Early detection of prostate cancer in African-American men through use of multiple biomarkers: human kallikrein 2 (hK2), prostate-specific antigen (PSA), and free PSA (fPSA)

Recent studies have reported enhanced prostate cancer detection in Caucasians with serum human glandular kallikrein 2 (hK2) in combination with total- (tPSA) and free-prostate-specific antigen (fPSA). The purpose of this study is to validate these findings in an African-American patient cohort. A total of 137 African-American men were found by routine screening to have tPSA levels above 2.5 ng/ml or an abnormal digital rectal examination. Sera were drawn prior to biopsy of the prostate and Hybritech PSA, FPSA and hK2 (for research use only, not for use in diagnostic procedures) concentrations were determined on Beckman Coulter's Access immunoanalyzer. These independent variables and the ratios of percent fPSA (%fPSA), hK2/tPSA, hK2/fPSA, and hK2*tPSA/fPSA were compared between cancer and non-cancer groups. In all, 49 of 137 men had prostate cancer. hK2 and its calculated ratios outperformed tPSA on receiver operator characteristic (ROC) analysis, but %fPSA had statistically the highest area under the curve (AUC) at 0.801. When restricting the analysis to only the tPSA range of 4.0-10 ng/ml, hK2/fPSA yielded the highest AUC (0.721). The ratio of hK2/fPSA was also found to increase the positive predictive value (PPV) of the %fPSA ranges less than 10 and 10-25%. %fPSA offered the best performance and highest specificity in prostate cancer detection in African-American males over the entire range of tPSA. hK2/fPSA may offer modest improvement in the tPSA range of 4.0-10 ng/ml. Furthermore, hK2/fPSA can enhance the PPV of low %fPSA values. Therefore, the use of multiple biomarkers may ultimately increase the specificity of prostate cancer screening in African-American men.     

Percent-free prostate specific antigen is elevated in men on haemodialysis or peritoneal dialysis treatment.

BACKGROUND: Men with chronic renal failure evaluated for transplantation are often tested for prostate specific antigen (PSA) to detect prostate cancer. PSA occurs in several 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 to tPSA (%fPSA) is widely used to enhance discrimination of benign disorders from prostate cancer. The low molecular mass of fPSA suggests elimination by renal glomerular filtration and that renal failure may significantly influence %fPSA. We evaluated whether established reference levels for %fPSA are applicable also to patients treated with haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). METHODS: The study included 20 men on intermittent haemodialysis with low-flux membranes and 25 men on CAPD, without known history of prostate cancer. The control group included 3129 men without known prostate cancer. We analysed fPSA and tPSA in serum by dual-label immunofluorometric assays, from which we calculated %fPSA and cPSA. Serum levels of different PSA forms were adjusted for age and presented as geometric means. RESULTS :Percent fPSA was significantly higher in patients on either haemodialysis (39.5%) or CAPD (39.6%) compared with controls (28.1%). Haemodialysis patients, but not CAPD patients, had significantly higher mean levels of fPSA. Levels of tPSA and cPSA for haemodialysis or CAPD patients did not differ significantly compared with controls. CONCLUSIONS: Recommended reference ranges for %fPSA, based on men with normal renal function, do not apply to uraemic men on dialysis. In these men, a high %fPSA should not be considered as a sign of benign disease. This is clinically important in the evaluation of dialysis patients for transplantation, as %fPSA is often used as a tool for detection of prostate cancer.     

Contemporary use of complexed PSA and calculated percent free PSA for early detection of prostate cancer: impact of changing disease demographics

