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1.  Predictive value of prostate-specific antigen for prostate cancer: a nested case-control study in EuroSIDA 
Journal of the International AIDS Society  2014;17(4Suppl 3):19510.
Introduction
Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV− men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV− men. We aimed to describe the kinetics and predictive value of PSA in HIV+ men.
Methods
Men with PCa (n=21) and up to two matched controls (n=40) with prospectively stored plasma samples before PCa (or matched date in controls) were selected. Cases and controls were matched on date of first and last sample, age, region of residence and CD4 count at first sample date. Total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG) were measured. Conditional logistic regression models investigated associations between markers and PCa. Sensitivity and specificity of using tPSA >4 µg/L to predict PCa was calculated. Mixed models were used to describe kinetics.
Results
Sixty-one men were included with a median six (IQR 2–9) years follow-up. Time between last sample and PCa was seven (4–11) months. Cases and controls were well matched at first sample, with a median age of 51 (IQR 48–57) and CD4 of 437 (243–610) cells/mm3. Median tPSA [2.8 (IQR: 1.6–4.6) and 0.8 (0.5–1.2) µg/L] and fPSA [0.4 (0.2–0.8) and 0.3 (0.2–0.4) µg/L] levels were higher in cases than controls at first sample. Both tPSA and fPSA increased significantly over time in cases (Figure 1), to a median at last sample of 6.1 (4.7–9.5) and 0.9 (0.6–1.3) µg/L, respectively, but were stable in controls, with a median at last sample of 0.8 (0.5–1.4) and 0.2 (0.2–0.4) µg/L (Figure). Higher levels of tPSA and fPSA were associated with higher odds of PCa at first sample [OR for 2-fold higher 4.7 (CI: 1.7–12.9) and 5.4 (1.7–17.4)]. Elevated tPSA values in cases were detectable ≥5 years before PCa (p<0.01). Testosterone [overall median 19.4 (IQR 15.3–23.9) nmol/L at first sample) and SHBG [50.0 (34.0–66.0) nmol/L] levels were similar in cases and controls at first and last sample (all p>0.7). The most informative predictor of PCa was tPSA (AUC=0.9), followed by fPSA (0.8). Testosterone (AUC = 0.5) and SHBG (0.5) were poor predictors of PCa. Overall, tPSA level >4 µg/L had 99% specificity and 37% sensitivity. Performance was best in the year prior to PCa (specificity: 99%, sensitivity: 88%).
Conclusions
PSA was highly predictive of PCa in HIV+ men. Our results indicate that PSA screening in HIV+ men may be useful, and further work is needed to identify potentially age-related cut-offs to maximize sensitivity and specificity to identify those for further evaluation at early stages of PCa.
doi:10.7448/IAS.17.4.19510
PMCID: PMC4224942  PMID: 25394019
2.  Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer 
Prostate-specific antigen (PSA) has been widely used as a serum marker for prostate cancer (PCa) screening or progression monitoring, which dramatically increased rate of early detection while significantly reduced PCa-specific mortality. However, a number of limitations of PSA have been noticed. Low specificity of PSA may lead to overtreatment in men who presenting with a total PSA (tPSA) level of < 10 ng/mL. As a type of free PSA (fPSA), [-2]proPSA is differentially expressed in peripheral zone of prostate gland and found to be elevated in serum of men with PCa. Two p2PSA-based derivatives, prostate health index (PHI) and %p2PSA, which were defined as [(p2PSA/fPSA) × √ tPSA] and [(p2PSA/fPSA) × 100] respectively, have been suggested to be increased in PCa and can better distinguish PCa from benign prostatic diseases than tPSA or fPSA. We performed a systematic review of the available scientific evidences to evaluate the potentials of %p2PSA and PHI in clinical application. Mounting evidences suggested that both %p2PSA and PHI possess higher area under the ROC curve (AUC) and better specificity at a high sensitivity for PCa detection when compare with tPSA and %fPSA. It indicated that measurements of %p2PSA and PHI significantly improved the accuracy of PCa detection and diminished unnecessary biopsies. Furthermore, elevations of %p2PSA and PHI are related to more aggressive diseases. %p2PSA and PHI might be helpful in reducing overtreatment on indolent cases or assessing the progression of PCa in men who undergo active surveillance. Further studies are needed before being applied in routine clinical practice.
PMCID: PMC4297331  PMID: 25606581
PSA; prostate cancer; [-2]proPSA; %p2PSA; PHI; biopsy
3.  An examination of the dynamic changes in prostate-specific antigen occurring in a population-based cohort of men over time 
BJU international  2012;110(3):375-381.
OBJECTIVES
To determine whether prostate-specific antigen velocity (PSA-V), PSA doubling time (PSA-DT), or PSA percentage change (PSA-PC) add incremental information to PSA alone for community-based men undergoing prostate cancer (PCa) screening.
PARTICIPANTS AND METHODS
A population-based cohort of 11 872 men from Olmsted County, MN undergoing PSA screening for PCa from 1993 to 2005 was analysed for PSA, PSA-DT, PSA-PC and PSA-V and subsequent PCa.Receiver-operating characteristics curves and logistic regression were used to calculate the area under the curve (AUC) and Aikaike’s information criterion.Reclassification analysis was performed and the net reclassification improvement and integrated discrimination improvement were measured.The method of Begg and Greenes was used to adjust for verification bias.
RESULTS
The single best predictor of future PCa was PSA (AUC = 0.773) with PSA-V (AUC = 0.729) and PSA-DT/PSA-PC (AUC = 0.689) performing worse.After age adjustment, combining PSA with PSA-V (AUC = 0.773) or PSA-DT/PSA-PC (AUC = 0.773) resulted in no better predictions than PSA alone.Reclassification analysis showed that adding PSA-V or PSA-DT/PSA-PC to PSA did not result in a meaningful amount of reclassification.
