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.     

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.     

The value of (-7, -5)pro-prostate-specific antigen and human kallikrein-2 as serum markers for grading prostate cancer

OBJECTIVE: To assess the value of the precursor form (-7,5pro) of prostate-specific antigen (PSA) and human kallikrein-2 (hK2) for detecting and grading prostate cancer, as better serum markers with improved specificity are needed in men with lower ranges of total (t)PSA. PATIENTS AND METHODS: tPSA, free PSA (fPSA), the precursor (-7,5)proPSA and hK2 were measured in a subset of participants of the European Randomised Study of Screening of Prostate Cancer. In a pilot study, sera from 143 men biopsied but with no prostate cancer, 142 with BPH, and 146 with prostate cancer were analysed to determine the relative value of serum markers for differentiating between the groups. Then, in 141 men with prostate cancer who had a radical prostatectomy, these serum markers were related to the pathological grading to analyse their value as prognostic variables. RESULTS: Levels of (-7,5)proPSA, hK2 and fPSA could be used to distinguish between BPH and cancer, but proPSA and hK2, alone or combined, did not improve the specificity of fPSA for discriminating BPH and cancer. There was also no correlation between these serum markers and pathological tumour grade. CONCLUSION: The clinical effect of using (-7,5)proPSA or hK2 for detecting and grading prostate cancer remains limited.     

A (-5, -7) proPSA based artificial neural network to detect prostate cancer

OBJECTIVE: The pro-forms of prostate specific antigen (-2,-5,-7 proPSA) and also %free PSA based artificial neural networks (ANN) have been suggested to enhance the discrimination between prostate cancer (PCa) and no evidence of malignancy (NEM). This study reports on the combined use of proPSA within a %free PSA based ANN to enhance specificity of PCa. METHODS: Serum samples from 898 patients with PCa (n=384) or NEM (n=514) within the PSA range 1-10 microg/l were analyzed for PSA, free PSA and (-5,-7) proPSA (Roche assays). Patient data from two centers - taken first from the Swiss site of the ERSPC (Aarau) and from a referral population (Berlin) have been analyzed. Leave-one-out ANN models with the variables PSA, %fPSA, proPSA, prostate volume and status of digital rectal examination (DRE) were constructed and compared by receiver-operating characteristic (ROC) curve analysis. RESULTS: (-5,-7) proPSA was only significantly different between NEM and PCa in the PSA range 4-10 microg/l. Within the PSA range 4-10 microg/l (Berlin group) the ANN including only the two variables %fPSA and proPSA could reach the same performance like the conventional ANN with PSA, %fPSA, age, prostate volume and DRE (both AUCs: 0.84) However, at 95% sensitivity all ANN could not improve specificity compared to %fPSA. CONCLUSIONS: ProPSA as single parameter did not improve specificity over %fPSA whereas proPSA and %fPSA within an ANN in the PSA range 4-10 microg/l substituted prostate volume and DRE. At 95% sensitivity only ANN with prostate volume and DRE perform significantly better than %fPSA.     

Probability of prostate cancer detection based on results of a multicenter study using the AxSYM free PSA and total PSA assays

