months was 85%, with 836 of the 979 patients who provided data reporting continence. There was statistically significant heterogeneity between surgeons (P = 0.001). We did not find evidence of an association between surgeons’ adjusted probabilities of functional recovery and 5-year probability of freedom from BCR.
Conclusions
Our data support previous studies regarding a large heterogeneity among surgeons in continence outcomes for patients undergoing RP. This indicates that some patients are receiving sub-optimal care. Quality assurance measures involving performance feedback, should be considered. When surgeons are aware of their outcomes, they can improve them to provide better care to patients.
doi:10.1186/1471-2490-14-25
PMCID: PMC3975576  PMID: 24602348
Prostate cancer; Radical prostatectomy; Erectile function; Urinary function
5.  Prostate Cancer Mortality in Areas With High and Low Prostate Cancer Incidence 
Background
The effect of prostate-specific antigen (PSA) screening on prostate cancer mortality remains debated, despite evidence from randomized trials. We investigated the association between prostate cancer incidence, reflecting uptake of PSA testing, and prostate cancer mortality.
Methods
The study population consisted of all men aged 50 to 74 years residing in eight counties in Sweden with an early increase in prostate cancer incidence and six counties with a late increase during two time periods. Incidence of metastatic prostate cancer was investigated in the period from 2000 to 2009, and prostate cancer–specific mortality and excess mortality were investigated in the period from 1990 to 1999 and the period from 2000 to 2009 by calculating rate ratios for high- vs low-incidence counties and rate ratios for the period from 2000 to 2009 vs the period from 1990 to 1999 within these two groups. All statistical tests were two-sided.
Results
There were 4528134 person-years at risk, 1577 deaths from prostate cancer, and 1210 excess deaths in men with prostate cancer in high-incidence counties and 2471373 person-years at risk, 985 prostate cancer deaths, and 878 excess deaths in low-incidence counties in the period from 2000 to 2009. Rate ratios in counties with high vs low incidence adjusted for time period were 0.81 (95% confidence interval [CI] = 0.73 to 0.90) for prostate cancer– specific mortality and 0.74 (95% CI = 0.64 to 0.86) for excess mortality, and the rate ratio of metastatic prostate cancer was 0.85 (95% CI = 0.79 to 0.92).
Conclusions
The lower prostate cancer mortality in high-incidence counties reflecting a high PSA uptake suggests that more-intense as compared with less-intense opportunistic PSA screening reduces prostate cancer mortality.
doi:10.1093/jnci/dju007
PMCID: PMC3982781  PMID: 24610909
6.  EVALUATING THE PROSTATE CANCER PREVENTION TRIAL HIGH GRADE PROSTATE CANCER RISK CALCULATOR IN TEN INTERNATIONAL BIOSY COHORTS: RESULTS FROM THE PROSTATE BIOPSY COLLABORATIVE GROUP 
World journal of urology  2012;32(1):185-191.
OBJECTIVES
To assess the applicability of the Prostate Cancer Prevention Trial High Grade (Gleason grade ≥ 7) Risk Calculator (PCPTHG) in ten international cohorts, representing a range of populations.
METHODS
25,512 biopsies from 10 cohorts (6 European, 1 UK, and 3 US) were included; 4 implemented 6-core biopsies and the remaining had 10- or higher schemes; 8 were screening cohorts and 2 were clinical. PCPTHG risks were calculated using prostate-specific antigen (PSA), digital rectal examination, age, African origin and history of prior biopsy and evaluated in terms of calibration plots, areas underneath the receiver operating characteristic curve (AUC), and net benefit curves.
RESULTS
The median AUC of the PCPTHG for high grade disease detection in the 10- and higher-core cohorts was 73.5% (range 63.9% to 76.7%) compared to a median of 78.1 (range = 72.0 to 87.6) among the four 6-core cohorts. Only the 10-core Cleveland Clinic cohort showed clear evidence of under-prediction by the PCPTHG, and this was restricted to risk ranges less than 15%. The PCPTHG demonstrated higher clinical net benefit in higher- compared to six-core biopsy cohorts, and among the former, there were no notable differences observed between clinical and screening cohorts, nor between European and US cohorts.