CONCLUSIONS
PSA is a better predictor of future PCa than PSA-V, PSA-DT, or PSA-PC.Adding PSA-V, PSA-DT, or PSA-PC to PSA does not result in clinically relevant improvements in the ability to predict future PCa.
doi:10.1111/j.1464-410X.2011.10925.x
PMCID: PMC3637967  PMID: 22313933
prostate cancer; prostate-specific antigen; PSA doubling time; PSA velocity; PSA percentage change
4.  Outcomes and Trends of Prostate Biopsy for Prostate Cancer in Chinese Men from 2003 to 2011 
PLoS ONE  2012;7(11):e49914.
Background
Prostate-specific antigen (PSA) screening is growing in popularity in China, but its impact on biopsy characteristics and outcomes are poorly understood.
Objective
Our objective was to characterize prostate biopsy outcomes and trends in Chinese men over a 10-year period, since the increasing use of PSA tests.
Methods
All men (n = 1,650) who underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China from 2003–2011 were evaluated. Demographic and clinical information was collected for each patient, including age, digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total prostate-specific antigen (tPSA) levels and free PSA ratio (fPSA/tPSA) prior to biopsy. Prostate biopsy was performed using six cores before October 2007 or ten cores thereafter. Logistic regression and multivariate analysis were used to evaluate our data.
Results
The overall positive rate of prostate biopsy for PCa was 47% and the rate decreased significantly over the years from 74% in 2003 to 33% in 2011 (P-trend = 0.004) . Age at diagnosis was slightly increased (P-trend = 0.04) while fPSA/tPSA was significantly decreased (P-trend = 1.11×10-5). A statistically significant trend was not observed for tPSA levels, prostate volume, or proportion of positive nodule. The model including multiple demographic and clinical variables (i.e., age, DRE, tPSA, fPSA/tPSA and transrectal ultrasound results) (AUC = 0.93) statistically outperformed models that included only PSA (AUC = 0.85) or fPSA/tPSA (AUC = 0.66) to predict PCa risks (P<0.05). Similar results were observed in a subgroup of men whose tPSA levels were lower than 20 ng/mL (AUC = 0.87, vs. AUC of tPSA  = 0.62, P<0.05).
Conclusions
Detection rates of PCa and high-grade PCa among men that underwent prostate biopsy at the institution has decreased significantly in the past 10 years, likely due to increasing use of PSA tests. Predictive performance of demographic and clinical variables of PCa was excellent. These variables should be used in clinics to determine the need for prostate biopsy.
doi:10.1371/journal.pone.0049914
PMCID: PMC3506536  PMID: 23189170
5.  Immunoassay for the discrimination of free prostate-specific antigen (fPSA) forms with internal cleavages at Lys145 or Lys146 from fPSA without internal cleavages at Lys145 or Lys146 
Journal of immunological methods  2011;369(0):74-80.
Total levels of circulating prostate-specific antigen (tPSA) are strongly associated with prostate cancer (PCa) risk and outcome but benign prostate disease is the most frequent cause of a moderately elevated PSA level. Free PSA (fPSA) forms are independently associated with PCa risk and contribute modest diagnostic enhancements above and beyond tPSA alone. We developed an immunoassay for fPSA subfractions containing internal cleavages at Lys145 or Lys146 (fPSA-N). The assay was based on blocking intact single-chain fPSA (fPSA-I) with antibody 4D4 which does not detect PSA containing internal cleavages at Lys145 or Lys146. We also measured fPSA-N in blood from healthy volunteers and in anti-coagulated plasma from 76 men with or without evidence of PCa at biopsy. The analytical and functional detection limits of this assay were 0.016 ng/mL and 0.10 ng/mL, respectively. The median recovery of male fPSA-N from female plasma was 95.0 %. All 12 female samples (average age 28 years) had fPSA-N concentrations at or below the analytical detection limit. The median fPSA-N concentration (0.050 ng/mL) in 9 healthy male volunteers (age < 40 years) was below the functional detection limit, 0.420 ng/mL in 27 patients with benign prostate conditions and 0.239 ng/mL in 49 patients with PCa. Deming regression analysis of the patient samples showed that the measured fPSA-N concentrations were generally 23% lower than the previously calculated (fPSA minus fPSA-I) concentrations, likely due to differences in the antibody combinations used. In conclusion, we have developed a sensitive, specific and direct immunoassay for fPSA-N which can be used to study the clinical relevance of this PSA isoform.
doi:10.1016/j.jim.2011.04.006
PMCID: PMC4273311  PMID: 21554885
prostate-specific antigen; free PSA isoform; internally cleaved PSA; nicked PSA; immunoassay; prostate cancer
6.  [−2 ] PRO-PSA IS MORE ACCURATE THAN TOTAL AND FREE PSA IN DIFFERENTIATING PROSTATE CANCER FROM BENIGN DISEASE IN A PROSPECTIVE PROSTATE CANCER SCREENING STUDY*, ** 
The Journal of urology  2010;183(4):1355-1359.
Purpose
Due to the limited specificity of prostate-specific antigen (PSA) for prostate cancer (CaP) screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme PSA called [−2] proPSA (p2PSA) may enhance the specificity of PSA-based screening. The objective of our study was to examine the utility of p2PSA in a prospective CaP screening study.
Materials and Methods
From a population of 2034 men undergoing CaP screening, we examined the relationship between p2PSA and CaP detection. Specifically, we compared the utility of total PSA, the ratio of free PSA (fPSA) to total PSA (%fPSA), the ratio of p2PSA to fPSA (%p2PSA) and a formula combining PSA, fPSA and p2PSA (called Beckman Coulter prostate health index or phi®) to predict CaP among men from the study undergoing prostate biopsy with PSA levels of 2.5–10 ng/ml and non-suspicious digital rectal examination (DRE).