OBJECTIVES: The determination of the percentage of free prostate-specific antigen (%fPSA) enhances the specificity of prostate cancer (CaP) detection. This study was undertaken to assess the performance of %fPSA in differentiating benign prostate disease from CaP and to determine the CaP probability estimates using the AxSYM Free PSA and AxSYM Total PSA assays. METHODS: In this prospective study, 297 men, 50 years old or older, with a total PSA level between 4 and 10 ng/mL and a nonsuspicious digital rectal examination were enrolled at 10 clinical sites. All subjects underwent at least sextant prostate biopsies to establish the diagnosis. fPSA and total PSA (tPSA) levels were determined using the AxSYM Free PSA and AxSYM Total PSA assays. Percent fPSA values were compared with tPSA values to determine the appropriate cutoffs for prostate biopsy and to calculate the CaP probability estimates. RESULTS: The strongest predictor of CaP in a logistic regression model was %fPSA (odds ratio 2.29), which contributed significantly more than age or tPSA to the predictive model. In this study population, a %fPSA cutoff of 26.4% would have detected 96% of subjects with CaP (sensitivity) and would have eliminated 27.4% of unnecessary biopsies (specificity). CaP probability estimates ranged from 9% to 69% and increased as the %fPSA value decreased. Men with a %fPSA level of 10% or lower had a 69% probability of CaP, and men with a %fPSA level of greater than 26% had a 9% probability of CaP. CONCLUSIONS: Percent fPSA values can help differentiate CaP from benign prostate disease and reduce unnecessary biopsies in 27% of men 50 years old or older whose digital rectal examination was normal and whose tPSA level was between 4 and 10 ng/mL. A %fPSA result can assist the physician and patient in determining the probability of CaP and assessing the need for prostate 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.     

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

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Evaluation of precursor prostate-specific antigen isoform ratios in the detection of prostate cancer

OBJECTIVE: Disease-associated isoforms of the prostate-specific antigen (PSA) have recently been identified. We evaluated the efficacy of using precursor isoforms of PSA (pPSA) and their ratios for the detection of prostate cancer. METHODS: Serum concentrations of [-2], [-4], and [-7]pPSA, BPSA, and free PSA (fPSA) were retrospectively measured in 43 selected men. Of the 43 men, 15 had clinical T2 prostate cancer with ultrasound-estimated prostate volumes (PVs) of >50 cm(3), 13 had clinical T2 prostate cancer with (PVs) <25 cm(3), and 15 were prostate cancer-free with PV >50 cm(3). We calculated sum pPSA ([-2]+[-4]+[-7]pPSA). We also compared the ratios of: free/total PSA, [-2]pPSA/fPSA, [-2]pPSA/BPSA, [-2]pPSA/(fPSA-BPSA), [-2]pPSA/(fPSA-sum pPSA), and [-2]pPSA/{fPSA-(sum pPSA+BPSA)} among these three groups. RESULTS: The median [-2]pPSA/(fPSA-sum pPSA) ratio was significantly higher in men with prostate cancer with or without large PV compared with men with large PV without prostate cancer. Values for median [-2]pPSA/free PSA ratio were higher in men with prostate cancer with or without large PV compared with men with large PV, and without prostate cancer, but the differences were not statistically significant. CONCLUSIONS: In this preliminary study, [-2]pPSA/(fPSA-sum pPSA) ratio was not associated with prostate gland volume but was associated with prostate cancer. This ratio may be useful in the detection of prostate cancer, particularly in men with larger glands.     

Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer

Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue. This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%). In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration. A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.     

PSA-related markers in the detection of prostate cancer and high-grade disease in the contemporary era with extended biopsy

OBJECTIVE: To determine the relationship of total PSA (tPSA), percent free PSA (%fPSA), and complexed PSA (cPSA) with prostate cancer detection and the diagnosis of poorly-differentiated cancers in the contemporary era. METHODS: We retrospectively reviewed the clinical and pathological records of 292 men who met the following inclusion criteria: (1) tPSA 2.5 to 10 ng/ml; (2) initial biopsy only; (3) extended biopsy scheme (>or=10 peripheral zone cores); (4) no previous prostate surgeries. The ability of PSA-related markers to detect cancer was determined by area under the receiver operating characteristics curve analysis (AUC-ROC). Various clinically relevant % fPSA cutoffs and cPSA ranges were analyzed to determine the association with poorly-differentiated cancers. RESULTS: Cancer was detected in 126 (43%) men, with mean Gleason score of 7. The cancer detection rates for various cutoffs of tPSA, cPSA and % fPSA were very similar. On ROC analysis for cancer diagnosis, the AUCs for tPSA, % fPSA, and cPSA were 0.53, 0.54, and 0.52, respectively. Men with % fPSA <15 were more likely to have poorly-differentiated cancer than those with % fPSA >or=15 (66% vs. 41%, P < 0.005). Similarly, cPSA ranges (2-4, 4.1-6, and >6) were associated with the detection of poorly-differentiated cancers (37%, 57%, and 80% P < 0.003). CONCLUSIONS: With the use of extended prostate sampling in the contemporary screening population, the addition of cPSA and % fPSA does not enhance the diagnostic performance of tPSA. However, the significant association between cPSA and poorly-differentiated cancers suggests that this may be a more useful initial test for prostate cancer screening.     