CONCLUSIONS
The PCPTHG requires minimal patient information and can be applied across a range of populations. PCPTHG risk thresholds ranging from 5 to 20%, depending on patient risk averseness, are recommended for clinical prostate biopsy decision-making.
doi:10.1007/s00345-012-0869-2
PMCID: PMC3702682  PMID: 22527674
Calibration; Discrimination; Net Benefit; High Grade Prostate Cancer; Risk; Prostate Cancer Prevention Trial
8.  Evaluating The PCPT Risk Calculator in Ten International Biopsy Cohorts: Results from the Prostate Biopsy Collaborative Group 
World journal of urology  2011;30(2):181-187.
Objectives
To evaluate the discrimination, calibration and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European Randomized study of Screening for Prostate Cancer (ERSPC), 1 United Kingdom, 1 Austrian and 3 US biopsy cohorts.
Methods
PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history and history of prior biopsy, and single imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves.
Results
AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort, and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well-calibrated in the SABOR, Tyrol and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts.
Conclusions
External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.
doi:10.1007/s00345-011-0818-5
PMCID: PMC3616370  PMID: 22210512
receiver operating characteristic curve; risk; prostate cancer; calibration; net benefit
9.  PSA velocity does not aid the detection of prostate cancer in men with a prior negative biopsy: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden and Rotterdam, Netherlands 
The Journal of urology  2010;184(3):907-912.
Purpose
Prostate specific antigen (PSA) velocity has been proposed as a marker to aid detection of prostate cancer. We sought to determine whether PSA velocity could predict the results of repeat biopsy in men with persistently elevated PSA after initial negative biopsy.
Materials and Methods
We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer (ERSPC), and who had one or more subsequent prostate biopsies after an initial negative finding. We evaluated whether PSA velocity improved predictive accuracy beyond that of PSA alone.
Results
There were a total of 2579 repeat biopsies, of which 363 (14%) were positive for prostate cancer, and 44 (1.7%) were high grade (Gleason score ≥7). Although PSA velocity was statistically associated with cancer risk (p<0.001), it had very low predictive accuracy (area-under-the-curve [AUC] of 0.55). There was some evidence that PSA velocity improved AUC compared to PSA for high grade cancer. However, the small increase in risk associated with high PSA velocity – from 1.7 % to 2.8% as velocity increased from 0 to 1 ng / ml / year - is of questionable clinical relevance.
Conclusions
Men with a prior negative biopsy have a lower risk for prostate cancer at subsequent biopsies, with high grade disease particularly rare. We found little evidence to support the use of PSA velocity to aid decisions about repeat biopsy for prostate cancer.
doi:10.1016/j.juro.2010.05.029
PMCID: PMC3412428  PMID: 20643434
10.  Importance of prostate volume in the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators: results from the prostate biopsy collaborative group 
World Journal of Urology  2011;30(2):149-155.
Objectives
To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume.
Methods
We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves).
Results
The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts.
Conclusions
Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume.
doi:10.1007/s00345-011-0804-y
PMCID: PMC3321270  PMID: 22203238
PSA; Risk; Prostate cancer; Prostate volume; Calibration; Net benefit
11.  The relationship between prostate-specific antigen and prostate cancer risk: the Prostate Biopsy Collaborative Group 
PURPOSE
The relationship between prostate specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesize that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.
EXPERIMENTAL DESIGN
We used data from 5 European and 3 US cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally-weighted scatterplot smoothing.
RESULTS
The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased risk of cancer (odds ratio for >6 vs. 6 core biopsy 1.35; 95% C.I. 1.18, 1.54; p<0.0005); recent screening led to a smaller increase in risk per unit change in PSA (p=0.001 for interaction term) and US cohorts had higher risk than the European cohorts (2.14; 95% C.I. 1.99, 2.30; p<0.0005).