Objectives. To assess the diagnostic performance of complexed prostate-specific antigen (cPSA), total PSA (tPSA), and calculated free/total PSA (f/t PSA) ratios in the differentiation of benign disease from prostate cancer (CaP) using a contemporary patient cohort.Methods. The cPSA, tPSA, and calculated fPSA values were determined using the Bayer Immuno-1 system. To validate our calculated f/t PSA ratio, we also retrospectively measured fPSA using the Abbott AxSYM immunoassay system in archival pretreatment sera obtained between 1990 and 1997 from 362 men with clinically and biopsy-confirmed benign prostatic hyperplasia (n = 179) or CaP (n = 183). The diagnostic utility of tPSA, cPSA, and the calculated f/t PSA ratio was assessed using a contemporary test population consisting of sera prospectively collected between June 1999 and June 2000 from 3006 men who had recently undergone a systematic biopsy by urologists in clinical practices throughout the United States. This contemporary patient sample had biopsy diagnoses of either no evidence of malignancy (n = 1857) or CaP (n = 1149). All serum samples had tPSA values between 2.0 and 20.0 ng/mL.Results. The measured versus calculated f/t PSA ratios had a Pearson’s correlation coefficient of 0.9130 in the retrospectively studied population of 362 men. The areas under the receiver operating characteristic curves (ROC-AUCs) for the measured and calculated f/t PSA ratios were indistinguishable (69.6% versus 69.2%, respectively). In the contemporary population (n = 3006), the ROC-AUC for tPSA, cPSA, and the calculated f/t PSA ratio was 52.2%, 53.9%, and 58.4%, respectively. We also compared the diagnostic performance using published cutoffs for tPSA (greater than 4.0 ng/mL), cPSA (greater than 3.8 ng/mL), and the f/t PSA ratio (greater than 15% and greater than 25%) in tPSA reflex ranges of 2 to 20 ng/mL and 2 to 10 ng/mL. We found that both cPSA and the f/t PSA ratio (greater than 25% cutoff) outperformed tPSA and yielded similar results in terms of biopsies spared and cancers missed.Conclusions. The calculated f/t PSA ratio and cPSA perform equally well in terms of the improvement of specificity in the discrimination of benign disease and CaP. The f/t PSA ratio and cPSA provide clinical benefits over the use of tPSA alone, such as an increased sparing of unnecessary biopsies performed with a manageable degree of risk of delayed cancer detection.     

Utilidad del cociente psa-l/psa-t y la dpsa para la discriminación entre hipertrofia benigna de próstata y cáncer de próstata

objectiveTo investigate the clinical significance of the free-to-total prostate-specific antigen ratio (f/tPSA) and PSA density (PSAD) for prostate cancer detection in patients with intermediate tPSA levels (4-10 ng/ml). To establish a cutoff to discriminate between benign prostatic disease (BPH) and prostate cancer (CaP), avoiding unnecessary biopsiesMethodsThis prospective study included 136 men, aged between 54 and 85 (mean 70,6) years old. Urinary tract symptoms were present in these patients. Serum samples were obtained to measure tPSA, fPSA, and f/tPSA; digital rectal examination and transrectal ultrasound eight-sector biopsies were performed. Prostate volume was measured and PSAD calculated. The pathologic study, carried out in 113 patients, showed 82 with BPH and 31 with prostate cancer in various stagesResultsThere were no significant differences between patients with BPH and CaP when comparing tPSA, fPSA, f/tPSA or digital rectal examination. PSAD and prostate volume were significantly different in patients with BPH and CaP. With a sensitivity of 94% (78,5-99), the f/tPSA cutoff was 0,28 with a 11% (5,2-19,8) specificity. With a sensitivity of 96,2% (80,3-99,4) cutoff for PSAD was 0,109 and specificity 25% (15,5-36,6)ConclusionsIn patients whose tPSA level is between 4 and 10 ng/ml, f/tPSA has no advantages over tPSA measurement for early detection of prostate cancer. DPSA can improve specificities, without compromising the detection of CaP     

Effect of NIH-IV prostatitis on free and free-to-total PSA

OBJECTIVE: To examine the effect of asymptomatic prostatic inflammation (NIH category IV prostatitis) on total PSA (tPSA), free serum PSA (fPSA) and the ratio of free-to-total prostate specific antigen (%fPSA). The role of free and %fPSA as a diagnostic tool for distinguishing between cancer and non-malignant diseases of the prostate was also investigated. MATERIAL AND METHODS: In a retrospective study 1090 prostate biopsies performed between January 2000 and September 2003 were evaluated and the levels of serum total and free PSA as well as the f/tPSA ratio were determined in samples obtained immediately before biopsy. 404 patients with full clinical and histological records were included in the study. All patients underwent 6 or 8 core primary prostate needle biopsies. RESULTS: A total of 404 patients were included in the analysis. 100 prostate cancer (PCa) (24.8%), 137 NIH-IV prostatitis (33.9%) and 143 patients with benign prostatic hyperplasias (BPH) (35.4%) were identified. 24 (5.9%) patients presented with both PCa and prostatitis on histology and were excluded from further analysis. The mean (median) levels of tPSA, fPSA and %fPSA were 11.94 ng/ml (8.0), 1.31 ng/ml (1.07) and 0.15 (0.14) for NIH-IV prostatitis; 11.94 ng/ml (8.35), 1.54 ng/ml and 0.13 (0.11) for prostate cancer; and 8.19 ng/ml (7.0), 1.48 ng/ml (1.03) and 0.18 (0.15) for BPH. No significant difference was found in tPSA levels between PCa and prostatitis (p = 0.32), while the difference in tPSA levels between PCa and BPH was significant (p = 0.007). Free PSA alone had no diagnostic power in distinguishing PCa from prostatitis (p = 0. 37) and BPH (p = 0. 61). By contrast, the f/tPSA ratio showed significant between-group differences (PCa versus prostatitis (p = 0. 011), PCa versus BPH (p = 0.0001). CONCLUSIONS: Chronic asymptomatic prostatitis NIH category IV has similar effects on total PSA and free PSA levels in serum as PCa. fPSA alone cannot distinguish prostate cancer from non-malignant inflammatory disease of the prostate. The ratio of free-to-total PSA is significantly different in PCa and NIH category IV prostatitis.     