Results
Despite similar total PSA levels (p=0.88), both %fPSA (p=0.02) and %p2PSA (p=0.0006) distinguished between positive and negative biopsy results. On receiver operating characteristic (ROC) analysis, %p2PSA (AUC 0.76) outperformed both PSA (AUC 0.50) and %fPSA (AUC 0.68) for differentiating between CaP and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity, positive and negative predictive values. The Beckman Coulter phi® (AUC 0.77) had the best overall performance characteristics.
Conclusions
This is the first prospective study to demonstrate that p2PSA provides improved discrimination between CaP and benign disease in screened men with PSA levels from 2.5 to 10 ng/ml and negative DRE.
doi:10.1016/j.juro.2009.12.056
PMCID: PMC3537165  PMID: 20171670
prostate-specific antigen; PSA; free PSA; PSA isoforms; proPSA
7.  Role of Prostate Volume in the Early Detection of Prostate Cancer in a Cohort with Slowly Increasing Prostate Specific Antigen 
Yonsei Medical Journal  2013;54(5):1202-1206.
Purpose
To investigate the relationship between prostate volume and the increased risk for being diagnosed with prostate cancer (PCa) in men with slowly increasing prostate specific antigen (PSA).
Materials and Methods
A cohort of 1035 men who visited our hospital's health promotion center and were checked for serum PSA levels more than two times between January 2001 and November 2011 were included. Among them, 116 patients had a change in PSA levels from less than 4 ng/mL to more than 4 ng/mL and underwent transrectal ultrasound guided prostate biopsy. Median age was 55.9 years and 26 (22.4%) had PCa. We compared the initial PSA level, the last PSA level, age, prostate volume, PSA density (PSAD), PSA velocity, and follow-up period between men with and without PCa. The mean follow-up period was 83.7 months.
Results
Significant predictive factors for the detection of prostate cancer identified by univariate analysis were prostate volume, follow-up period and PSAD. In the multivariate analysis, prostate volume (p<0.001, odds ratio: 0.890) was the most significant factor for the detection of prostate cancer. In the receiver operator characteristic curve of prostate volume, area under curve was 0.724. At the cut-off value of 28.8 mL for prostate volume, the sensitivity and specificity were 61.1% and 73.1% respectively.
Conclusion
In men with PSA values more than 4 ng/mL during the follow-up period, a small prostate volume was the most important factor in early detection of prostate cancer.
doi:10.3349/ymj.2013.54.5.1202
PMCID: PMC3743199  PMID: 23918570
Prostatic neoplasms; prostate-specific antigen; early diagnosis; organ size
8.  Screening for Prostate Cancer: An Update 
The Canadian journal of urology  2008;15(6):4363-4374.
The introduction of total prostate specific antigen (tPSA) testing in serum has revolutionized the detection and management of men with prostate cancer (PCa). This review will highlight some of the exciting new developments in the field of PCa screening in general and from our SPORE research program at Memorial-Sloan Kettering Cancer Center. First, it is important to understand that the inherent variability of tPSA levels affects the interpretation of any single results. Total variation in tPSA includes both analytical (i.e., pre-analytical sample handling, laboratory processing, assay performance, and standardization) and biological variation (i.e., metabolism, renal elimination, medication, physical and sexual activity, size and integrity of the prostate). Second, recent evidence demonstrates that no single tPSA cut-off separates men at high-risk for PCa from men at low-risk or men with “significant” (high-grade, high-volume) cancer from those with low-grade, indolent cancer. Taken together with a man’s age, family history, ethnicity, and digital rectal exam results, tPSA levels add to the overall estimate of the risk of cancer, allowing men to share in the decision about a biopsy. Third, men who will eventually develop PCa have increased tPSA levels years or decades before the cancer is diagnosed. These tPSA levels may reflect the long duration of prostate carcinogenesis and raise the question about a causal role for tPSA in PCa development and progression. tPSA measurements before age 50 could help risk-stratify men for intensity of PCa screening. Fourth, enhancing the diagnostic accuracy of tPSA, especially its specificity, is of particular importance, since higher specificity translates into fewer biopsies in men not affected by PCa. While tPSA velocity has been shown to improve the specificity of tPSA, its sensitivity is too low to avoid prostate biopsy in a patient with an elevated tPSA level. Moreover, prospective screening studies have reported that tPSA velocity does not add diagnostic value beyond tPSA level. At this time, tPSA velocity appears most useful after diagnosis and after treatment, but its value in screening and prognostication remains to be shown. Finally, while free PSA molecular isoforms and human kallikrein-related peptidase 2 (hK2) hold the promise for detection, staging, prognosis, and monitoring of PCa, evidence from large prospective clinical trials remain to be reported.
PMCID: PMC2742707  PMID: 19046489
prostate-specific antigen; human glandular kallikrein; prostate cancer; prognosis; detection
9.  Effect of Histological Inflammation on Total and Free Serum Prostate-Specific Antigen Values in Patients Without Clinically Detectable Prostate Cancer 
Korean Journal of Urology  2014;55(8):527-532.
Purpose
We are often confronted with patients in the "gray zone" (prostate-specific antigen [PSA]<10 ng/mL) whose biopsies reveal no malignancy but only inflammation. We investigated the relationship between histological inflammation and total PSA (tPSA), free PSA (fPSA), and percentage of free PSA (f/tPSA) levels in patients without prostate cancer (PC).
Materials and Methods
We studied 106 men with tPSA<10 ng/mL who had undergone biopsy that was negative for PC and who had no clinical prostatitis. Inflammation observed at biopsies was scored for inflammation type in each biopsy core by use of a four-point scale and was then correlated with tPSA, fPSA, and f/tPSA.