CONCLUSIONS
Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated.
doi:10.1158/1078-0432.CCR-10-1328
PMCID: PMC2937360  PMID: 20736330
prostate cancer; PSA; prediction; multicenter studies; screening
12.  Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated PSA: data from the European Randomized Study of Prostate Cancer Screening in Gothenburg, Sweden 
Cancer  2010;116(11):2612-2620.
Background
Risk models to predict prostate cancer on biopsy, whether they include only prostate-specific antigen (PSA) or other markers, are intended for use in all men of screening age. Yet the association between PSA and cancer likely depends on a man’s recent screening history.
Methods
To examine the effect of prior screening on prostate cancer risk prediction using a previously reported four-kallikrein panel: total, free, and intact PSA, and kallikrein-related peptidase 2 (hK2). The study cohort comprised 1241 men in Gothenburg, Sweden, undergoing biopsy for elevated PSA during their second or later visit for the European Randomized study of Screening for Prostate Cancer. We calculated the predictive accuracy of a four-kallikrein panel.
Results
Total PSA was not predictive of prostate cancer. A previously published four-kallikrein model increased predictive accuracy compared to total PSA and age alone (area-under-the-curve [AUC] 0.66 vs. 0.51; p<0.001), but was poorly calibrated and missed many cancers. A model developed with recently screened men gave important improvements in discrimination (AUC 0.67 vs. 0.56; p<0.001). Use of this model would reduce the number of biopsies by 413 per 1000 men with elevated PSA, miss 60 of 216 low-grade (Gleason ≤6) cancers, but miss only 1 of 43 high-grade cancers.
Conclusions
Prior participation in PSA-screening dramatically changes the performance of statistical models predicting biopsy outcome. A four-kallikrein panel can predict prostate cancer in men with a recent screening history, providing independent replication that multiple kallikrein-forms contribute important diagnostic value in men with elevated PSA.
doi:10.1002/cncr.25010
PMCID: PMC2882167  PMID: 20336781
prostate cancer; screening; prostate specific antigen; kallikreins; molecular markers
13.  Prostate-Specific Antigen Velocity for Early Detection of Prostate Cancer 
European urology  2009;56(5):753-760.
Background
It has been suggested that changes in prostate-specific antigen (PSA) over time (ie, PSA velocity [PSAV]) aid prostate cancer detection. Some guidelines do incorporate PSAV cut points as an indication for biopsy.
Objective
To evaluate whether PSAV enhances prediction of biopsy outcome in a large, representative, population-based cohort.
Design, setting, and participants
There were 2742 screening-arm participants with PSA <3 ng/ml at initial screening in the European Randomized Study of Screening for Prostate Cancer in Rotterdam, Netherlands, or Göteborg, Sweden, and who were subsequently biopsied during rounds 2[en]6 due to elevated PSA.
Measurements
Total, free, and intact PSA and human kallikrein 2 were measured for 1[en]6 screening rounds at intervals of 2 or 4 yr. We created logistic regression models to predict prostate cancer based on age and PSA, with or without free-to-total PSA ratio (%fPSA). PSAV was added to each model and any enhancement in predictive accuracy assessed by area under the curve (AUC).
Results and limitations
PSAV led to small enhancements in predictive accuracy (AUC of 0.569 vs 0.531; 0.626 vs 0.609 if %fPSA was included), although not for high-grade disease. The enhancement depended on modeling a nonlinear relationship between PSAV and cancer. There was no benefit if we excluded men with higher velocities, which were associated with lower risk. These results apply to men in a screening program with elevated PSA; men with prior negative biopsy were not evaluated in this study.
