tPSA Assays Research Articles

Discordant prostate specific antigen test results despite WHO assay standardization.

Total PSA (tPSA) and free PSA (fPSA) are the most commonly used biomarkers for early detection of prostate cancer. Despite standardization efforts, many available PSA assays may still produce discordant results. In the present study, we compared four PSA assays calibrated to the WHO standards 96/670 and 96/668 for tPSA and fPSA, respectively. Within the scope of the Prostate Cancer Early Detection Study Based on a ''Baseline'' PSA Value in Young Men (PROBASE), we tested tPSA and fPSA in serum samples from 50 patients in the four different PROBASE sites using four WHO-calibrated assays from Roche (Elecsys, Cobas), Beckman-Coulter (Access-II) and Siemens (ADVIA Centaur). The comparison was performed using the Passing-Bablok regression method. Compared to Access, the median tPSA levels for Centaur, Elecsys, and Cobas were +3%, +11%-20%, and +17%-23%, respectively, while for median fPSA levels the differences for Centaur, Elecsys, and Cobas were +49%, +29%-31%, and +22%, respectively. Despite all investigated assays being WHO-calibrated, the Elecsys and Cobas tPSA assays produced considerably higher results than the Access and Centaur assays. Differences in fPSA-recovery between all investigated assays were even more pronounced. When applying the tPSA cutoff of 3.1 μg/L recommended for WHO-calibrated assays, the use of higher calibrated assays may lead to unnecessary prostate biopsies. Conversely, if the historical threshold of 4 μg/L is applied when using WHO-calibrated assays, it could lead to falsely omitted prostate biopsies.

Assessing the necessity of including a crossover period with dual reporting when changing total prostate-specific antigen methods

ObjectivesOptions are limited for the laboratory when changing analytical methods for tumor markers. Standardization between methods should alleviate this burden. Our objective was to assess the necessity of dual reporting for total prostate-specific antigen (tPSA) when changing methods that have been calibrated against the World Health Organization PSA reference material. Design and methodsFollowing an initial validation where 40 patient samples were divided and analyzed on the Roche E-modular (current method) and Abbott ARCHITECT (new method) for tPSA, a crossover period ensued with dual reporting of tPSA over 54days (n=1110 samples with both tPSA results reported). Passing & Bablok regression was performed, with agreement during the crossover period also determined by two methods. Method#1: if the percent difference between the result pair was ≤0.33×the intraindividual biological variation (0.33×CVi=6.0%) for tPSA; and Method#2: if the Roche tPSA result was within an acceptable analytical range based on Abbott's maximum allowable imprecision for the tPSA assay (CV≤8%) to determine if there was a range of optimal agreement that might not require dual reporting. ResultsDuring the crossover period, Passing & Bablok regression yielded the following relationship: Abbott tPSA=1.04(95% CI: 1.03 to 1.04)×(Roche tPSA)−0.02(95% CI: −0.03 to −0.02). Only 52% (95%CI: 49 to55) of the results were in agreement by Method#1 whereas 95% (95% CI: 92 to 97) of the results between 3.3 and 19μg/L were found to have acceptable agreement based on Method#2. ConclusionsThese findings suggest that dual reporting of tPSA is required when changing methods. However, the extent of dual reporting may be limited to specific concentration ranges with future studies required to validate selective dual reporting when changing tPSA assays.

Analytical performance of a new one-step quantitative prostate-specific antigen assay, the FREND™ PSA Plus

