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.     

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).     

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.     

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.     

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.     

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.     

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.     

Assay-specific artificial neural networks for five different PSA assays and populations with PSA 2–10 ng/ml in 4,480 men

Use of percent free PSA (%fPSA) and artificial neural networks (ANNs) can eliminate unnecessary prostate biopsies. In a total of 4,480 patients from five centers with PSA concentrations in the range of 2–10 ng/ml an IMMULITE PSA-based ANN (iANN) was compared with other PSA assay-adapted ANNs (nANNs) to investigate the impact of different PSA assays. ANN data were generated with PSA, fPSA (assays from Abbott, Beckman, DPC, Roche or Wallac), age, prostate volume, and DRE status. In 15 different ROC analyses, the area under the curve (AUC) in the PSA ranges 2–4, 2–10, and 4–10 ng/ml for the nANN was always significantly larger than the AUC for %fPSA or PSA. The nANN and logistic regression models mostly also performed better than the iANN. Therefore, for each patient population, PSA assay-specific ANNs should be used to optimize the ANN outcome in order to reduce the number of unnecessary biopsies.     

Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen

PURPOSE: We developed and validated a nomogram which predicts presence of prostate cancer (PCa) on needle biopsy. MATERIALS AND METHODS: We used 3 cohorts of men who were evaluated with sextant biopsy of the prostate and whose presenting prostate specific antigen (PSA) was not greater than 50 ng/ml. Data from 4,193 men from Montreal, Canada were used to develop a nomogram based on age, digital rectal examination (DRE) and serum PSA. External validation was performed on 1,762 men from Hamburg, Germany. Data from these men were subsequently used to develop a second nomogram in which percent free PSA (%fPSA) was added as a predictor. External validation was performed using 514 men from Montreal. Both nomograms were based on multivariate logistic regression models. Predictive accuracy was evaluated with areas under the receiver operating characteristic curve and graphically with loess smoothing plots. RESULTS: PCa was detected in 1,477 (35.2%) men from Montreal, 739 (41.9%) men from Hamburg and 189 (36.8%) men from Montreal. In all models all predictors were significant at 0.05. Using age, DRE and PSA external validation AUC was 0.69. Using age, DRE, PSA and %fPSA external validation AUC was 0.77. CONCLUSIONS: A nomogram based on age, DRE, PSA and %fPSA can highly accurately predict the outcome of prostate biopsy in men at risk for PCa.     

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.     

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.     

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.     

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.     

Complexed prostate specific antigen density is better than the other PSA derivatives for detection of prostate cancer in men with total PSA between 2.5 and 20 ng/ml: results of a prospective multicenter study

PURPOSE: This prospective, multicenter study was initiated to evaluate the diagnostic performance of PSA, free/total PSA (f/tPSA) and complexed PSA (cPSA) with volume-based parameters for early detection of prostate cancer in patients with PSA between 2.5 and 20 ng/ml. MATERIALS AND METHODS: 408 subjects with serum PSA values between 2.5 and 20 ng/ml regardless of digital rectal examination (DRE) were included in to the study. The diagnostic validity, sensitivity, specificity and cut-off values were evaluated by Receiver Operating Characteristic (ROC) curve analysis. RESULTS: Of 408 patients 77 (18.9%) were positive for prostate cancer. Digital rectal examination was non-suspicious in 86% (351/408) of the patients. Area under curve (AUC) values for cPSA were better than PSA and f/tPSA in patients with PSA values of 2.5-10 ng/ml and 4-10 ng/ml, as well as the whole group. Furthermore, on ROC curve analysis cPSAD was the best predictor of prostate cancer for all PSA ranges regardless of the DRE findings except PSA values between 2.5 and 4 ng/ml. The cut-off value of cPSAD at 90% sensitivity was 0.06 ng/ml/cm(3) with a 35.3% specificity saving 126 unnecessary biopsies in the whole group. CONCLUSION: cPSA might be a better initial test than PSA for prostate cancer detection and measurement of cPSA alone and its derivatives obviate the need for additional fPSA testing.     