Conclusions
In men with PSA of about ≥3 ng/ml, we found little justification for formal calculation of PSAV or for use of PSAV cut points to determine biopsy. Informal assessment of PSAV will likely aid clinical judgment, such as a sudden rise in PSA suggesting prostatitis, which could be further evaluated before biopsy.
doi:10.1016/j.eururo.2009.07.047
PMCID: PMC2891354  PMID: 19682790
cancer detection; predictive models; prostate biopsy; prostate cancer; prostate-specific antigen; PSA velocity
14.  Outcomes in Localized Prostate Cancer: National Prostate Cancer Register of Sweden Follow-up Study 
Background
Treatment for localized prostate cancer remains controversial. To our knowledge, there are no outcome studies from contemporary population-based cohorts that include data on stage, Gleason score, and serum levels of prostate-specific antigen (PSA).
Methods
In the National Prostate Cancer Register of Sweden Follow-up Study, a nationwide cohort, we identified 6849 patients aged 70 years or younger. Inclusion criteria were diagnosis with local clinical stage T1–2 prostate cancer from January 1, 1997, through December 31, 2002, a Gleason score of 7 or less, a serum PSA level of less than 20 ng/mL, and treatment with surveillance (including active surveillance and watchful waiting, n = 2021) or curative intent (including radical prostatectomy, n = 3399, and radiation therapy, n = 1429). Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical stage T1, Gleason score 2-6, and serum PSA level of <10 ng/mL). The study cohort was linked to the Cause of Death Register, and cumulative incidence of death from prostate cancer and competing causes was calculated.
Results
For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% (95% confidence interval [CI] = 2.7% to 4.8%) in the surveillance group and 2.7% (95% CI = 2.1% to 3.45) in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% (95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance group and 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative intent group. The 10-year risk of dying from competing causes was 19.2% (95% CI = 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0% to 11.4%) in the curative intent group.
Conclusion
A 10-year prostate cancer–specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.
doi:10.1093/jnci/djq154
PMCID: PMC2897875  PMID: 20562373
15.  Increase in percent free prostate-specific antigen in men with chronic kidney disease 
Nephrology Dialysis Transplantation  2008;24(4):1238-1241.
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, ∼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 m2 (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 μg/L and 47.2%, respectively, compared to controls, 0.29 μg/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.
doi:10.1093/ndt/gfn632
PMCID: PMC2721427  PMID: 19028756
diagnosis; glomerular filtration rate; chronic kidney disease; prostate cancer; prostate-specific antigen
16.  A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden 
BMC Medicine  2008;6:19.
Background
Prostate-specific antigen (PSA) is widely used to detect prostate cancer. The low positive predictive value of elevated PSA results in large numbers of unnecessary prostate biopsies. We set out to determine whether a multivariable model including four kallikrein forms (total, free, and intact PSA, and human kallikrein 2 (hK2)) could predict prostate biopsy outcome in previously unscreened men with elevated total PSA.
Methods
The study cohort comprised 740 men in Göteborg, Sweden, undergoing biopsy during the first round of the European Randomized study of Screening for Prostate Cancer. We calculated the area-under-the-curve (AUC) for predicting prostate cancer at biopsy. AUCs for a model including age and PSA (the 'laboratory' model) and age, PSA and digital rectal exam (the 'clinical' model) were compared with those for models that also included additional kallikreins.
Results
Addition of free and intact PSA and hK2 improved AUC from 0.68 to 0.83 and from 0.72 to 0.84, for the laboratory and clinical models respectively. Using a 20% risk of prostate cancer as the threshold for biopsy would have reduced the number of biopsies by 424 (57%) and missed only 31 out of 152 low-grade and 3 out of 40 high-grade cancers.
Conclusion
Multiple kallikrein forms measured in blood can predict the result of biopsy in previously unscreened men with elevated PSA. A multivariable model can determine which men should be advised to undergo biopsy and which might be advised to continue screening, but defer biopsy until there was stronger evidence of malignancy.
doi:10.1186/1741-7015-6-19
PMCID: PMC2474851  PMID: 18611265
17.  Assessment of Intra-Individual Variationin Prostate-Specific Antigen Levels in a Biennial Randomized Prostate Cancer Screening Program in Sweden 
The Prostate  2005;65(3):216-221.