Outcome prediction for prostate cancer detection rate with artificial neural network (ANN) in daily routine

BackgroundWe evaluated the use of the artificial neural network (ANN) program “ProstataClass” of the Department of Urology and the Institute of Medical Informatics at the Charité-Universitätsmedizin Berlin in daily routine to increase prostate cancer (CaP) detection rate and to reduce unnecessary biopsies.Materials and methodsFrom May 2005 to April 2007, a total of 204 patients were included in the study. The Beckman Access PSA assay was used, and pretreatment prostate specific antigen (PSA) was measured prior to digital rectal examination (DRE) and 12 core systematic transrectal ultrasound (TRUS) guided biopsies. The individual ANN predictions were generated with the use of the ANN application for the Beckman Access PSA and free PSA assays, which relies on age, PSA, percent free prostate specific antigen (%fPSA), prostate volume, and DRE. Diagnostic validity of total prostate specific antigen (tPSA), %fPSA, and the ANN was evaluated by ROC curve analysis.ResultsPSA and %fPSA ranged from 4.01 to 9.91 ng/ml (median: 6.65) and 5% to 48% (median: 15%), respectively. Of all men, 46 (22.5%) demonstrated suspicious DRE findings. Total prostate volume ranged from 7.1 to 119.2 cc (median: 35). Overall, 71 (34.8%) CaP were detected. Of men with suspicious DRE, 28 (60.9%) had CaP on initial biopsy. The ANN was 78% accurate in the original report. The AUC of ROC curve analysis was 0.51 for PSA, 0.66 for %PSA, and 0.72 for the ANN-Output, respectively.ConclusionsOur results in this independent cohort show that ANN is a very helpful parameter in daily routine to increase the CaP detection rate and reduce unnecessary biopsies.     

Serum prostate-specific antigen levels (PSA) in men without clinical evidence of prostate cancer: age-specific reference ranges for total PSA, free PSA, and percent free PSA

Objectives. To investigate the relationship between age and total prostate-specific antigen (tPSA), free PSA (fPSA), and percent free PSA (%fPSA) in men 48 to 79 years old without clinical evidence of prostate cancer. We determined age-specific ranges for each parameter and compared the results with previously published studies in similar populations.Methods. Nine hundred eighty-three men (96% white) from the random-sample community-based Massachusetts Male Aging Study were analyzed. Men with PSA 4.1 ng/mL or greater were referred for biopsy and those with positive biopsies or with medical record, cancer registry, or self-reported evidence of prostate cancer were excluded.Results. The median tPSA increased 38.6% per decade (95% confidence interval 28.7% to 49.3%). Because of the greater variability at older ages, the 95th percentile increased faster than the median, leading to the following age-specific upper limits of normal: 2.84 for 50 to 59 years, 5.87 for 60 to 69 years, and 9.03 for 70 to 79 years. The pattern of association between fPSA and age was similar to tPSA. The 50th and 5th percentiles of %fPSA were 25.3% and 13.2%, respectively, regardless of age.Conclusions. Establishing age-specific screening cutoffs based on the age-specific upper limits of normal will ensure low false-positive biopsy rates but may also lead to low true positive rates (ie, low sensitivity) in older age groups. Both sensitivity and specificity should be considered when counseling patients. The independence of %fPSA with age confirms others’ findings.     