Results
Different patterns of inflammation were found in each set of biopsies. Regression factor analysis was used to form two groups according to inflammation type: more chronic and more acute. Median tPSA, fPSA, and f/tPSA levels in the more chronic and more acute inflammation groups were 6.4 ng/mL, 1.09 ng/mL, and 15%, and 7.3 ng/mL, 0.79 ng/mL, and l2%, respectively. A significant difference was found in fPSA (p=0.003) and f/tPSA (p<0.001), whereas the difference in tPSA was not significant (p=0.200). Total PSA correlated with fPSA (r=0.4, p<0.001) but not with inflammation type (r=0.12, p>0.010). A correlation existed between inflammation type and fPSA (r=-0.31, p=0.001) and f/tPSA (r=-0.43, p<0.001) in that the fPSA and f/tPSA were lower in the group with more acute inflammation.
Conclusions
Subclinical inflammation has a significant influence on fPSA in patients with tPSA<10 ng/mL but without PC or clinical prostatitis. Subclinical inflammation is not characterized by elevated tPSA alone but also by a decreased fPSA, a tendency similar to that in PC.
doi:10.4111/kju.2014.55.8.527
PMCID: PMC4131081  PMID: 25132947
Biopsy; Inflammation; Prostate-specific antigen; Prostatic neoplasms; Prostatitis
10.  Rapid elimination kinetics of free PSA or human kallikrein-related peptidase 2 after initiation of gonadotropin-releasing hormone-antagonist treatment of prostate cancer: potential for rapid monitoring of treatment responses 
Background
The utility of conventional prostate-specific antigen (PSA) measurements in blood for monitoring rapid responses to treatment for prostate cancer is limited because of its slow elimination rate. Prior studies have shown that free PSA (fPSA), intact PSA (iPSA) and human kallikrein-related peptidase 2 (hK2) are eliminated more rapidly after radical prostatectomy. In contrast, all three markers have similarly slow elimination rates after castration induced by GnRH agonists, possibly due to the slow onset of castration. Therefore, we assessed elimination rates of tPSA, fPSA, iPSA and hK2 after rapid induction of castration with degarelix (Firmagon®), a novel GnRH antagonist.
Methods
This study included 24 patients treated with degarelix. Blood was taken at 1, 3, 7, 14, 21, and 28 days after injection of degarelix. Free and total PSA were measured with a commercial dual-label assay, and with in-house research assays of intact PSA and hK2.
Results
Median (interquartile range, IQR) tPSA at baseline was 23.4 (15.8, 59.8). Twenty-two patients (92%) reached castrate levels of testosterone within 24 hours of degarelix initiation, and all patients did so within 72 hours. All kallikrein forms declined in an exponential fashion after degarelix administration. The median time to 50% reduction in biomarker level was 8–9 days for tPSA or complexed PSA versus 2–4 days for hK2, iPSA and fPSA. The percentage eliminated at day 3 and day 7 was significantly higher for hK2, iPSA and fPSA than for tPSA (all p<0.02), while tPSA and complexed PSA were similar.
Conclusions
The rapid decline of fPSA, iPSA and hK2 after fast induction of castration with degarelix is similar to that reported after prostatectomy and offers a novel, informative method to monitor rapid onset of therapeutic action targeting signaling of the androgen receptor,
doi:10.1515/cclm-2011-0967
PMCID: PMC3474140  PMID: 22718641
androgen deprivation therapy; human kallikrein-related peptidase 2; prostate cancer; prostate-specific antigen; tumor markers
11.  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
12.  Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen 
BMC Medicine  2014;12:26.
Background
Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.
Methods
Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).
Results
If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.
Conclusions
Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening.
doi:10.1186/1741-7015-12-26
PMCID: PMC3922189  PMID: 24512643
Prostate cancer; Early detection; Overdiagnosis; PSA; Screening
13.  Free Prostate-Specific Antigen Provides More Precise Data on Benign Prostate Volume Than Total Prostate-Specific Antigen in Korean Population 
Purpose
To investigate the efficacy of total prostate-specific antigen (tPSA) and free prostate-specific antigen (fPSA) for the estimation of prostate volume (PV) in pathologically-proven benign prostatic hyperplasia (BPH) patients.
Methods
From January 2010 to March 2013, 165 Korean men with a PSA less than 10 ng/mL who were diagnosed without prostate cancer by prostate biopsy were enrolled. Patients were classified into three age groups: ≤60, 61-70, and >70 years old. The results were organized to estimate and compare the ability of serum tPSA and fPSA to assess the PV.
Results
Enrolled patients had a median age of 63.5 years (44 to 80), a median tPSA of 5.72 ng/mL, a median fPSA of 0.98 ng/mL and a median PV of 53.68 mL, respectively. Among the associations between tPSA, fPSA, age, and PV, the highest correlation was verified between fPSA and PV (r=0.377, P<0.0001); the correlation coefficient between tPSA and PV was much lower (r=0.262, P<0.001). All stratified age cohorts showed the same findings. The ROC curves (for PV greater than 30, 40, and 50 mL) showed that fPSA (area under the curve [AUC]=0.781, 0.718, and 0.700) outperformed tPSA (AUC=0.657, 0.583, and 0.67) in its ability to predict clinically significant PV enlargement.
Conclusion
Both tPSA and fPSA significantly correlated with PV in Korean men, while the correlation efficiency between fPSA and PV was more powerful. fPSA may be a useful tool in making therapeutic decisions and follow-up management in BPH patients.
doi:10.5213/inj.2013.17.2.73
PMCID: PMC3713245  PMID: 23869271
Prostate-specific antigen; Prostatic hyperplasia; Organ volume
14.  Age-Specific Prostate Specific Antigen Cutoffs for Guiding Biopsy Decision in Chinese Population 
PLoS ONE  2013;8(6):e67585.