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.     

Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml

BACKGROUND: We measured serum levels of human glandular kallikrein 2 (hK2) in patients treated with radical retropubic prostatectomy (rrP) for clinically localized prostate cancer (PCa) with a total PSA (tPSA)-level below 10 ng/ml to investigate whether hK2 can be applied to preoperatively distinguish organ-confined (pT2a/b) from nonorgan-confined (> or = pT3a)-PCa more accurately than total PSA. Further, we evaluated hK2, free- and tPSA-concentrations in all pathologic stages of PCa. METHODS: 161 serum samples from men scheduled for rrP were collected 1 day before surgery prior to any prostatic manipulation. Pathologic work-up revealed > or = pT3a-PCa in 48 and pT2a/b-PCa in 113 patients. HK2-levels in serum were measured using an immunofluorometric assay with an analytical sensitivity of 0.5 pg/ml, a functional sensitivity of 5 pg/ml and insignificant cross-reactivity with PSA (< 0.005%). Total (tPSA) and free PSA (fPSA) levels were measured using a commercially available assay from which we calculated %fPSA and an algorithm that combined hK2 and PSA-levels [hK2] x [tPSA/fPSA]. Means, medians, and ranges were calculated for pT2a/b vs. >/= pT3a-PCa and for all pathologic stages. Statistical significance of differences was calculated using Mann-Whitney-U and Kruskal-Wallis tests. Calculation of receiver-operator-characteristic (ROC) curves were performed for hK2, [hK2] x [tPSA/fPSA] and tPSA to compare diagnostic performance. RESULTS: A mean tPSA level in serum of 6.12 ng/ml in > or = pT3a-PCa was not significantly different (P = 0.366) from 5.78 ng/ml in pT2a/b-PCa. Also, there were no statistically significantly different levels of fPSA (P = 0.947) or %fPSA (0.292) for these two groups. By contrast, mean hK2-level in pT2a/b-PCa of 80 pg/ml was significantly different (P = 0.004) from a mean hK2 level of 120 pg/ml in > or = pT3a-PCa as shown by Mann-Whitney-analysis Moreover, the algorithm of [hK2] x [tPSA/fPSA] was significantly lower (P = 0.0004) in pT2a/b-PCa vs. > or = pT3a-PCa. Calculation of areas under curve (AUC) by receiver-operator-characteristics (ROC) demonstrated that the AUC for hK2 (0.64) was larger and the AUC for [hK2] x [tPSA/fPSA] (=0.68) significantly larger (P = 0.007) compared to the AUC of tPSA (0.55). Furthermore, Kruskal-Wallis Test revealed a highly significant correlation to pathologic stage using hK2 (P = 0.008) and [hK2] x [tPSA/fPSA] (P = 0.0015) compared to no significant differences in serum concentration of tPSA (P = 0.296). Also at tPSA-levels from 10-20 ng/ml, the hK2-levels in pT2a/b-PCa were close to significantly different (P = 0.051) from those in men with >/= pT3a-PCa, while the algorithm of [hK2] x [tPSA/fPSA] in that tPSA-range was significantly lower (P = 0.002) in pT2a/b-PCa compared to > or = pT3a0-PCa. CONCLUSIONS: Highly significant differences in serum concentration enable hK2 to be a powerful predictor of organ-confined disease and pathologic stage of clinically localized prostate cancer, especially in the PSA-range below 10 ng/ml. As such, there are important clinical consequences for the application of hK2 for the adequate treatment of prostate cancer patients, i.e., the option of nerve-sparing surgery. (c) 2001 Wiley-Liss, Inc.     