Derivatives of prostate‐specific antigen as predictors of incidental prostate cancer

OBJECTIVE

To search for an optimal derivative of prostate‐specific antigen (PSA) identifying patients at risk of incidental prostate cancer.

PATIENTS AND METHODS

In all, 693 patients who underwent transurethral resection of the prostate (TURP) with a normal digital rectal examination, no history of prostate cancer and a PSA level of 2.5–10 ng/mL were studied. The total PSA (tPSA), percentage of free/total PSA (%fPSA), complexed PSA (cPSA), PSA density, cPSA density and the ratio of fPSA to cPSA were measured. Specificity, sensitivity, positive and negative predictive values were determined for all possible threshold values indicating the risk of incidental prostate cancer (T1a or T1b). Furthermore, the patients were subdivided according to age and the presence of an indwelling transurethral catheter. The areas under the receiver operating characteristic curves (AUC) were compared.

RESULTS

In the whole sample, the %fPSA was the best test predicting all incidental prostate cancers (AUC 0.618, reference: tPSA 0.494), whereas cPSA density was the best predictor of T1b disease (AUC 0.720, reference: tPSA 0.548). Stratification by age did not meaningfully alter the results, the presence of a transurethral catheter, however, was associated with a superiority of tests based on fPSA (AUC 0.620–0.670) compared with tests based on tPSA or cPSA (AUC 0.421–0.581).

CONCLUSION

Replacing tPSA by PSA derivatives (%fPSA or cPSA density) and stratifying by the presence of an indwelling transurethral catheter may improve the prediction of the risk of incidental prostate cancer and spare unnecessary biopsies before TURP in the tPSA range 2.5–10 ng/mL.     

Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting

Background

Total prostate-specific antigen (tPSA), ratio of free PSA (fPSA) to tPSA (%fPSA), and PSA density (PSAD) testing have a very low accuracy in the detection of prostate cancer (PCa). There is an urgent need for more accurate biomarkers.

Objective

To compare the diagnostic accuracy of PSA isoform p2PSA and its derivatives in determining the presence of PCa at initial biopsy with the accuracy of other predictors in patients with tPSA 2.0-10 ng/ml.

Design, setting, and participants

We conducted an observational prospective study in a real clinical setting of consecutive men with tPSA 2.0-10 ng/ml and negative digital rectal examination who were scheduled for prostate biopsy at a tertiary academic center.

Intervention

Outpatient transrectal ultrasound-guided prostate biopsies were performed according to a standardized institutional saturation scheme (18-22 cores).

Measurements

We determined the diagnostic accuracy of serum tPSA, %fPSA, PSAD, p2PSA, %p2PSA [(p2PSA/fPSA) × 100] and the Beckman Coulter Prostate Health Index (phi; [p2PSA/fPSA × √tPSA]).

Results and limitations

Overall, 107 of 268 patients (39.9%) were diagnosed with PCa at extended prostate biopsies. Statistically significant differences between patients with and without PCa were observed for age, prostate and transition zone volume, PSAD, %p2PSA, and phi (all p values < 0.05). In univariate accuracy analysis, phi and %p2PSA were the most accurate predictors of PCa (area under the curve: 75.6% and 75.7%, respectively), followed by transition zone volume (66%), prostate volume (65%), patient age (63%), PSAD (61%), %fPSA (58%), and tPSA (53%). In multivariate accuracy analyses, both phi (+11%) and %p2PSA (+10%) significantly improved the accuracy of established predictors in determining the presence of PCa at biopsy (p < 0.001). Although %p2PSA and phi were significantly associated with Gleason score (Spearman ρ: 0.303 and 0.387, respectively; p ≤ 0.002), they did not improve the prediction of Gleason score ≥7 PCa in multivariable accuracy analyses (p > 0.05).

Conclusions

In patients with a tPSA between 2.0 and 10 ng/ml, %p2PSA and phi are the strongest predictors of PCa at initial extended biopsies and are significantly more accurate than the currently used tests (tPSA, %fPSA, and PSAD) in determining the presence of PCa at biopsy.     

An artificial neural network for five different assay systems of prostate-specific antigen in prostate cancer diagnostics

OBJECTIVE

To compare separate prostate‐specific antigen (PSA) assay‐specific artificial neural networks (ANN) for discrimination between patients with prostate cancer (PCa) and no evidence of malignancy (NEM).