Comparative evaluation of various prostate specific antigen ratios for the early detection of prostate cancer

OBJECTIVE: To compare the performance of various ratios using total prostate specific antigen (PSA), complexed PSA (cPSA) and free PSA (fPSA) in the early detection of prostate cancer. PATIENTS AND METHODS: The study included 535 consecutive patients evaluated at a prostate cancer detection clinic between January 1998 and October 1999. Patients had blood samples drawn before transrectal ultrasonography and prostate biopsy to measure PSA, cPSA and fPSA. Receiver operating characteristic (ROC) curves (sensitivity vs 1 - specificity) were used to evaluate the performance of PSA, cPSA, f/tPSA, cPSA/tPSA, fPSA/cPSA, tPSA/prostate volume (PV), fPSA/PV, and cPSA/PV. The areas under the curve (AUC) were calculated for each ratio. The performance of each ratio over all patients or in those with a tPSA of 4-6 or 4-10 ng/mL were evaluated. RESULTS: Of the 535 patients, 204 (38%) had biopsy-confirmed prostate cancer. The AUC obtained with tPSA alone was 0.64; when measured for all patients the cPSA/PV (0.78), PSA/PV (0.77), f/tPSA (0.76) and fPSA/cPSA (0.75) performed better than tPSA alone. Furthermore, in patients with a tPSA of 4-10 ng/mL, tPSA/PV (0.72), cPSA/PV (0.71), f/tPSA (0.69), fPSA/cPSA (0.69) and cPSA/tPSA (0.62) performed better than tPSA alone (0.52). Finally, in patients with a tPSA of 4-6 ng/mL, PSA/PV and cPSA/PV performed better than the other ratios. CONCLUSIONS: The use of PSA ratios gives a higher sensitivity and specificity for detecting prostate cancer than the use of tPSA alone.     

Performance of a neural network in detecting prostate cancer in the prostate-specific antigen reflex range of 2.5 to 4.0 ng/mL

Objectives. To explore the potential role of a neural network-derived algorithm in enhancing the specificity of prostate cancer detection compared with the determination of prostate-specific antigen (PSA) and free PSA (fPSA) while maintaining a 90% detection rate. Recent information suggests that the incidence of detectable prostate cancer is similar in men whose PSA values range from 2.5 to 4.0 ng/mL and from 4.0 to 10.0 ng/mL. If the PSA threshold triggering a prostate biopsy is lowered to 2.5 ng/mL, approximately 13% of men older than 50 would be added to the patient biopsy pool.Methods. One hundred fifty-one men were enrolled in a prospective, Institutional Review Board-approved protocol to evaluate the incidence of cancer in a population of men who participated in an early-detection program and whose PSA level was between 2.5 and 4.0 ng/mL. All the men underwent biopsy using an 11-core multisite-directed biopsy scheme, and all biopsy specimens were examined by one pathologist. All men had a second blood specimen drawn before the biopsy for a determination of serum PSA, creatinine kinase, prostatic acid phosphatase, and fPSA. A new neural network algorithm was developed with PSA, creatinine kinase, prostatic acid phosphatase, fPSA, and age as input variables to produce a single-valued prostate cancer detection index (PCD-I). This new algorithm was then prospectively tested in the 151 men. Performance parameters (including sensitivity, specificity, positive and negative predictive values, and biopsies saved) were calculated, and a comparative analysis was performed to evaluate the differences among the new algorithm, percent fPSA, PSA density, and PSA density-transition zone.Results. Cancer was histologically confirmed in 24.5% (37 of 151) of the men. The median age of the men was 62 years (range 43 to 74). At a sensitivity of 92%, the specificity for percent fPSA was 11%. The new algorithm (PCD-I) demonstrated an additional enhancement of specificity to 62% at 92% sensitivity. Clinically, the PCD-I would result in a savings of 49% (74 of 151) of all biopsies or 63.6% (71 of 114) of all unnecessary biopsies.Conclusions. A new generation algorithm, derived from a neural network (PCD-I) incorporating the parameters of age, creatinine kinase, PSA, prostatic acid phosphatase, and fPSA can significantly enhance the specificity and reduce the number of biopsies while maintaining a 92% sensitivity rate.     