We evaluated the analytical performance of a new one-step rapid quantitative sandwich immunoassay for total prostate-specific antigen (tPSA), the FREND™ PSA Plus (FREND PSA) (NanoEnTek Inc., Seoul, Korea). The imprecision, linearity, hook effect, detection limit (LoD), and interference were evaluated and trueness verification and matrix validation were performed. For method comparison, 79 patient specimens were analyzed with FREND PSA and two comparative tPSA assays (Architect® total PSA and cobas® total PSA assay). Total CVs of the imprecision for low (0.208 ng/mL), medium (4.051 ng/mL), and high PSA levels (5.469 ng/mL) were 15.9%, 6.4%, and 9.1%, respectively. Linearity was observed from 1.01 to 19.15 ng/mL and the hook phenomenon was absent up to 171.48 ng/mL. The LoD was 0.094 ng/mL. The regression equations between FREND (y) and Architect or cobas were as follows: y=0.0133+1.054x (r=0.973), y=-0.2144+1.066x (r=0.977), respectively. Differences between FREND PSA and the comparative methods at a medical decision level of 4.0 ng/mL were less than the optimum specification bias (9.3%). The percentage biases from the trueness verification and interference test were less than the desirable specifications for bias (18.7%). The plasma tPSA level measured with lithium heparin or K2EDTA was comparable to that in the serum. The FREND PSA provided reliable analytical performance and test results in comparison to two widely used tPSA assays. It is a simple and rapid test for tPSA and can be applied in point-of-care testing.

Standardization of assay methods reduces variability of total PSA measurements: an Irish study

What's known on the subject? and What does the study add? Today, numerous assays for PSA detection are available from various manufacturers. However, these various assays do not detect PSA equally and several studies have demonstrated variability between them. In order to harmonise PSA results and reduce the discrepancies, reference materials are available for assay calibration. We have demonstrated significantly variability between 6 different assay methods currently in use in 9 hospitals despite assay calibration. Variability in PSA values was reduced with the standardisation of the assay method in 4 hospitals. Our results highlight the dilemma of PSA assay variability and stress the need for nationwide standardisation of PSA testing. To determine whether standardization of total prostate-specific antigen (tPSA) assay methods reduces variability in tPSA measurements. Blood samples from 84 patients attending a single urology department were distributed across nine hospitals selected throughout Ireland for the independent determination of tPSA under the same conditions. The selected hospitals collectively used six different assay methods for tPSA detection: Beckman Hybritech WHO Calibrated (used as reference method), Tosoh AIA 1800, Roche E170 (used in three hospitals), Abbott AxSYM, Immulite 2500 2nd Generation (used in two hospitals) and Siemens ADVIA Centaur. The method of tPSA detection was next standardized in a subset of four hospitals using the same assay method and the measurements were repeated. The difference in mean tPSA in the cohort across the hospitals tested was determined and the Bland-Altman test was used to assess the agreement between each test. Analysis was performed over both the full (0.5-30 µg/L, N = 84) and a narrow (3-7 µg/L, n = 25) tPSA range. The range and the mean tPSA of the full cohort were inflated across the eight test hospitals, when compared with the reference hospital. The poorest agreement between assay methods was associated with a bias of 2.2 ± 2.4 µg/L. The variability in tPSA measurements between assay methods was inconsistent across the range of tPSA values tested and increased with increasing mean tPSA. Agreement in reported tPSA was excellent after standardization of tPSA assay methods (bias <0.2 µg/L). Over the narrow 3-7 µg/L PSA range, 12/25 (48%) patients had a tPSA range of values across all hospitals in excess of 2 µg/L. Following standardization of the tPSA assay method, patient tPSA ranges were <0.5 µg/L for 13/25 (52%) patients. We have shown that the lack of standardization of tPSA assay methods across a panel of Irish hospitals leads to significant variability in the measured tPSA values for the same patient samples. Variability in tPSA values was reduced with the standardization of the assay method in four hospitals. Standardization of PSA testing on a nationwide scale is warranted.

Prostate cancer screening: clinical impact of WHO calibration of Beckman Coulter Access® prostate-specific antigen assays

The goal of this study was to evaluate the clinical impact of using the same total prostate-specific antigen (tPSA) and free PSA (fPSA) assays calibrated with World Health Organization (WHO) materials or with Hybritech Tandem-R calibrator. From the initial correlation study that included 150 patients, the clinical impact of the WHO calibration was simulated using a large cohort (n=4548) of referred patients. Interim reports of the European Study of Screening for Prostate Cancer (ERSPC) were used to evaluate the clinical outcomes of patients and the risk of prostate cancer (PCa). WHO calibration of tPSA assays leads to a reduction of about 20% in measured results (tPSA WHO=0.81 tPSA Hybritech+0.04; fPSA WHO=0.78 fPSA Hybritech+0.00; %fPSA WHO=0.92 %fPSA Hybritech+0.00). The simulation showed that the WHO calibration is associated with a risk of missing 15% of PCa. The discrepancies between the two calibrations lead to significant clinical misinterpretation with decreased detection of PCa if tPSA cut-off thresholds are not adjusted.