PATIENTS AND METHODS

In 780 patients (455 with PCa, 325 with NEM) we measured total PSA (tPSA) and free PSA (fPSA) with five different 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). ANN models were developed with five input factors: tPSA, percentage free/total PSA (%fPSA), age, prostate volume and digital rectal examination status for each assay separately to examine two tPSA ranges of 0–10 and 10–27 ng/mL.

RESULTS

Compared with the median tPSA concentrations (range from 4.9 [Bayer] to 6.11 ng/mL [DPC]) and especially the median %fPSA values (range from 11.2 [DPC] to 17.4%[Abbott], for tPSA 0–10 ng/mL), the areas under the receiver operating characteristic curves (AUC) for all calculated ANN models did not significantly differ from each other. The AUC were: 0.894 (Abbott), 0.89 (Bayer), 0.895 (Beckman), 0.882 (DPC) and 0.892 (Roche). At 95% sensitivity the specificities were without significant differences, whereas the individual absolute ANN outputs differed markedly.

CONCLUSIONS

Despite only slight differences, PSA assay‐specific ANN models should be used to optimize the ANN outcome to reduce the number of unnecessary prostate biopsies. We further developed the ANN named ‘ProstataClass’ to provide clinicians with an easy to use tool in making their decision about follow‐up testing.     

Ⅳ型前列腺炎炎症分级和范围与前列腺特异性抗原之间的关系

目的:探讨Ⅳ型前列腺炎炎症组织病理学分级和范围与前列腺特异性抗原(PSA)的关系。方法:对120例临床可疑前列腺癌患者采用B超引导下经会阴前列腺穿刺病理活检,排除前列腺癌及不合并炎症的前列腺增生病例,仅BPH合并前列腺炎病例入选,采用NIH-Ⅳ型前列腺炎组织病理学分类方法对每例患者标本按炎症位置、范围和分级3方面分3级比较,评价炎症与血清PSA的关系。结果:120例患者中BPH合并前列腺炎症46例。①组织病理学炎症范围分级,1级35例,2级7例,3级4例,tPSA分别为(8.46±4.09)μg/L、(15.26±5.26)μg/L和(21.05±7.58)μg/L,fPSA分别为(1.75±0.93)μg/L、(2.54±0.72)μg/L和(3.19±1.13)μg/L,PSAD分别为0.15±0.11、0.26±0.07和0.42±0.19。三级之间比较tPSA(P=0.001)、fPSA(P=0.008)和PSAD(P<0.001)差异均具有显著性。②组织病理学炎症分级,1级32例,2级10例,3级4例。tPSA分别为(8.37±4.07)μg/L、(13.30±5.69)μg/L和(21.05±7.58)μg/L。fPSA分别为(1.76±0.93)μg/L、(3.27±2.21)μg/L和(3.19±1.13)μg/L。PSAD分别为0.14±0.11、0.25±0.06和0.42±0.19。三级之间比较tPSA(P=0.002)、fPSA(P=0.024)和PSAD(P<0.001)差异均有显著性。③组织病理学炎症位置分级,1级19例,2级17例,3级10例,三级之间tPSA、fPSA、%fPSA差异均无显著性(P>0.05)。④组织病理学炎症范围与tPSA(r=0.6,P<0.001)、fPSA(r=0.5,P=0.001)和PSAD(r=0.6,P<0.001)呈显著正相关关系。组织病理学炎症分级与tPSA(r=0.5,P<0.001)、fPSA(r=0.4,P=0.008)和PSAD(r=0.7,P<0.001)呈显著正相关关系,与%fPSA呈显著负相关关系(r=-0.4,P=0.013)。结论:无症状前列腺炎症患者组织病理学炎症的分级和范围与血PSA显著相关,病理医生应对前列腺穿刺标本进行炎症描述,其对高分级前列腺炎症患者可避免反复活检。     

Clinical evaluation of percent free prostate-specific antigen using the AxSYM system in the best analytical scenario

