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Purpose: Prostate cancer (PCa) is one of the most common cancers and one of the leading causes of death worldwide. Thus, one major issue in PCa research is to accurately distinguish between indolent and clinically significant (csPCa) to reduce overdiagnosis and overtreatment. In this study, we aim to validate the usefulness of diagnostic nomograms (DN) to detect csPCa, based on previously published urinary biomarkers., Methods: Capillary electrophoresis/mass spectrometry was employed to validate a previously published biomarker model based on 19 urinary peptides specific for csPCa. Added value of the 19-biomarker (BM) model was assessed in diagnostic nomograms including prostate-specific antigen (PSA), PSA density and the risk calculator from the European Randomized Study of Screening. For this purpose, urine samples from 147 PCa patients were collected prior to prostate biopsy and before performing digital rectal examination (DRE). The 19-BM score was estimated via a support vector machine-based software based on the pre-defined cutoff criterion of - 0.07. DNs were subsequently developed to assess added value of integrative diagnostics., Results: Independent validation of the 19-BM resulted in an 87% sensitivity and 65% specificity, with an AUC of 0.81, outperforming PSA (AUC  PSA : 0.64), PSA density (AUC  PSAD : 0.64) and ERSPC-3/4 risk calculator (0.67). Integration of 19-BM with the rest clinical variables into distinct DN, resulted in improved (AUC range: 0.82-0.88) but not significantly better performances over 19-BM alone., Conclusion: 19-BM alone or upon integration with clinical variables into DN, might be useful for detecting csPCa by decreasing the number of biopsies., (© 2022. The Author(s).)

Background: One of the major challenges in prostate cancer (PCa) treatment is distinguishing insignificant PCa from those forms that need active treatment. We evaluated the impact of PSA isoforms on risk stratification in patients with low-risk PCa as well as in active surveillance (AS) candidates who underwent radical prostatectomy., Methods: A total of 112 patients with biopsy confirmed Gleason score (GS) 6 PCa of four different international institutions were prospectively enrolled in the study. Blood withdrawal was performed the day before radical prostatectomy. In addition, patients were classified according to the EAU and NCCN criteria for AS candidates. PSA, free PSA (fPSA) and proPSA were measured using dual monoclonal antibody sandwich immunoassays. In addition, the Prostate Health Index (PHI=proPSA/fPSA × √PSA) was calculated. Final histology of the radical prostatectomy specimens was correlated to PSA, its isoforms and PHI., Results: Serum proPSA levels were significantly elevated in those patients with an upgrade in final histology (GS⩾7). In addition, higher proPSA levels were predictive for extraprostatic extension (⩾pT3a) as well as for positive surgical margins. Interestingly, PHI had an even higher predictive power when compared with proPSA alone concerning GS upgrading, extraprostatic extension and surgical margins in both the total and the AS patient group., Conclusion: We showed in a multicenter study that proPSA is a valuable biomarker to detect patients with aggressive PCa in a cohort of GS 6 patients, who would benefit from active tumor therapy. Combining proPSA with the standard markers PSA and fPSA using PHI further increases the predictive accuracy significantly. Moreover, our data support the use of PHI for monitoring PCa patients under AS.

Background: Active surveillance (AS) is increasingly offered to patients with low risk prostate cancer. The present study was conducted to evaluate the risk of tumor under-grading and -staging for AS eligibility. Moreover, we analyzed possible biomarkers for predicting more unfavorable final tumor histology., Methods: 197 patients who underwent radical prostatectomy (RPE) but would have met the EAU (European Association of Urology) criteria for AS (PSA<10 ng/ml, biopsy GS ≤ 6, ≤ 2 cancer-positive biopsy cores with ≤ 50% of tumor in any core and clinical stage ≤ T2a) were included in the study. These AS inclusion parameters were correlated to the final histology of the RPE specimens. The impact of preoperative PSA level (low PSA ≤ 4 ng/ml vs. intermediate PSA of >4-10 ng/ml), PSA density (<15 vs. ≥ 15 ng/ml) and the number of positive biopsy cores (1 vs. 2 positive cores) on predicting upgrading and final adverse histology of the RPE specimens was analyzed in uni- and multivariate analyses. Moreover, clinical courses of undergraded patients were assessed., Results: In our patient cohort 41.1% were found under-graded in the biopsy (final histology 40.1% GS7, 1% GS8). Preoperative PSA levels, PSA density or the number of positive cores were not predictive for worse final pathological findings including GS >6, extraprostatic extension and positive resection margin (R1) or correlated significantly with up-grading and/or extraprostatic extension in a multivariate model. Only R1 resections were predictable by combining intermediate PSA levels with two positive biopsy cores (p = 0.004). Sub-analyses showed that the number of biopsy cores (10 vs. 15 biopsy cores) had no influence on above mentioned results on predicting biopsy undergrading. Clinical courses of patients showed that 19.9% of patients had a biochemical relapse after RPE, among all of them were undergraded in the initial biopsy., Conclusion: In summary, this study shows that a multitude of patients fulfilling the criteria for AS are under-diagnosed. The use of preoperative PSA levels, PSA density and the number of positive cores were not predictable for undergrading in the present patient collective.