Clinical Impact of New Prostate-Specific Antigen WHO Standardization on Biopsy Rates and Cancer Detection

Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection. tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 microg/L. A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 microg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 microg/L, respectively). Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary.

Different prostate-specific antigen assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies: Stephan C, Kramer J, Meyer HA, Kristiansen G, Ziemer S, Deger S, Lein M, Loening SA, Jung K, Department of Urology, Charité Universitätsmedizin Berlin, CCM, Germany

To show the effect of different results for total prostate specific antigen (tPSA) and percentage free/total PSA (%fPSA) obtained with different assays for differentiating between benign and malignant prostate diseases. Data were used for tPSA and fPSA levels from 596 patients with prostate cancer (314) or no evidence of cancer (282) within the PSA range 0.5–10 ng/ml, analyzed with assays from Abbott (AxSYM), Beckman Coulter (Access), DPC (Immulite 2000), and Roche (Elecsys 2010), and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur), as already reported. Receiver operating characteristics (ROC), specificities at assay-dependent and fixed thresholds, and the percentages of correct classification rates of patients were calculated. Whereas the areas under the ROC curves were no different among all tPSA assays, the assay-specific thresholds at 90% sensitivity were 2.5 to 3.1 ng/ml. When using fixed 2.5 or 4 ng/ml tPSA thresholds there was a wide sensitivity range, with significant differences among almost all assays, resulting in significantly different classification rates of patients. These differences were even larger when using fixed %fPSA thresholds. The current situation of differences among PSA values measured with different assays do not allow the recommendation of uniform PSA limits as biopsy criteria. For that purpose, better harmonization of PSA values between the different PSA test systems must be realized.

Different prostate‐specific antigen assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies

To show the effect of different results for total prostate specific antigen (tPSA) and percentage free/total PSA (%fPSA) obtained with different assays for differentiating between benign and malignant prostate diseases. Data were used for tPSA and fPSA levels from 596 patients with prostate cancer (314) or no evidence of cancer (282) within the PSA range 0.5-10 ng/mL, analysed with assays from Abbott (AxSYM), Beckman Coulter (Access), DPC (Immulite 2000), and Roche (Elecsys 2010), and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur), as already reported. Receiver operating characteristics (ROC), specificities at assay-dependent and fixed thresholds, and the percentages of correct classification rates of patients were calculated. Whereas the areas under the ROC curves were no different among all tPSA assays, the assay-specific thresholds at 90% sensitivity were 2.5-3.1 ng/mL. When using fixed 2.5 or 4 ng/mL tPSA thresholds there was a wide sensitivity range, with significant differences among almost all assays, resulting in significantly different classification rates of patients. These differences were even larger when using fixed %fPSA thresholds. The current situation of differences among PSA values measured with different assays do not allow the recommendation of uniform PSA limits as biopsy criteria. For that purpose, better harmonization of PSA values between the different PSA test systems must be realized.

Comparison of Total Prostate-Specific Antigen and Derivative Levels in a Screening Population of Black, White, and Korean-American Men

Numerous studies have assessed serum total PSA (tPSA) levels among different races. We extended the serum biomarker profiling using prostate-specific antigen (PSA) derivatives in age-matched screening populations that included white, black, and Korean-American patients. The median ages were 61 years for white and black patients and 63 years for Korean-American patients. Serum samples from 70 men in each ethnic group were analyzed using 3 different tPSA assays (Tosoh AIA 600II, Bayer Immuno-1, Roche Elecsys 2010). The percentage of free PSA (fPSA) was measured directly by Roche Elecsys 2010 immunoassay and then calculated from complexed PSA (cPSA) and tPSA results determined with the Bayer Immuno-1. The percentage of cPSA was determined using cPSA and tPSA assayed by the Immuno-1 method. Statistical analyses included nonparametric Kruskal-Wallis and analysis of variance (ANOVA) evaluations. There were no differences noted in the tPSA values based on ANOVA among the 3 races irrespective of the assay platform methodology employed. Also, the PSA derivatives, percentages of fPSA and cPSA, evaluated using the Kruskal-Wallis test, showed no significant differences for either derivative assayed on 2 different assay platforms among the 3 groups. In a contemporary screening population comparing tPSA, percentage of fPSA, and percentage of cPSA levels in 3 races, there were no significant differences identified among the groups.