Background
Age-specific prostate specific antigen (PSA) cutoffs for prostate biopsy have been widely used in the USA and European countries. However, the application of age-specific PSA remains poorly understood in China.
Methods
Between 2003 and 2012, 1,848 men over the age of 40, underwent prostate biopsy for prostate cancer (PCa) at Huashan Hospital, Shanghai, China. Clinical information and blood samples were collected prior to biopsy for each patient. Men were divided into three age groups (≤60, 61 to 80, and >80) for analyses. Digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total PSA (tPSA), and free PSA (fPSA) were also included in the analyses. Logistic regression was used to build the multi-variate model.
Results
Serum tPSA levels were age-dependent (P = 0.008), while %fPSA (P = 0.051) and PSAD (P = 0.284) were age-independent. At a specificity of 80%, the sensitivities for predicting PCa were 83%, 71% and 68% with tPSA cutoff values of 19.0 ng/mL (age≤60),21.0 ng/mL (age 61–80), and 23.0 ng/mL (age≥81). Also, sensitivities at the same tPSA levels were able to reach relatively high levels (70%–88%) for predicting high-grade PCa. Area (AUC) under the receive operating curves (ROCs) of tPSA, %fPSA, PSAD and multi-variate model were different in age groups. When predicting PCa, the AUC of tPSA, %fPSA, PSAD and multi-variate model were 0.90, 0.57, 0.93 and 0.87 respectively in men ≤60 yr; 0.82, 0.70, 0.88 and 0.86 respectively in men 61–80 yr; 0.79, 0.78, 0.87 and 0.88 respectively in men>80 yr. When predicting Gleason Score ≥7 or 8 PCa, there were no significant differences between AUCs of each variable.
Conclusion
Age-specific PSA cutoff values for prostate biopsy should be considered in the Chinese population. Indications for prostate biopsies (tPSA, %fPSA and PSAD) should be considered based on age in the Chinese population.
doi:10.1371/journal.pone.0067585
PMCID: PMC3692456  PMID: 23825670
15.  DEVELOPMENT AND VALIDATION OF A NOMOGRAM PREDICTING THE OUTCOME OF PROSTATE BIOPSY BASED ON PATIENT AGE, DIGITAL RECTAL EXAMINATION AND SERUM PROSTATE SPECIFIC ANTIGEN 
The Journal of urology  2005;173(6):1930-1934.
Purpose
We developed and validated a nomogram which predicts presence of prostate cancer (PCa) on needle biopsy.
Materials and Methods
We used 3 cohorts of men who were evaluated with sextant biopsy of the prostate and whose presenting prostate specific antigen (PSA) was not greater than 50 ng/ml. Data from 4,193 men from Montreal, Canada were used to develop a nomogram based on age, digital rectal examination (DRE) and serum PSA. External validation was performed on 1,762 men from Hamburg, Germany. Data from these men were subsequently used to develop a second nomogram in which percent free PSA (%fPSA) was added as a predictor. External validation was performed using 514 men from Montreal. Both nomograms were based on multivariate logistic regression models. Predictive accuracy was evaluated with areas under the receiver operating characteristic curve and graphically with loess smoothing plots.
Results
PCa was detected in 1,477 (35.2%) men from Montreal, 739 (41.9%) men from Hamburg and 189 (36.8%) men from Montreal. In all models all predictors were significant at 0.05. Using age, DRE and PSA external validation AUC was 0.69. Using age, DRE, PSA and %fPSA external validation AUC was 0.77.
Conclusions
A nomogram based on age, DRE, PSA and %fPSA can highly accurately predict the outcome of prostate biopsy in men at risk for PCa.
doi:10.1097/01.ju.0000158039.94467.5d
PMCID: PMC1855288  PMID: 15879784
prostatic neoplasms; biopsy; nomograms; validation studies
16.  DISTRIBUTION AND ASSOCIATIONS OF [-2]PRO-PROSTATE-SPECIFIC ANTIGEN IN COMMUNITY-DWELLING BLACK AND WHITE MEN 
The Journal of Urology  2011;187(1):92-96.
Purpose
To provide cross-sectional normative data for [-2]pro-prostate-specific antigen ([-2]proPSA) from the Olmsted County Study of Urinary Symptoms and Health Status among Men (OCS) and the Flint Men’s Health Study (FMHS) and to describe the associations with clinical urologic measures and risk of prostate cancer diagnosis.
Materials and Methods
Measurements of [-2]proPSA were obtained from n=420 white men from Olmsted County, Minnesota and n=328 black men from Genesee County, Michigan. Cross-sectional associations between [-2]proPSA and prostate enlargement / elevated PSA level were assessed. Cox proportional hazard models were used to assess associations between [-2]proPSA and incident diagnosis of prostate cancer.
Results
Baseline [-2]proPSA level was slightly higher among black men (median (25th, 75th percentiles) =6.3 (4.1, 8.9) pg/mL) than among white men (median=5.6 (3.9, 7.7) pg/mL), p=0.01. Baseline [-2]proPSA level was highly predictive of biopsy-confirmed prostate cancer (CaP) in the OCS cohort. Relative to men in the lower quartile of [-2]proPSA, men in the upper quartile had almost an 8-fold increase in the risk of CaP (hazard ratio (HR): 7.8, 95% confidence interval (CI): 2.2, 27.8) after adjustment for age and baseline PSA.