Background: The aim of the study was to evaluate the correlation between preoperative [-2]proPSA, the Gleason Score (GS) and the risk of non-organ-confined (NOC) disease in patients undergoing radical prostatectomy (RP)., Methods: Beckman Coulter Access immunoassay was used to study serum specimens of 381 patients enrolled in a prostate cancer (PCa) early detection program. Inclusion criteria were three or more available serum specimens over 4 years before diagnosis. The values obtained were correlated with the GSs and pathological stages of specimens obtained at RP., Results: [-2]proPSA levels were significantly higher in the cancer group (n=208) than in the benign group (n=173). Already 4 years before diagnosis [-2]proPSA differed significantly between PCa and benign prostate in all measured time points, however, highest prediction value was 2 and 1 years before diagnosis (P<0.001). When stratified [-2]proPSA levels according to GS of RP specimens, [-2]proPSA was highest in patients with ≥GS8 and lowest in those with ≤GS6.The difference in [-2]proPSA values between GS≥8 and GS≤7 was highly significant (P<0.01) already 3 years before diagnosis. Investigating the correlation between extraprostatic extension and the preoperative [-2]proPSA levels we found preoperative [-2]proPSA values significantly higher in men with NOC PCa compared with organ-confined (OC) cancers.The highest predictive value of [-2]proPSA to differ between OC and extraprostatic extension was found 3 and 2 years before RP., Conclusions: Patients with high [-2]proPSA levels in the years before cancer diagnosis are at a higher risk of having aggressive PCas. Thus, the [-2]proPSA should be included in the treatment decision-making for managing screen-detected PCa.

When offering watchful waiting or active monitoring protocols to prostate cancer (PCa) patients, differentiation between Gleason scores (GS) 6 and 7 at biopsy is important. However, upgrading after prostatectomy is common. We investigated the impact of different PSA levels on misclassification in the PSA range of 2-3.9 and 4-10 ng ml(-1). A total of 448 patients with GS 6 PCa on prostate biopsy were evaluated by comparing biopsy and prostatectomy GS. Possible over diagnosis was defined as GS <7, pathological stage pT2a and negative surgical margins, and possible under diagnosis was defined as pT3a or greater, or positive surgical margins; the percentage of over- or under diagnosis was determined for correctly and upgraded tumors after prostatectomy. A match between biopsy and prostatectomy GS was found in 210 patients (46.9%). Patients in the PSA range of 2.0-3.9 and 4.0-10.0 ng ml(-1) were upgraded in 32.6 and 44.0%, respectively. Over diagnosis was more common than under diagnosis (23.2% vs 15.6%). When upgraded there was a significant increase in under diagnosis. As almost 40% of GS 6 tumors on biopsy are GS 7 or higher after surgery with a significant rise in under diagnosis there is a risk of misclassification and subsequent delayed or even insufficient treatment, when relying on favorable biopsy GS.

Objective: To evaluate the clinical and pathological characteristics of screen vs non-screen-detected prostate cancers, to determine if there is a difference in the same prostate-specific antigen (PSA) range., Patients and Methods: In all, 997 patients who had had a radical prostatectomy were evaluated; 806 were Tyrolean screening volunteers, and 191 were from outside Tyrol, representing the 'referred prostate cancer' group. PSA level, age, prostate volume and pathological characteristics were assessed, as was the amount of over- and under-diagnosis., Results: There were no statistically significant differences in patient age or PSA levels in the two groups. Even in the same PSA range there were statistically significantly more extraprostatic cancers in the referral group, at 31.7% and 17.4%, respectively. In the referred and screening groups there was over-diagnosis in 7.9% and 16.8%, and under-diagnosis in 40.8% and 27.8%, respectively., Conclusion: This study suggests that screening volunteers have a statistically significantly higher rate of organ-confined prostate cancers, and a statistically significantly lower rate of extracapsular extension and positive surgical margins than their counterparts in the referral group even in the same PSA range. As the pathological stage and surgical margin status are significant predictors of recurrence, these findings support the concept of PSA screening.

Objectives: To evaluate possible over- and under-diagnosis of prostate cancer in a screened vs a referral population in the same range of prostate-specific antigen (PSA)., Patients and Methods: In all, 1445 patients undergoing radical prostatectomy and with a PSA level of <10 ng/mL were evaluated; 237 were from outside Tyrol (Austria) and represented the unscreened group, and 1208 were Tyrolean screening volunteers. Over-diagnosis was defined as a pathological stage of pT2a and a Gleason score of <7 with no positive surgical margins. Under-diagnosis was defined as a pathological stage of >or=pT3a or positive surgical margins. The chi-square test was used to assess the differences, with P < 0.05 considered to indicate statistical significance., Results: There were no significant differences in patient age or PSA levels between the study groups. There was over-diagnosis in the screening and referral groups in 17.4% and 8.9%, respectively, and under-diagnosis in 18.6% and 42.2%, respectively., Conclusion: This study suggests that patients with prostate cancer participating in a screening programme are less likely to be under-diagnosed or have extracapsular disease than their counterparts in a referral population, even in the same PSA range, after radical prostatectomy. Furthermore, there was more under-diagnosis in the referral group than over-diagnosis in the screened group.

Objective: To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate-specific antigen level (4-10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy., Patients and Methods: In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0-10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated., Results: Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years., Conclusions: These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.