Impact of age on complexed PSA levels in men with total PSA levels of up to 20 ng/mL

Objectives To evaluate the relationship between age and complexed prostate-specific antigen (cPSA) in healthy white men with no evidence of prostatic disease and total PSA (tPSA) levels of 0 to 20 ng/mL. Methods A total of 10,530 tests for cPSA and tPSA in men between 40 and 79 years old were performed at Innsbruck University, Austria, between 2001 and 2002. After excluding 263 patients because of follow-up biopsy findings indicating prostatic disease, 10,267 PSA tests were available for study. All serum samples were analyzed using the Bayer Immuno 1 cPSA and tPSA assays. cPSA and tPSA values were determined in subjects with tPSA levels between 0 and 20 ng/mL. The concentrations were calculated for the 50th, 90th, and 95th percentiles of four age groups (40 to 49, 50 to 59, 60 to 69, and 70 to 79 years). For statistical analysis, the Kruskal-Wallis test was used. The 95th percentile was defined as the upper limit of normal. Results A total of 10,267 PSA tests were available for study. cPSA and tPSA levels correlated linearly and positively with age ( P <0.001). Percent free PSA showed a significant increase with age ( P <0.001), which may be attributed to the increase in prostate volume with advancing age. Conclusions Both cPSA and tPSA levels were found to increase with age. The low tPSA and cPSA levels observed at the 95th percentile in men aged 40 to 59 years suggest that lower cutoff values should be used in place of the currently accepted tPSA level of 4 ng/mL. Lower cutoff values may help improve the detection of prostate cancer among otherwise healthy men.

Increased discrimination between benign prostatic hyperplasia and prostate cancer with equimolar total prostate specific antigen measurement

Although prostate specific antigen (PSA) is widely used in the discrimination of benign prostatic hyperplasia (BPH) and prostate cancer, its diagnostic value is controversial due to an appreciable false positive rate. In the present study, we compared a recently introduced assay method, equimolar PSA measurement, to non-equimolar PSA measurement and also determined the diagnostic value of percent free PSA with changing total PSA (tPSA) measurements. Between April 1999 and December 2001, the sera of 61 patients with BPH and 41 with prostate cancer were examined. Total PSA and free PSA was determined using the Immulite 2000 assay system, whereas equimolar tPSA measurement was performed using Bayer PSA Q for the Chiron ACS 180 system. Comparative analysis of the two different assays revealed better diagnostic sensitivity and specificity values for equimolar tPSA measurement, which in turn would have led to 10% of the patients avoiding an unnecessary biopsy. Additionally, percent free PSA with the changing denominator of tPSA assays showed that the free PSA/equimolar tPSA ratio was the best tumor marker among the studied forms of PSA. It was concluded that equimolar tPSA measurement using recombinant Fab fragments is superior to the classical measurements with monoclonal antibodies, and that the use of percent free PSA with the equimolarly measured tPSA has better sensitivity and specificity in the discrimination of benign and malignant diseases of the prostate.

Combining free and total prostate specific antigen assays from different manufacturers: the pitfalls.