Serum human glandular kallikrein 2 (hK2) for distinguishing stage and grade of prostate cancer

BACKGROUND: Human glandular kallikrein (hK2) has been shown to add important information regarding the early detection and staging of prostate cancer. Preliminary analysis pointed out that hK2 may discriminate between pT2 and pT3 tumors, and that hK2 may predict Gleason grade 4/5 cancer volume, better than prostate-specific antigen (PSA) or percent free PSA (%fPSA). We investigated the role of hK2 serum values for predicting pathological stage, grade and Gleason score. METHODS: Prostate-specific antigen, free PSA and hK2 were measured on 222 untreated prostate cancer patients who had received radical prostatectomy at the Charité Hospital, Berlin, Germany. Pathological work up revealed pT2-cancer in 111 patients and pT3-cancer in 111 patients. Grade 2 was found in 118 patients whereas grade 3 tumors were found in 104 patients. RESULTS: For pT2 and pT3 patients, the %fPSA (P=0.006), the ratios hK2/fPSA (P=0.08) and hK2xtPSA/fPSA (P=0.002) were all significant different whereas hK2 (P=0.143) and PSA (P=0.1) did not differ. Between grade 2 and grade 3 tumors, the hK2 alone (P=0.27), the %fPSA (P=0.13), the ratios hK2/fPSA (P=0.94) and hK2xtPSA/fPSA (P=0.12) did not separate, whereas PSA (P=0.039) showed a difference. The same relationships were found between the two groups in Gleason score<7 and >or=7. Neither the hK2 ratio, nor % fPSA was different. CONCLUSION: Human glandular kallikrein was not different between pT2 and pT3, nor between G2 versus G3 or Gleason scores<7 and >or=7 prostate cancer. Together with %fPSA, hK2 may only help to distinguish preoperatively between pT2 and pT3 prostate cancer but cannot add further information.     

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.     

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.     

前列腺特异性抗原前体用于前列腺癌早期诊断

PSA前体(proPSA)是血清游离PSA的特殊形式,由天然proPSA及其各种剪接的亚型组成,其中[-2]proPSA和[-4]proPSA和前列腺癌(PCa)的相关性高于[-7]proPSA和[-5]proPSA。临床研究表明,[-2]proPSA可以显著提高PCa的检测能力,特别是血清PSA低于4μg/L时。本文对proPSA的形成机制、特点及其对PCa早期诊断的影响进行了综述。     

The value of a single biopsy with 12 transperineal cores for detecting prostate cancer in patients with elevated prostate specific antigen