Clinical utility of human glandular kallikrein 2 within a neural network for prostate cancer detection

OBJECTIVE

To assess, using artificial neural networks (ANNs), human glandular kallikrein 2 (hK2), prostate‐specific antigen (PSA), and percentage free/total PSA (f/tPSA), for discriminating between prostate cancer and benign prostatic hyperplasia (BPH).

MATERIAL AND METHODS

Serum samples from 475 patients with prostate cancer (n = 347) or BPH (n = 128) within the PSA range of 1–20 ng/mL were analysed for tPSA, fPSA and hK2 (research assay, Toronto, Canada). Data were analysed in the ranges of 1–4, 2–4, 4–10, and 2–20 ng/mL tPSA. Back‐propagation ANN models with the variables PSA, f/tPSA, and hK2, hK2/fPSA and hK2/(f/tPSA) were constructed. The diagnostic validity was evaluated by receiver‐operating characteristic (ROC) curve analysis.

RESULTS

Whereas the median concentration of hK2 was not significantly different between patients with BPH or prostate cancer in any of the tPSA ranges, the f/tPSA, hK2/fPSA and hK2/(f/tPSA), and the hK2‐based ANN outputs were always significantly different between patients with prostate cancer or BPH. Using ROC curve comparison, all variables were significantly better than hK2 in all ranges. The hK2‐based ANN performed better than f/tPSA except in the 4–10 ng/mL tPSA range. At 90% and 95% sensitivity, the hK2‐based ANN was also significantly better than f/tPSA in the 1–4 ng/mL tPSA range. hK2/(f/tPSA) achieved equal results to the hK2‐based ANN except in the range 2–20 ng/mL tPSA.

CONCLUSIONS

The hK2‐based ANN improves the outcome of f/tPSA but not hK2/(f/tPSA) in almost all analysed subgroups. When comparing the results at 90% and 95% sensitivity the hK2‐based ANN only performed significantly better than f/tPSA in the lowest tPSA range. Only in lower tPSA ranges do hK2‐based ANNs show an advantage for further improving prostate cancer detection.

     

前列腺穿刺活检结果预测模型的建立

目的基于前列腺特异性抗原(PSA)等指标,建立能够预测前列腺穿刺活检结果的数学模型.方法收集2009年7月至2015年3月在解放军总医院进行前列腺穿刺活检患者的年龄、前列腺体积、游离PSA(fPSA)和总PSA(tPSA)等临床资料.所有研究对象中随机选择80％为建模组,其余20％为验证组.在建模组中利用单因素和多因素 Logistic 分析筛选出预测前列腺癌的独立性影响因素,构建回归方程,并以此为基础建立预测前列腺穿刺结果的数学模型.利用受试者工作特征(receiver operating characteristic,ROC)曲线评估该模型对前列腺癌的诊断价值,并与临床常用的 PSA 及其相关参数比较诊断价值的差异.结果选取资料完整且 tPSA 100 ng/ml以下的患者纳入研究,共958例.其中建模组767例(tPSA 4~20 ng/ml者587例),验证组191例.在建模组中,将所有指标纳入单因素和多因素 Logistic 回归分析,发现年龄、tPSA 和前列腺体积是前列腺癌独立的预测因素.将所有指标(包括 fPSA)纳入回归方程,构建数学模型Y＝－4．765＋0.074×(年龄)＋0．057×(tPSA)＋0．052×(fPSA)－0．029×(前列腺体积).在建模组和验证组中, ROC曲线分析显示该模型预测前列腺癌的 ROC 曲线下面积高于 tPSA、f/tPSA 和 PSA 密度.取Y＝－0．076,即约登指数最大值作为本模型最佳临界值,预测前列腺癌的灵敏度为76．2％、特异度为76．6％、阳性预测值76．5％、阴性预测值76．3％.结论本预测模型与单独应用PSA及其相关参数相比具有更高的诊断价值,并且可以在不增加患者检查项目的前提下提高预测前列腺癌的能力.     