We investigated the impact of interchanging free prostate specific antigen (f-PSA) concentrations from 10 different assays over a reference total PSA (t-PSA) on predicting prostate histology with free-to-total PSA ratios (f/t-PSA). Archival sera from 80 t-PSA- and age-matched pairs of histologically confirmed prostate cancer (PCA) and benign prostatic hyperplasia (BPH) patients with t-PSA levels between 2 and 25 microg/l were investigated. Serum aliquots were analyzed for t- and f-PSA using a reference method (Access, Beckmann-Coulter Hybritech) and 10 commercially available f-PSA assays. Passing Bablok and linear regression were performed to investigate the interassay agreement between f-PSA assays. To compare diagnostic performance, ROC curves for PCA detection were calculated for the 10 f/t-PSA combinations using the reference t-PSA as denominator. Sensitivities, specificities and f/t-PSA cut-offs were calculated for varying points of the ROC curve. Despite good correlation of all 10 f-PSA assays with the reference method 4 showed significantly lower mean f-PSA levels. For f/t-PSA as a predictor of prostate histology, areas under the ROC curve (AUC) varied between 0.65 and 0.71 and, if compared to the reference method (AUC=0.70), were significantly lower in three cases. Ensuring 80% specificity, sensitivities ranged between 34% and 54% (reference method: 53%) and f/t-PSA cutpoints differed considerably depending on the f-PSA assay used (range: 0.15-0.24; reference: 0.15). Similar variations were noted at 95% specificity and 80% and 95% sensitivity. Arbitrary combinations of f- and t-PSA assays should not be used to calculate f/t-PSA ratios unless adequate studies have validated the diagnostic performance and cut-offs of that particular assay choice.

Evaluation of the clinical performance of equimolar- and skewed-response total prostate-specific antigen assays versus complexed and free PSA assays and their ratios in discriminating between benign prostatic hyperplasia and prostate cancer

Background: Prostate-specific antigen (PSA) exists in human serum in two principal forms, free PSA (fPSA) and protein-complexed PSA, predominantly PSA-ACT (α 1-antichymotrypsin). Equimolar response (EMR) total PSA (tPSA) immunoassays measure each of these forms equally while skewed-response (SKR) assays overestimate or underestimate the tPSA concentration. The advantages of EMR over SKR tPSA assays are controversial. Methods: We used five nonhuman serum-based samples each containing a different proportion of fSPA:PSA-ACT (0:100 to 100:0, %:%) and patients' serum samples from men with histologically confirmed benign prostatic hyperplasia (BPH) ( n=94) or PCA ( n=30) and a wide range of fPSA concentrations to investigate the molar response status of six tPSA assays. Receiver–operator characteristic (ROC) curve analysis was used to compare the discriminatory power of these assays in distinguishing men with BPH from those with PCA. Results: The Bayer Immuno-1 tPSA (BtPSA) assay demonstrated EMR characteristics and diagnostic accuracy similar to the Hybritech Tandem-E and Tandem-R tPSA assays. At 90% sensitivity, EMR tPSA assays had higher specificity than SKR tPSA assays. Conclusions: The BtPSA assay is an EMR tPSA assay and EMR assays provide improved diagnostic specificity over SKR tPSA assays.

Complexed prostate-specific antigen as a staging tool: results based on a multicenter prospective evaluation of complexed prostate-specific antigen in cancer diagnosis

Within a 7-site prospective evaluation of the Bayer complexed prostate-specific antigen PSA (cPSA) assay, we analyzed the ability of cPSA to predict extracapsular extension (ECE) before radical prostatectomy. Included in this analysis were 152 men diagnosed with cancer, who subsequently underwent radical prostatectomy. Sera were tested with the Bayer total PSA (tPSA) and cPSA assays, and the Beckman free PSA (fPSA) and tPSA assays. Treating surgical pathology result as a binary variable (organ confined vs ECE), mean tPSA, cPSA, fPSA/tPSA (f/tPSA) ratios, tPSA density (tPSAD), and cPSA density (cPSAD) were compared by receiver operating characteristic (ROC) curves and univariate analysis. In all, 28 men (18.4%) had pathologically identified ECE. Between those with and without ECE, significant differences were observed for tPSA ( P = 0.0127), cPSA ( P = 0.0120), tPSAD ( P = 0.0001), and cPSAD ( P = 0.0002), but not f/tPSA ( P = 0.3774) or c/tPSA ( P = 0.2882). All tested parameters except f/tPSA ( P = 0.376) and c/tPSA ( P = 0.288) predicted ECE ( P <0.05) by logistic regression. The ROC area under the curve (AUC) was identical for tPSA and cPSA (0.621) and for tPSAD (0.692) and cPSAD (0.691). Kendall-τ correlation coefficients also demonstrated the strongest correlation with ECE for cPSAD and tPSAD. Either alone or as a tPSAD calculation, cPSA carries equivalent staging ability to tPSA. The use of f/tPSA appears to be less effective in staging than either cPSA or tPSA, whereas the use of either cPSAD or tPSAD provides maximal staging accuracy. Therefore, cPSA could be applied as an accurate predictor of ECE independently or in a nomogram along with other predictive variables.