OBJECTIVE: Percent free prostate-specific antigen (PSA) is a promising tool for prostate cancer (CaP) diagnosis. However, its diagnostic performances have not yet been established. The present study was carried out with the aim of evaluating percent free PSA in the most favourable analytical conditions. MATERIALS AND METHODS: Eighty-eight patients affected by newly diagnosed, untreated, primary CaP, and 169 cases with biopsy-confirmed, untreated, benign prostatic hypertrophy (BPH) were prospectively enrolled. Abbott AxSYM total and free PSA were measured by the same technician using the same instrument and the same reagent batch. RESULTS: Percent free PSA was more effective than total PSA in differential diagnosis between CaP and BPH in every evaluated dose range of total PSA. In cases with total PSA >4 microg/l, percent free PSA could have reduced by about 50% the rate of unnecessary biopsies with a probably still acceptable 93% cancer detection rate. The likelihood of CaP after the determination of percent free PSA was in fact higher than 50% using cut-off points which provide low sensitivity values (i.e. 58% in men aged 50-59 years). CONCLUSIONS: Percent free PSA is superior to total PSA in distinguishing primary CaP from BPH in patients with total PSA between 2 and 30 microg/l and in reducing the rate of unnecessary biopsies in men with total PSA higher than 4 microg/l. However, percent free PSA should be cautiously interpreted in decision making in individual patients since post-test probability is relatively low in men aged 50-70 years.     

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection

Background

Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity.

Objective

To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia–associated PSA (BPHA).

Design, setting, and participants

Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University.

Measurements

BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA).

Results and limitations

The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity.

Conclusions

This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).     

The free/total prostate-specific antigen ratio (%fPSA) is the best predictor of tumor involvement in the radical prostatectomy specimen among men with an elevated PSA

BACKGROUND: The relationship between the free-to-total prostate-specific antigen ratio (%fPSA) and prostate cancer (CaP) pathology remains controversial. Previous reports have shown a direct correlation between %fPSA and prostate volume as well as an indirect correlation between %fPSA and unfavorable CaP pathology, particularly among men with an elevated PSA. We evaluated the use of %fPSA to predict CaP pathology including percent of tumor involvement in the radical prostatectomy (RP) specimen. METHODS: We prospectively analyzed 124 consecutive patients with CaP who underwent RP. In all patients, preoperative frozen serum was analyzed for assessment of %fPSA (Abbott Axsym). Pathologic review was performed using whole mount sections and total tumor volume was determined by planimetry. Statistical comparison between %fPSA and pathology was performed using log transformation. RESULTS: Percent fPSA was indirectly correlated with prostate volume in both the entire group (N=124) and among those patients (N=87) with a total PSA >4 ng/mL (P<0.001). Overall, both %fPSA and total PSA also correlated with total tumor volume (P=0.03 and P=0.01, respectively) and Gleason sum (P<0.001 and P<0.01). When we evaluated the percent of tumor involvement (tumor density) defined as the volume of tumor per gland divided by total gland volume, for the entire population, both total PSA and %fPSA were predictive with equal significance (P<0.001). However, among the subset of patients with a PSA>4.0 ng/mL, there was only a significant correlation between tumor density and %fPSA as compared to total PSA (P<0.001 vs. P=0.06, respectively). CONCLUSIONS: Independent of prostate volume, %fPSA is reflective of CaP pathology. Specifically, %fPSA was inversely correlated with tumor volume, Gleason sum and ECE. Among patients with modest PSA elevations, %fPSA was better than PSA in predicting percent of tumor involvement (tumor density) in the RP specimen.     

Prostate specific antigen isoforms and human glandular kallikrein 2--which offers the best screening performance in a predominantly black population?

PURPOSE: Free prostate specific antigen, complexed PSA and human glandular kallikrein 2 have independently been tested against the gold standard of total PSA for prostate cancer screening in largely white populations. With the incidence of prostate cancer much higher in black men, we sought to evaluate these markers simultaneously in a predominantly black population. MATERIALS AND METHODS: A total of 138 men, of whom 108 were black, underwent ultrasound guided biopsy of the prostate for tPSA levels greater than 2.5 ng/ml or an abnormal digital rectal examination. Sera were drawn before biopsy and analyzed for tPSA, fPSA, cPSA and hK2 concentrations using standard methods (hK2 assay is for research use only, not for use in diagnostic procedures). The areas under the receiver operator characteristic curves were determined for each marker as well as biomarker combinations. Additionally, each parameter's specificity, positive and negative predictive values, and theoretical screening efficiency were assessed at or above the 95% sensitivity level. RESULTS: A total of 43 (31.1%) men had prostate cancer by biopsy. While the AUC for %fPSA was statistically the highest (0.822, p <0.001), cPSA offered the highest specificity (31.6%) and positive predictive power (31.7%) of any of the tested biomarkers at comparable sensitivity (greater than 95%). The calculated efficiency of cPSA (51.4%) was also higher than the other markers. Nearly 20% of biopsies would be avoided using cPSA vs standard tPSA screening methods. CONCLUSIONS: Comparing the major PSA isoforms and hK2, cPSA alone appears to offer superior diagnostic discrimination for cancer detection in a predominantly black population.     