PURPOSE: Prostate cancer detection on standard sextant biopsy is considered inadequate. Various biopsy protocols have been introduced to improve cancer diagnosis. We report our experience with transperineal 12-core prostate biopsy. MATERIALS AND METHODS: In a prospective study 650 patients underwent prostate specific antigen (PSA) measurement during a 15-month period, of whom 141 with PSA greater than 4 ng./ml. also underwent transperineal 12-core prostate biopsy using the fan technique. Median PSA was 8 ng./ml. (range 4.1 to 5,000). RESULTS: Prostate cancer was detected in 72 of the 141 patients (51%), including 44 of the 97 (45%) with PSA between 4.1 and 10 ng./ml. This incidence is higher than previously reported in the literature using other biopsy techniques. Disease was low grade Gleason 2 to 4 in 4 cases (5%), intermediate grade Gleason 5 to 6 in 26 (35%) and high grade Gleason 7 to 10 in the remaining 42 (60%). CONCLUSIONS: A high cancer detection rate is achieved by 12-core transperineal prostate biopsy. Most tumors represent clinically significant cancer. Further randomized trials are required to confirm these data.     

PSA markers in prostate cancer detection

The PSA revolution that has occurred over the previous 2 decades has positively impacted the detection and treatment of men with prostate cancer. Although methods to improve specificity have shown promise (eg, PSAD, age-specific PSA, and PSA velocity), meaningful interpretation has yet to be uniformly accepted within clinical practice. The identification of other molecular forms of PSA within serum has led to a new era in PSA markers. Initial application employing %fPSA has provided improved discrimination between benign and malignant prostatic disease; however, questions remain regarding the ultimate threshold value. The discovery of various free forms of PSA--such as proPSA, BPSA, and iPSA--also have introduced the potential for improved specificity in detection. Although early results are encouraging, further evaluation is anticipated. The development of improved methods to detect and measure cPSA has demonstrated provocative results, and exhibits the potential to replace PSA as a standard diagnostic test in cancer screening.     

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).     

Percent free prostate specific antigen and cancer detection in black and white men with total prostate specific antigen 2.5 to 9.9 ng./ml

PURPOSE: The ratio of free-to-total prostate specific antigen (PSA), or percent free PSA, is a useful adjunct to total PSA for estimating the risk of prostate cancer when total PSA is 2.5 to 9.9 ng./ml. Relationships between cancer detection and total PSA are influenced by race but to our knowledge relationships between cancer detection and percent free PSA have not been studied. MATERIALS AND METHODS: A total of 222 black and 298 white consecutive and evaluable men with total PSA 2.5 to 9.9 ng./ml. underwent prostate biopsy for suspected cancer at a Veterans Affairs Medical Center. Clinical measurements included digital rectal examination, total and free serum PSA, prostate volume, PSA density and Gleason score of malignant biopsy specimens. RESULTS: Median percent free PSA was 14.1 (range 3.6 to 49.2) in 201 men with prostate cancer and 21.9 (range 5.7 to 83.3) in 319 without detectable cancer (p <0.0001). Significant racial differences in demographic characteristics and clinical measurements were limited to total PSA, which was higher in black men (p = 0.03). Cancer was detected in 156 black (47%) and 206 white (33%) men (p = 0.001). Areas under receiver operating characteristics curves for percent free PSA and total PSA were 0.66 and 0.58, respectively, for black men (p = 0.15), and 0.76 and 0.58, respectively, for white men (p <0.00001). Percent free PSA was 35.2 in black men and 29.2 in white men, and specificity was 9.1% and 28.7%, respectively, when sensitivity for percent free PSA was set at 95%. Of 156 black and 206 white men with percent free PSA less than 25, 83 (53%) and 85 (41%), respectively, had detectable cancer (p = 0.03). Of 66 black and 92 white men with percent free PSA 25 or greater 21 (32%) and 12 (13%), respectively, had detectable cancer (p = 0.005). CONCLUSIONS: Our study demonstrates racial differences in relationships between percent free PSA and cancer detection in men with suspected prostatic carcinoma and total PSA 2.5 to 9.9 ng./ml. Clinical application of the commonly used percent free PSA cutoff of less than 25 to determine the advisability of prostate biopsy may lead to under diagnosis of early stage prostate cancer in black men, who are at greater risk of morbidity and mortality from disease than white men.