Complexed prostate-specific antigen for early detection of prostate cancer in men with serum prostate-specific antigen levels of 2 to 4 nanograms per milliliter

Complexed PSA (cPSA) has been shown to improve specificity in the detection of prostate cancer over that of total PSA (tPSA) testing in men with tPSA values greater than the cutoff value of 4.0 ng/mL. However, recent studies have reported a 25% incidence of prostate cancer in men with tPSA values in the 2.5- to 4.0-ng/mL range. We performed a multicenter study of cPSA in a population of men who underwent prostate biopsies because of elevated PSA levels or abnormal digital rectal examination (DRE). As part of this study, we sought to assess the clinical value of cPSA in comparison to tPSA, the free/tPSA ratio (f/tPSA) and the complexed/tPSA ratio (c/tPSA) in early detection of prostate cancer in men with tPSA values in the range of 2 to 4 ng/mL. The study was performed at 7 centers. Sera were drawn from men who underwent biopsy procedures consisting of >10 prostate tissue cores. Receiver operating characteristic (ROC) analysis was performed from the results of patients with tPSA values in the range of 2 to 4 ng/mL, including men with suspicious as well as unremarkable findings on DRE. Sera were collected and tested with the Bayer tPSA and cPSA assay and the Beckman free PSA and tPSA assays. ROC analysis was performed for all samples in the 2- to 4-ng/mL PSA range. At biopsy, 158 men had no evidence of malignancy and 57 (26.5%) were diagnosed with prostate cancer. ROC analysis indicated that the area under the curve (AUC) for cPSA was 0.64, which was statistically significantly greater than that achieved for tPSA (AUC, 0.57; P <0.0001). The AUC for f/tPSA and c/tPSA were 0.60 and 0.63, respectively, which was not statistically significantly different from that of tPSA or cPSA ( P ≥0.252). A cutpoint of 2.5 ng/mL for tPSA and 2.1 ng/mL for cPSA provided a specificity of 20.3% and 34.2%, respectively, and sensitivity levels of 86%. Using cutpoints of 25% for f/tPSA and 74% for c/tPSA provided a specificity of 11.0% and 21.5%, respectively, and sensitivity levels of 97%. In all, >92% of the cancers treated with radical prostatectomy were organ confined, and the histologic grading of the tumors ranged from moderately to poorly differentiated with Gleason scores from 5 to 9. These data confirm that there is a high incidence of clinically significant prostate cancer in men with tPSA levels <4.0 ng/mL. Measurement of cPSA proved useful in stratifying men with tPSA values in the 2- to 4-ng/mL range into high- and low-risk groups for prostate cancer. The use of cPSA as a single test was found to enhance detection of prostate cancer over that of testing with tPSA and PSA ratios in men with tPSA values in the range of 2 to 4 ng/mL.

The impact of intraoperative manipulation of the prostate on total and free prostate-specific antigen.