The significance of the free-to-complexed prostate-specific antigen (PSA) ratio in prostate cancer detection in patients with a PSA level of 4.1-10.0 ng/mL

OBJECTIVE: To compare the ratio of free prostate specific antigen (fPSA), total PSA (tPSA) and complexed PSA (cPSA, measured using a novel immunoassay) with other variables used to detect prostate cancer in patients with intermediate serum PSA levels of 4.1-10.0 ng/mL. PATIENTS AND METHODS: From July 1997 to August 1998, 140 consecutive patients were assessed; all had intermediate serum PSA levels and/or abnormal findings on a digital rectal examination. All patients underwent transrectal ultrasonography (TRUS)-guided biopsy, and the prostate and transition zone volumes were determined by TRUS. Free and tPSA were measured using the Tandem-R assay (Hybritech Corp., San Diego, CA). PSA complexed with alpha1-antichymotrypsin (cPSA) was measured using an appropriate assay. The ability of cPSA, free-to-total PSA ratio (f/tPSA), free-to-complexed PSA ratio (f/cPSA), tPSA density of the whole prostate (PSAD), of the transition zone (tPSATZ), and cPSA density of the whole prostate (cPSAD) and of the transition zone (cPSATZ) to improve the power of PSA in detecting prostate cancer was evaluated using receiver operating characteristic (ROC) curves. Results Of the 140 patients, 126 had histologically confirmed benign disease and 14 had prostate cancer. The cPSA alone had better specificity for detecting prostate cancer than had tPSA alone but the difference was not significant. The area under the ROC curve for f/cPSA was larger than those for all other variables. With a 93% sensitivity for detecting prostate cancer, a f/cPSA threshold of 25% would result in fewer unnecessary biopsies (40% f/cPSA specificity) than with all other PSA variables. The difference in the resolution was significant between f/cPSA and tPSA, cPSA, tPSAD and tPSATZ, but not with f/tPSA, cPSAD or cPSATZ. In patients with a prostate volume of < 30 mL, the cPSATZ showed better specificity for prostate cancer than tPSA alone. CONCLUSION: Measuring the level of cPSA and its derivatives may provide better differentiation of prostate cancer and benign disease than tPSA alone in patients with a tPSA level of 4.1-10.0 ng/mL.     

Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial

PURPOSE: Complexed (c) prostate specific antigen (PSA) has been shown to enhance specificity for prostate cancer (CaP) detection over total PSA (tPSA), although a large multi-institutional prospective evaluation was required to confirm these findings. We compared the clinical performance of cPSA with tPSA as a first line test for CaP detection and secondarily to determine if PSA ratios, namely percent free PSA (fPSA) and percent cPSA, can provide further enhancement in diagnostic performance over cPSA or tPSA. MATERIALS AND METHODS: Consecutive men scheduled for initial biopsy of the prostate were enrolled prospectively at each of 7 university centers and community based urology practices. Serum was collected and tested with the Immuno 1 (Bayer Diagnostics, Tarrytown, New York), tPSA and cPSA, and Access (Beckman, Inc., San Diego, California) fPSA and tPSA methods. RESULTS: A total of 831 patients were evaluated, of whom 313 (37.5%) were diagnosed with CaP. ROC curve analysis performed from the results of all samples and those within the clinically relevant cPSA ranges of 1.5 to 3.2, 1.5 to 5.1, 1.5 to 8.3 and 3.2 to 8.3 ng/ml (tPSA 2 to 4, 2 to 6, 2 to 10 and 4 to 10 ng/ml, respectively) indicated a significant improvement in the AUC ROC curve for cPSA compared with tPSA (p < or =0.001). Using cutoff points that provide a sensitivity of 80% to 95% for CaP detection within the 1.5 to 8.3 ng/ml cPSA range cPSA provided a statistically significant enhancement in specificity over tPSA of 6.2% to 7.9%. Within the cPSA range of 1.5 to 3.2 ng/ml using a cutoff point of 2.5 ng/ml for tPSA and 2.2 ng/ml for cPSA provided a specificity of 21.2% and 35%, respectively, and 85% sensitivity for CaP detection. PSA ratios provided no further enhancement in specificity over cPSA within these ranges. CONCLUSIONS: The use of cPSA as a single test provided improved specificity over tPSA. Percent fPSA and percent cPSA offered little to no additional benefit in the differentiation of benign and malignant disease at clinically relevant cPSA concentrations.     