Conclusions
Levels of [-2]proPSA in these cohorts of community-dwelling black and white men are much lower than seen in previous studies. These data suggest that levels of [-2]proPSA may help identify prostate cancer in men with serum PSA levels in an indeterminate range, although the reference ranges for white and black men may differ slightly.
doi:10.1016/j.juro.2011.09.060
PMCID: PMC3307097  PMID: 22093189
prostate enlargement; prostate cancer; biomarkers; proPSA
17.  Prostate-Specific Antigen Testing of Older Men 
Background
Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection.
Methods
We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age.
Results
All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%–100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%–100%) of the cancers would still be detected by age 75 years.
Conclusions
These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.
PMCID: PMC3474977  PMID: 10528023
18.  Free to total serum prostate specific antigen ratio in symptomatic men does not help in differentiating benign from malignant disease of the prostate 
Introduction:
Free to total prostate specific antigen ratio (f/t PSA) has been used to help improving specificity of PSA in the range of 4-10 ng/ml based on the data on population based screening. There is no data on test characteristics of f/t PSA in men presenting with clinical symptoms of benign prostatic hyperplasia (BPH). This study is aimed to determine the usefulness of f/t PSA in symptomatic men.
Methodology:
From January 2006 to June 2012, men of 50-75 years with lower urinary tract symptoms (LUTS), normal rectal examination and PSA between 4-20 ng/ml had free and total PSA assessment. Men with clinical evidence of prostatitis, retention, history of 5α blocker reductase inhibitors and those who had surgery or biopsy on the prostate in last 3 months were excluded. Receiver operating characteristic curves were derived for f/t PSA and total PSA. The effect of age, prostate volume and Gleason score on the f/t PSA was also analyzed. All statistical analyses were performed on SPSS 16 (Chicago, USA).
Results:
Out of 170 men with the mean age of 67.4 ± 6.6 years, 43 (25.3%) had cancer on biopsy. Area under the curve for predicting the presence or absence of prostate cancer in all the men with f/t ratio was 0.63 (confidence interval [CI]: 0.54-0.71). The median value of f/t PSA for men with cancer was 5.5% (1-25%) and 9.2% (1-63%) for those with no cancer. Cut-offs derived at 95% specificity at PSA between 4-10 ng/ml and 4-20 ng/ml were 0.5% and 1% respectively. The specificity of f/t PSA ratio at cut-off levels 7%, 10% and 15% was 73%, 60%, 45% for PSA range of 4-10 ng/ml and 63%, 47% and 35% for PSA range of 4-20 ng/ml PSA. Age, prostate volume and Gleason grade did not show any effect on f/t PSA.
Conclusion:
In men with LUTS the specificity of various f/t PSA ratio cut-offs; described for population based screening, is too low to be used as an aid to defer the decision of biopsy in PSA ranges of 4-20 ng/ml.
doi:10.4103/0970-1591.124202
PMCID: PMC3897049  PMID: 24497678
Free to total prostate specific antigen ratio; prostate cancer; screening
19.  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
20.  Cancer Screening: A Mathematical Model Relating Secreted Blood Biomarker Levels to Tumor Sizes  
PLoS Medicine  2008;5(8):e170.
Background
Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.
Methods and Findings
Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm3 and 3,610.14 mm3 for CA125 and between 0.21 mm3 and 131.51 mm3 for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm3 and 1.52 × 106 mm3 for CA125 and between 27 mm3 and 3.45 × 105 mm3 for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.
Conclusions
This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.
Sanjiv Gambhir and colleagues describe a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays.
Editors' Summary
Background.
Cancers—disorganized masses of cells that can occur in any tissue—develop when cells acquire genetic changes that allow them to grow uncontrollably and to spread around the body (metastasize). If a cancer (tumor) is detected when it is small, surgery can often provide a cure. Unfortunately, many cancers (particularly those deep inside the body) are not detected until they are large enough to cause pain or other symptoms by pressing against surrounding tissue. By this time, it may be impossible to remove the original tumor surgically and there may be metastases scattered around the body. In such cases, radiotherapy and chemotherapy can sometimes help, but the outlook for patients whose cancers are detected late is often poor. Consequently, researchers are trying to develop early detection tests for different types of cancer. Many tumors release specific proteins—“cancer biomarkers”—into the blood and the hope is that it might be possible to find sets of blood biomarkers that detect cancers when they are still small and thus save many lives.
Why Was This Study Done?
For most biomarkers, it is not known how the amount of protein detected in the blood relates to tumor size or how sensitive the assays for biomarkers must be to improve patient survival. In this study, the researchers develop a “linear one-compartment” mathematical model to predict how large tumors need to be before blood biomarkers can be used to detect them and test this model using published data on two established cancer biomarkers—CA125 and prostate-specific antigen (PSA). CA125 is used to monitor the progress of patients with ovarian cancer after treatment; ovarian cancer is rarely diagnosed in its early stages and only one-fourth of women with advanced disease survive for 5 y after diagnosis. PSA is used to screen for prostate cancer and has increased the detection of this cancer in its early stages when it is curable.
What Did the Researchers Do and Find?
To develop a model that relates secreted blood biomarker levels to tumor sizes, the researchers assumed that biomarkers mix evenly throughout the patient's blood, that cancer cells secrete biomarkers into the fluid that surrounds them, that 0.1%–20% of these secreted proteins enter the blood at a continuous rate, and that biomarkers are continuously removed from the blood. The researchers then used their model to calculate the smallest tumor sizes that might be detectable with these biomarkers by feeding in existing data on CA125 and on PSA, including assay detection limits and the biomarker secretion rates of cancer cells growing in dishes. When only tumor cells secreted the biomarker and 10% of the secreted biomarker reach the blood, the model predicted that ovarian tumors between 0.11 mm3 (smaller than a grain of salt) and nearly 4,000 mm3 (about the size of a cherry) would be detectable by measuring CA125 blood levels (the range was determined by varying the amount of biomarker secreted by the tumor cells and the assay sensitivity); for prostate cancer, the detectable tumor sizes ranged from similar lower size to about 130 mm3 (pea-sized). However, healthy cells often also secrete small quantities of cancer biomarkers. With this condition incorporated into the model, the estimated detectable tumor sizes (or total tumor burden including metastases) ranged between grape-sized and melon-sized for ovarian cancers and between pea-sized to about grapefruit-sized for prostate cancers.