Comparison of two investigative assays for the complexed prostate-specific antigen in total prostate-specific antigen between 4.1 and 10.0 ng/mL

OBJECTIVES: To determine the ability of complexed prostate-specific antigen (cPSA) levels to diagnose prostate cancer. METHODS: Between September 1998 and March 1999, cPSA levels in 182 consecutive patients with an abnormal digital rectal examination (DRE) or a total PSA (tPSA; Tandem-R assay) level greater than 4.1 ng/mL were examined. Levels of cPSA were measured by the Markit-M PSA-ACT (alpha(1)-antichymotrypsin) assay (cPSA-MM) and Bayer Immuno 1 complexed PSA assay (cPSA-BI). Free PSA (fPSA) was measured by the Tandem-R free PSA assay. RESULTS: Of the 140 patients with tPSA between 4.1 and 10.0 ng/mL, 116 were histologically confirmed as having benign tissue; the remaining 24 were diagnosed with prostate cancer. To ensure a 92% sensitivity of cancer detection, a cutoff value for the tPSA, cPSA-MM, and cPSA-BI assays of 4.8 ng/mL, 2.7 ng/mL, and 4.6 ng/mL, respectively, was determined. The percentage of negative biopsies prevented at these cutoff (ie, specificity) values was 14%, 23%, and 24%. No significant differences among these three assays were found. At 92% sensitivity, the cutoff value for the fPSA/tPSA, fPSA/cPSA-MM, and fPSA/cPSA-BI ratios was 18%, 27%, and 18%, respectively. The specificity was 35%, 49%, and 51%. No significant differences were found among these three fPSA ratios. Significant differences were noted between tPSA and the fPSA/cPSA-MM ratio and between tPSA and the fPSA/cPSA-BI ratio. No differences were seen among the other PSA parameters. CONCLUSIONS: No difference in the ability of cPSA levels to distinguish prostate cancer and noncancer was observed between cPSA-MM and cPSA-BI or between their fPSA ratios. Only the fPSA/cPSA-MM and fPSA/cPSA-BI ratios provided significantly enhanced diagnostic performance compared with tPSA.     

Contemporary prostate cancer prevalence among T1c biopsy-referred men with a prostate-specific antigen level < or = 4.0 ng per milliliter

OBJECTIVE: To investigate the prostate cancer (PCa) prevalence and risk factors of men with prostate-specific antigen (PSA) level< or =4.0 ng/ml and an unsuspicious digital rectal examination (DRE) in a large biopsy referral cohort. MATERIALS AND METHODS: Between 1997 and 2005, 855 men underwent initial transrectal ultrasound (TRUS)-guided prostate biopsy at the University Hospital Hamburg-Eppendorf. Patients with any previous surgical or medical treatment were excluded from analyses. Logistic regression analyses were performed to determine risk factors of PCa at biopsy and high-grade PCa defined as biopsy Gleason sum> or =7. RESULTS: Overall PCa detection rate was 23.1%. The majority had a biopsy Gleason sum of 6 (79.5%) and 20.5% had a biopsy Gleason sum> or =7. Total PSA (tPSA) and percentage of free PSA (%fPSA) were statistically significantly different in men with and without PCa (all p<0.001). In tPSA strata < or = 0.5, 0.6-1.0, 1.1-2.0, 2.1-3.0, and 3.1-4.0 ng/ml, PCa prevalence was 4.0%, 10.6%, 14.8%, 24.5%, and 32.1%, respectively. In logistic regression analyses addressing PCa and Gleason sum > or = 7 at biopsy, %fPSA and prostate volume represented independent and most informative risk factors. CONCLUSION: Our data demonstrate that a substantial percentage (23.1%) of men with a PSA< or =4.0 ng/ml and an unsuspicious DRE in a biopsy referral population harbor PCa, with 20.5% being high grade. Low %fPSA and low prostate volume represent important parameters in PCa and in high grade disease detection at biopsy, respectively.