It is well documented that mechanical manipulation of the prostate can elevate total PSA (t-PSA) levels in serum. However, less is known about its effects on free PSA (f-PSA) and the free-to-total PSA ratio (f/t-PSA). We therefore examined the impact of prostate manipulation on t-PSA and f-PSA during surgical procedures involving the prostate. Intraoperative blood samples for t-PSA and f-PSA measurement (Hybritech) were collected every 15 min during 14 radical retropubic prostatectomies (RRP) and 10 radical cystoprostatectomies (RCP). Prostatic manipulation induced significant elevations in t-PSA and f-PSA during RRP and RCP. Postmanipulatory peaks were markedly higher for f-PSA than for t-PSA. The mean maximum f-PSA levels showed a 4.3- (RRP) and 7.9-fold (RCP) increase, followed by a rapid decline after prostate removal. t-PSA increased 1.2- (RRP) and 1.3-fold (RCP), and declined more slowly. Postmanipulatory f/t-PSA ratios also increased significantly, reaching mean elevations of +0.29 and +0.28 over preoperative ratios during RRP and RCP, respectively. Prostate manipulation can induce transient increases in t-PSA, f-PSA and f/t-PSA in benign and malignant prostates. The extent of these alterations and their course over time must be taken into account when postmanipulatory changes in PSA forms are investigated. Timing of postmanipulatory venipunctures and the molar response ratio of t-PSA assays used (equimolar versus nonequimolar) seem to have substantial impact on the results of such studies.

Comparative Analysis of the Role of Prostate Specific Antigen Parameters in Clinical Practice

Introduction: Serum prostate specific antigen at the cutoff levels of 4 ng/ml has low specificity for prostate cancer. We evaluated various PSA parameters (i.e., total PSA density [tPSAD], free PSA density [fPSAD], the ratio of free to total PSA [f/t ratio], and age-specific PSA) in terms of cancer diagnosis and reducing the number of negative results for prostatic biopsies. Materials and Methods: A series of 305 patients was studied. Serum tPSA and fPSA levels were measured. Prostate volume was measured with transrectal ultrasound, and sextant biopsies were performed. The f/t ratio, tPSAD, and fPSAD were calculated. Sensitivity and specificity were calculated for age-specific PSA. Receiver operating characteristic curve analysis was used to analyze the diagnostic performance of these PSA parameters. A subpopulation of patients with serum PSA levels between 4 and 10 ng/ml also was analyzed with a specific view to reducing negative results of biopsies. The Mann-Whitney U test was used to analyze the difference in these parameters between patients with benign and malignant histologies. Results: There was significant difference in these PSA parameters between patients with benign and malignant histologies (p < 0.05). tPSAD had the largest area under the curve for total population as well as for patients with tPSA levels between 4 and 10 ng/ml. Although the f/t ratio had a larger area under the curve than did tPSA assay in patients with PSA levels between 4 and 10 ng/ml, the difference was not statistically significant. Using a tPSAD of 0.12 ng/ml/ml as the cutoff level of negative results of prostate biopsies could be reduced by 37% in patients with PSA levels between 4 and 10 ng/ml. Although the f/t ratio could reduce negative results of biopsies by 33.8% at the cutoff value of 0.26, 15.6% of cancers would be missed. Age-specific PSA could reduce 31% of negative prostatic biopsies, but 28% of cancers would be missed. Using combined tPSAD and the f/t ratio did not improve reductions of negative biopsy results. Conclusion: tPSA density has the highest sensitivity and specificity in differentiating benign from malignant prostates. By using tPSA density, negative results of prostate biopsies can be reduced by 37%, while missing only a small number of cancers.

Prostate-specific antigen ratio correlates with aggressiveness of histology grades of prostate cancer

Objectives: To compare prostate-specific antigen (PSA) ratio to total PSA (tPSA) assay for prostate cancer diagnosis and to study the correlation of PSA ratio with histology grade of prostate cancer. Methods: Among 334 selected cases, 136 had benign prostate diseases and 198 had prostate cancer. All cases underwent transrectal ultrasound (TRUS) and tissue biopsies within 6 months of their tPSA measurements. All of the tPSA levels taken were between 2 and 20 μg/L. The serum tPSA and free PSA were assayed using the Abbott AxSYM immunoassay system (Abbott Laboratories; Abbott Park, IL, USA). The PSA ratios of patients with prostate cancer were compared to those with benign prostate diseases (BPD) using the Student’s t test. Correlation between the histology grades and PSA ratios was calculated by Pearson test. Receiver operating characteristic (ROC) curves were generated from sensitivities and specificity of various PSA ratios and tPSA levels. Results: We found an inverse correlation between PSA ratios and aggressiveness of histology grades ( r = −0.995, p < 0.01). The higher the histology grade, the lower the PSA ratio tended to be, and the more sensitive and specific the PSA ratio was in the diagnosis of prostate cancer. No correlation was found between histology grades and tPSA levels. A PSA ratio of 0.25 diagnosed 93% of patients with Gleason score greater than 7 and 83% of all prostate cancer patients. It would have reduced unnecessary biopsies by 23% compared to the tPSA level of 4 μg/L. Sensitivity of PSA ratios was higher and specificity was lower in high tPSA level group than they were in low tPSA level group. Conclusions: PSA ratio inversely correlates to aggressiveness of prostate cancer and has a potential to predict histology grade of prostate cancer. PSA ratio improves sensitivity and specificity for prostate cancer diagnosis compared to tPSA assay.