The role of the percentage free PSA in the diagnosis of prostate cancer in Blacks: Findings in indigenous West African men using TRUS guided biopsy

Introduction

In Western and Asian literature, the measurement of percentage free prostate specific antigen (%fPSA) has been known to enhance the predictive role of total prostate specific antigen (tPSA) in early prostate cancer (Ca-P) detection. Relationship between the tPSA and Ca-P are known to be influenced by race. To the best of our knowledge, the relationship between %fPSA and Ca-P has not been studied in sub-Saharan Africa using current established biopsy protocol.

Internal validation of an artificial neural network for prostate biopsy outcome

Objectives:   To carry out an internal validation of the retrospectively trained artificial neural network (ANN) 'ProstataClass'.
Methods:   A prospectively collected database of 393 patients undergoing 8–12 core prostate biopsy was analyzed. Data of these patients were applied to the online available ANN 'ProstataClass' using the Elecsys total prostate-specific antigen (tPSA) and free PSA (fPSA) assays. Beside the internal validation of the ANN 'ProstataClass' an additional ANN (named as ANN internal validation: ANNiv) only using the 393 prospective patient data was evaluated. The new ANN model was constructed with the MATLAB Neural Network Toolbox. Diagnostic accuracy was evaluated by receiver operator characteristic (ROC) curves comparing the areas under the ROC curves (AUC) and specificities at 90% and 95% sensitivity.
Results:   Within a tPSA range of 1.0–22.8 ng/mL, 229 men (58.3%) had prostate cancer (PCa). tPSA, %fPSA and the number of positive digital rectal examinations (DRE) differed significantly from the cohort of patients of the ANN 'ProstataClass', whereas age and prostate volume were comparable. AUCs for tPSA, %fPSA and the ANN 'ProstataClass' were 0.527, 0.726 and 0.747 ( P  = 0.085 between %fPSA and ANN). The AUC of the ANNiv (0.754) was significantly better compared with %fPSA ( P  = 0.021), whereas the AUC of two ANN models built on external cohorts (0.726 and 0.729) showed no differences to %fPSA and the other ANN models.
Conclusions:   Significant differences of DRE status and %fPSA medians decrease the power of the 'ProstataClass' ANN in the internal validation cohort. The effect of retrospective data evaluation the 'ProstataClass' cohort and prospective fPSA measurement may be responsible for %fPSA differences. All ANN models built with different PSA and fPSA assays performed equally if applied to the two cohorts.     

Comparisons of the various combinations of free, complexed, and total prostate-specific antigen for the detection of prostate cancer

OBJECTIVES: We compared the ability of three prostate-specific antigen (PSA) ratios - free-to- total PSA ratio (fPSA/tPSA), free-to-complexed PSA ratio (fPSA/cPSA), and complexed-to-total PSA ratio (cPSA/tPSA) - to distinguish prostate cancer from benign prostatic hyperplasia (BPH). METHODS: We tested 258 consecutive patients who underwent transrectal ultrasound-guided prostate needle biopsy because of an abnormal digital rectal examination or a Tandem-R PSA of >4.1 ng/ml. Free PSA (fPSA) and total PSA (tPSA) were measured by Tandem-R assay. alpha(1)-Antichymotrypsin-complexed PSA (cPSA) was measured by Markit-M PSA-ACT assay. RESULTS: Of the 258 patients, 204 had BPH, and 54 had prostate cancer. The specificity at 96% sensitivity for fPSA/tPSA, fPSA/cPSA, and cPSA/tPSA was 23, 25, and 33%, respectively. Of 162 patients with tPSA between 4.1 and 10.0 ng/ml, 132 had BPH and 30 had prostate cancer. The specificity at 96% sensitivity for f/tPSA, f/cPSA and c/tPSA was 32, 44, and 41%, respectively. There was no significant difference in the area under the receiver-operating characteristic curves among fPSA/tPSA, fPSA/cPSA, and cPSA/tPSA in the overall PSA range or in tPSA between 4.1 and 10.0 ng/ml. CONCLUSION: fPSA/tPSA, fPSA/cPSA, and cPSA/tPSA did not differ in their ability to distinguish prostate cancer from BPH.