BACKGROUND
The degree of variability in prostate-specific antigen (PSA) measurements is important for interpreting test results in screening programs, and particularly for interpreting the significance of changes between repeated tests. This study aimed to determine the long-term intra-individual variation for PSA in healthy men.
METHODS
A randomly selected cohort of men in a biennial prostate cancer screening program (ERSPC) conducted in Sweden from 1995–1996 to 2001–2002. We studied men who had total PSA (tPSA) levels <2.0 ng/ml in 2001–2002. This included 791 men with tPSA ≤ 0.61 ng/ml (group A), 1,542 men with tPSA ≤ 0.99 ng/ml (group B), and 1,029 men with tPSA 1.00–1.99 ng/ml (group C). The intra-individual variability of free PSA (fPSA) and tPSA was assessed by calculating coefficients of variation (CV) for each individual’s PSA measurements from the first and second round of screening (1995–1996 and 1997–1998).
RESULTS
Intra-individual CV (geometric means) for tPSA were 13.7%, 12.7%, and 11.5% in groups A, B, and C, respectively. Corresponding CVs for fPSA were significantly lower, ranging from 12.1% to 10.4%. The estimated biological variation of tPSA and fPSA in groups A to C were 12.5%, 11.4%, 10.0% and 9.7%, 7.8%, 7.5%, respectively.
CONCLUSIONS
In healthy men with PSA levels less than 2 ng/ml, the natural long-term variability for tPSA was less than 14%, and with 95% probability, a change in tPSA greater than 30% indicates a change beyond normal random variation.
doi:10.1002/pros.20286
PMCID: PMC1951509  PMID: 15948137
PSA; biological variation; critical difference; screening
18.  Individualized Screening Interval for Prostate Cancer Based on Prostate-Specific Antigen Level  
Archives of internal medicine  2005;165(16):1857-1861.
Background
The aim of the present study was to evaluate the future cumulative risk of prostate cancer in relation to levels of prostate-specific antigen (PSA) in blood and to determine whether this information could be used to individualize the PSA testing interval.
Methods
The study included 5855 of 9972 men (aged 50–66 years) who accepted an invitation to participate in a prospective, randomized study of early detection for prostate cancer. We used a protocol based on biennial PSA measurements starting from 1995 and 1996. Men with serum PSA levels of 3.0 ng/mL or more were offered prostate biopsies.
Results
Among the 5855 men, 539 cases of prostate cancer (9.2%) were detected after a median follow-up of 7.6 years (up to July 1, 2003). Cancer detection rates during the follow-up period in relation to PSA levels were as follows: 0 to 0.49 ng/mL, 0% (0/958); 0.50 to 0.99 ng/mL, 0.9% (17/1992); 1.00 to 1.49 ng/mL, 4.7% (54/1138); 1.50 to 1.99 ng/mL, 12.3% (70/571); 2.00 to 2.49 ng/mL, 21.4% (67/313); 2.50 to 2.99 ng/mL, 25.2% (56/222); 3.00 to 3.99 ng/mL, 33.3% (89/267); 4.00 to 6.99 ng/mL, 38.9% (103/265); 7.00 to 9.99 ng/mL, 50.0% (30/60); and for men with an initial PSA of 10.00 ng/mL or higher, 76.8% (53/69). Not a single case of prostate cancer was detected within 3 years in 2950 men (50.4% of the screened population) with an initial PSA level less than 1 ng/mL.
Conclusions
Retesting intervals should be individualized on the basis of the PSA level, and the large group of men with PSA levels of less than 1 ng/mL can safely be scheduled for a 3-year testing interval.
doi:10.1001/archinte.165.16.1857
PMCID: PMC1950470  PMID: 16157829

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