What Do These Findings Mean?
The accuracy of the calculated tumor sizes provided by the researchers' mathematical model is limited by the lack of data on how tumors behave in the human body and by the many assumptions incorporated into the model. Nevertheless, the model predicts detection limits for ovarian and prostate cancer that broadly mirror the clinical performance of both biomarkers. Somewhat worryingly, the model also indicates that a tumor may have to be very large for blood biomarkers to reveal its presence, a result that could limit the clinical usefulness of biomarkers, especially if they are secreted not only by tumor cells but also by healthy cells. Given this finding, as more information about how biomarkers behave in the human body becomes available, this model (and more complex versions of it) should help researchers decide which biomarkers are likely to improve early cancer detection and patient outcomes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050170.
The US National Cancer Institute provides a brief description of what cancer is and how it develops and a fact sheet on tumor markers; it also provides information on all aspects of ovarian and prostate cancer for patients and professionals, including information on screening and testing (in English and Spanish)
The UK charity Cancerbackup also provides general information about cancer and more specific information about ovarian and prostate cancer, including the use of CA125 and PSA for screening and follow-up
The American Society of Clinical Oncology offers a wide range of information on various cancer types, including online published articles on the current status of cancer diagnosis and management from the educational book developed by the annual meeting faculty and presenters. Registration is mandatory, but information is free
doi:10.1371/journal.pmed.0050170
PMCID: PMC2517618  PMID: 18715113
21.  Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study 
Bancroft, Elizabeth K. | Page, Elizabeth C. | Castro, Elena | Lilja, Hans | Vickers, Andrew | Sjoberg, Daniel | Assel, Melissa | Foster, Christopher S. | Mitchell, Gillian | Drew, Kate | Mæhle, Lovise | Axcrona, Karol | Evans, D. Gareth | Bulman, Barbara | Eccles, Diana | McBride, Donna | van Asperen, Christi | Vasen, Hans | Kiemeney, Lambertus A. | Ringelberg, Janneke | Cybulski, Cezary | Wokolorczyk, Dominika | Selkirk, Christina | Hulick, Peter J. | Bojesen, Anders | Skytte, Anne-Bine | Lam, Jimmy | Taylor, Louise | Oldenburg, Rogier | Cremers, Ruben | Verhaegh, Gerald | van Zelst-Stams, Wendy A. | Oosterwijk, Jan C. | Blanco, Ignacio | Salinas, Monica | Cook, Jackie | Rosario, Derek J. | Buys, Saundra | Conner, Tom | Ausems, Margreet G. | Ong, Kai-ren | Hoffman, Jonathan | Domchek, Susan | Powers, Jacquelyn | Teixeira, Manuel R. | Maia, Sofia | Foulkes, William D. | Taherian, Nassim | Ruijs, Marielle | den Enden, Apollonia T. Helderman-van | Izatt, Louise | Davidson, Rosemarie | Adank, Muriel A. | Walker, Lisa | Schmutzler, Rita | Tucker, Kathy | Kirk, Judy | Hodgson, Shirley | Harris, Marion | Douglas, Fiona | Lindeman, Geoffrey J. | Zgajnar, Janez | Tischkowitz, Marc | Clowes, Virginia E. | Susman, Rachel | Ramón y Cajal, Teresa | Patcher, Nicholas | Gadea, Neus | Spigelman, Allan | van Os, Theo | Liljegren, Annelie | Side, Lucy | Brewer, Carole | Brady, Angela F. | Donaldson, Alan | Stefansdottir, Vigdis | Friedman, Eitan | Chen-Shtoyerman, Rakefet | Amor, David J. | Copakova, Lucia | Barwell, Julian | Giri, Veda N. | Murthy, Vedang | Nicolai, Nicola | Teo, Soo-Hwang | Greenhalgh, Lynn | Strom, Sara | Henderson, Alex | McGrath, John | Gallagher, David | Aaronson, Neil | Ardern-Jones, Audrey | Bangma, Chris | Dearnaley, David | Costello, Philandra | Eyfjord, Jorunn | Rothwell, Jeanette | Falconer, Alison | Gronberg, Henrik | Hamdy, Freddie C. | Johannsson, Oskar | Khoo, Vincent | Kote-Jarai, Zsofia | Lubinski, Jan | Axcrona, Ulrika | Melia, Jane | McKinley, Joanne | Mitra, Anita V. | Moynihan, Clare | Rennert, Gad | Suri, Mohnish | Wilson, Penny | Killick, Emma | Moss, Sue | Eeles, Rosalind A.
European Urology  2014;66(3):489-499.
Background
Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.
Objective
To report the first year's screening results for all men at enrolment in the study.
Design, setting and participants
We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy.
Outcome measurements and statistical analysis
PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types.
Results and limitations
We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups.
Conclusions
The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease.
Patient summary
In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.
Take Home Message
This report demonstrates that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these higher-risk men resulted in the identification of tumours that were more likely to require treatment.
doi:10.1016/j.eururo.2014.01.003
PMCID: PMC4105321  PMID: 24484606
BRCA1; BRCA2; Prostate cancer; Prostate-specific antigen; Targeted screening
22.  Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection among US men 
Cancer causes & control : CCC  2011;22(11):1483-1495.
Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection were evaluated among 3927 U.S. men, 40–85 years of age, who participated in the 2001–2006 National Health and Nutrition Examination Surveys. Five recommended definitions of prostate cancer detection were adopted using total and free prostate specific antigen (tPSA and fPSA) laboratory measurements. Men were identified as high-risk based on alternative cut-offs, namely, tPSA>10 ng/ml, tPSA>4 ng/ml, tPSA> 2.5 ng/ml, %fPSA<25% and %fPSA<15%. %fPSA was defined as (fPSA÷tPSA)×100%. Serum levels of vitamin A (retinol, retinyl esters) and carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein+zeaxanthin, lycopene) were defined as quartiles and examined as risk/protective factors for PSA biomarkers. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using binary logistic models. After adjustment for known demographic, socioeconomic and lifestyle confounders, high serum levels of retinyl esters (tPSA>10 ng/ml: Q4vs.Q1→OR=0.38, 95% CI: 0.14–1.00) and α-carotene (%fPSA<15%: Q4vs.Q1→OR=0.49, 95% CI: 0.32–0.76) were associated with a lower odds whereas high serum level of lycopene (tPSA>2.5 ng/ml: Q4vs.Q1→OR=1.49, 95% CI: 1.01–2.14) was associated with a greater odds of prostate cancer detection. Apart from the three significant associations observed, no other exposure-outcome association was significant. Monitoring specific antioxidant levels may be helpful in early detection of prostate cancer.
doi:10.1007/s10552-011-9822-8
PMCID: PMC3443554  PMID: 21800039
vitamin A; carotenoids; prostate cancer; prostate-specific antigen
23.  proPSA Measurements in Serum and Tissue are Associated with Treatment Necessity Among Men Enrolled in Expectant Management for Prostate Cancer 
Purpose
We assessed the association of quantitative clinical and pathologic information, including serum and tissue proPSA, with outcomes among men with prostate cancer (PCa) managed expectantly.
Experimental Design
We identified 71 men enrolled in expectant management (EM) with frozen serum and tissue available from diagnosis. 39 subsequently developed unfavorable biopsies (Gleason score>=7, >=3 cores positive for cancer, >50% of any core involved with cancer), while 32 maintained favorable biopsies (median follow-up: 3.93 years). Serum tPSA, fPSA and [−2]proPSA were measured by the Beckman Coulter immunoassay. [−5/−7]proPSA was evaluated in cancer and benign adjacent tissue areas (BAA) by quantitative immunohistochemistry. Cox proportional hazards and Kaplan-Meier analyses were used to identify significant associations with unfavorable biopsy conversion.
Results
The ratio [−2]proPSA/%fPSA in serum was significantly higher at diagnosis (0.87+/−0.44pg/mL vs. 0.65+/−0.36pg/mL, p=0.02) in men developing unfavorable biopsies. [−5/−7]proPSA tissue staining was more intense (4104.09+/−3033.50 vs. 2418.06+/−1606.04, p=0.03) and comprised a greater fractional area (11.58%+/−7.08% vs. 6.88%+/−5.20%, p=0.01) in BAA of these men. Serum [−2]proPSA/%fPSA [HR:2.53(1.18–5.41), p=0.02], BAA [−5/−7]proPSA %area [HR:1.06(1.01–1.12), p=0.02] and BAA [−5/−7]proPSA stain intensity [HR:1.000213(1.000071–1.000354), p=0.003] were significantly associated with unfavorable biopsy in Kaplan-Meier and Cox analyses. Serum [−2]proPSA/%fPSA significantly correlated with BAA [−5/−7]proPSA %area (rho=0.40, p=0.002) and BAA [−5/−7]proPSA stain intensity (rho=0.33, p=0.016).
Conclusions
In a prospective cohort of men enrolled into EM for PCa, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment. The increase in serum proPSA/%fPSA might be driven by increased proPSA production from “pre-malignant” cells in the prostate BAA.
doi:10.1158/1078-0432.CCR-09-1263
PMCID: PMC2787812  PMID: 19934305
Prostate cancer; expectant management; proPSA; serum; benign-adjacent; cancer; unfavorable biopsy conversion; prediction
24.  Evaluation of molecular forms of PSA and human kallikrein 2 in predicting biochemical failure following radical prostatectomy 
Most pretreatment risk-assessment models to predict biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer rely on total prostate-specific antigen (PSA), clinical stage, and biopsy Gleason grade. We investigated whether free PSA (fPSA) and human glandular kallikrein-2 (hK2) would enhance the predictive accuracy of this standard model. Preoperative serum samples and complete clinical data were available for 1,382 patients who underwent RP for localized prostate cancer from 1993 − 2005. A case-control design was utilized, and conditional logistic regression models were used to evaluate the association between preoperative predictors and BCR after RP. We constructed multivariable models with fPSA and hK2 as additional preoperative predictors to the base model. Predictive accuracy was assessed with the area under the ROC curve (AUC). There were 146 BCR cases; the median follow up for patients without BCR was 3.2 years. Overall, 436 controls were matched to 146 BCR cases. The AUC of the base model was 0.786 in the entire cohort; adding free PSA and hK2 to this model enhanced the AUC to 0.798 (p=0.053), an effect largely driven by free PSA. In the subgroup of men with tPSA ≤10 ng/ml (48% of cases), adding free PSA and hK2 enhanced the AUC of the base model to a similar degree (from 0.720 to 0.726, p=0.2). Free PSA is routinely measured during prostate cancer detection. We suggest that the role of fPSA in aiding preoperative prediction should be investigated in further cohorts.
doi:10.1002/ijc.23983
PMCID: PMC2776773  PMID: 19003994
free PSA; PSA; human kallikrein 2; prostate cancer; biochemical recurrence; radical prostatectomy
25.  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

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