Free/total prostate-specific antigen ratio can prevent unnecessary prostate biopsies

Objectives. To evaluate the ability of free/total prostate-specific antigen (PSA) ratio to improve specificity of prostate cancer detection, compare Diagnostic Products Corporation (DPC) Immulite and Ciba Corning ACS 180 total (t)PSA assay, and define an assay-specific cutoff point and reflex range for DPC PSA ratio (PSAR). Methods. In a prospective study, 206 men were enrolled with measurement of both assays. Group 1 consisted of 173 men with a suspicion of prostate cancer (PCA). Thirteen men with known PCA (group 2) and 20 men younger than 32 years (group 3) were used as control groups. Results. Our results in group 1 (115 with benign prostatic hyperplasia [BPH], 58 with PCA) revealed a sensitivity of 82.7%, a specificity of 45.2%, and an accuracy of 57.8% for the DPC tPSA assay (cutoff point more than 4.0 ng/mL) within the entire PSA range. tPSA values of the ACS 180 assay were 1.97-fold higher. Within the tPSA gray zone of 2.5 to 10 ng/mL (66 BPH, 23 PCA), specificity and accuracy of DPC tPSA can be improved by using the DPC PSAR (cutoff point less than 19%) from 33.3% to 71.2% and 42.7% to 70.8%, respectively, maintaining the same sensitivity level of 69.6%. Conclusions. By combining tPSA testing with PSAR within the gray zone, 39.7% (25 of 63) of unnecessary biopsies can be saved, without missing any additional cancers compared with tPSA testing alone. The optimal reflex range for DPC PSAR is 2.5 to 10 ng/mL and the best PSAR cutoff point for biopsy criterion is less than 19% in our high-risk population, with a cancer yield of 34%. Because we still do not have an international PSA standard, it is important to use assay-specific “normal values” and PSAR cutoff points.

Advantages of replacing the total PSA assay with the assay for PSA-alpha 1-antichymotrypsin complex for the screening and management of prostate cancer.

Several advantages become immediately apparent when the prostate specific antigen (PSA, or tPSA) assay is replaced by the assay specific for the serum PSA-alpha 1-antichymotrypsin (PSA-ACT) complex. For instance, random contributions to the tPSA value by various serum minor PSA isoforms can be avoided, making possible the determination of a more accurate relation of the PSA-ACT concentration to the tumor activity. Discrepancies in percent free PSA (% fPSA) values from the same specimens due to the use of different commercial kits also can be eliminated, mainly because the PSA-ACT assay does not have the problems in antibody selection and calibrator preparation usually associated with the tPSA assay. We found that at the present time different cutoffs of % fPSA for the differentiation of BPH from prostate cancer must be established for each individual tPSA assay. Cutoffs established using values from one tPSA assay should not be used for making clinical decisions when their tPSA values are determined by a different kit. Moreover, when we monitored the patients during treatment with serum tPSA, specific fPSA, and specific PSA-ACT complex assays simultaneously, it was clear that any interpretation of the patient's clinical status based on tPSA values alone could be misleading. Because there is less PSA-ACT complex in BPH specimens relative to that found in cancer serum samples, expressing fPSA as "fPSA/PSA-ACT x 100" and measuring PSA-ACT complex concentrations instead of tPSA during screening improve the measurable contrast between BPH and prostate cancer. Although individually modest, collectively these advantages can add up to considerable improvements.