Traditional Prostate-specific Antigen Research Articles

When surface-enhanced Raman spectroscopy meets complex biofluids: A new representation strategy for reliable and comprehensive characterization

BackgroundSurface-enhanced Raman spectroscopy (SERS) has gained increasing importance in molecular detection due to its high specificity and sensitivity. Complex biofluids (e.g., cell lysates and serums) typically contain large numbers of different bio-molecules with various concentrations, making it extremely challenging to be reliably and comprehensively characterized via conventional single SERS spectra due to uncontrollable electromagnetic hot spots and irregular molecular motions. The traditional approach of directly reading out the single SERS spectra or calculating the average of multiple spectra is less likely to take advantage of the full information of complex biofluid systems. ResultsHerein, we propose to construct a spectral set with unordered multiple SERS spectra as a novel representation strategy to characterize full molecular information of complex biofluids. This new SERS representation not only contains details from each single spectra but captures the temporal/spatial distribution characteristics. To address the ordering-independent property of traditional chemometric methods (e.g., the Euclidean distance and the Pearson correlation coefficient), we introduce Wasserstein distance (WD) to quantitatively and comprehensively assess the quality of spectral sets on biofluids. WD performs its superiority for the quantitative assessment of the spectral sets. Additionally, WD benefits from its independence of the ordering of spectra in a spectral set, which is undesirable for traditional chemometric methods. With experiments on cell lysates and human serums, we successfully achieve the verification for the reproducibility between parallel samples, the uniformity at different positions in the same sample, the repeatability from multiple tests at one location of the same sample, and the cardinality effect of the spectral set. SERS spectral sets also manage to distinguish different classes of human serums and achieve higher accuracy than the traditional prostate-specific antigen in prostate cancer classification. SignificanceThe proposed SERS spectral set is a robust representation approach in accessing full information of biological samples compared to relying on a single or averaged spectra in terms of reproducibility, uniformity, repeatability, and cardinality effect. The application of WD further demonstrates the effectiveness and robustness of spectral sets in characterizing complex biofluid samples, which extends and consolidates the role of SERS.

Multiplexed Opto-Microfluidic Biosensing: Advanced Platform for Prostate Cancer Detection.

Cancer stands as a prominent global cause of mortality, necessitating early detection to augment survival rates and alleviate economic burdens on healthcare systems. In particular, prostate cancer (PCa), impacting 1.41 million men globally in 2020, accentuates the demand for sensitive and cost-effective detection methods beyond traditional prostate-specific antigen (PSA) testing. While clinical techniques exhibit limitations, biosensors emerge as compact, user-friendly alternatives to traditional laboratory approaches. However, existing biosensors predominantly concentrate on PSA detection, prompting the necessity for advancing toward multiplex sensing platforms. This study introduces a compact opto-microfluidic sensor featuring a substrate of gold nanospikes, fabricated via electrodeposition, for enhanced sensitivity. Embedded within a microfluidic chip, this nanomaterial enables the precise and concurrent measurement of PSA, alongside two complementary PCa biomarkers, matrix metalloproteinase-2 (MMP-2) and anti-α-methylacyl-CoA racemase (anti-AMACR) in diluted human plasma, offering a comprehensive approach to PSA analysis. Taking advantage of the localized surface plasmon resonance principle, this biosensor offers robustness and sensitivity in real sample analysis without the need for labeling agents. With the limit of detection at 0.22, 0.37, and 0.18 ng/mL for PSA, MMP-2, and anti-AMACR, respectively, this biosensing platform holds promise for point-of-care analysis, underscoring its potential impact on medical diagnostics.

A correlation and red, amber, green (RAG) analysis of Boditech i-CHROMA™ Prostate Specific Antigen (PSA) Point of Care Test (POCT) Method and Roche PSA laboratory methods

Background: This study evaluated and compared the performance of the Boditech i-CHROMA™ point-of-care testing (POCT) method for the quantification of prostate-specific antigen (PSA) against traditional laboratory PSA method (Roche Methods – Roche Cobas c303/501/502/503, Roche Cobas e402/ e801 and Roche Cobas e411) using external quality control material from RIQAS. Materials and method: External quality control distributions from RIQAS were analysed using the Boditech i-CHROMA™ PSA method; these were then compared with the results of the Roche Methods – Roche Cobas c303/501/502/503, Roche Cobas e402/ e801 and Roche Cobas e411 provided by participants in the scheme. The mean results of the Roche methods were compared using linear regression and Red Amber Green (RAG) analysis, a scoring system where red is indicative of a raised PSA (>6.0 ng/mL), amber is indicative of a slightly raised PSA (5.0 – 6.0 ng/mL). Green indicates a normal PSA (<5.0 ng/mL). Results: The data showed that between the Boditech i-CHROMA™ PSA results and the Roche Cobas c303/501/502/503, there was an excellent correlation (r2 = 0.9843). The RAG analysis showed the Boditech i-CHROMA™ PSA method identified 26 reds, two ambers, and six greens compared with 27 reds, two ambers, and six greens determined by the Roche Cobas c303/501/502/503 method. The data showed an excellent correlation between the Boditech i-CHROMA™ PSA results and the Roche Cobas e402/ e801 PSA methods (r2 = 0.9842). The RAG analysis showed the Boditech i-CHROMA™ PSA method identified 30 reds, three ambers, and eight greens compared with 31 reds, two ambers, and eight greens identified by the Roche Cobas e402/ e801 PSA methods. The data showed an excellent correlation between the Boditech i-CHROMA™ PSA results and the Roche Cobas e411 PSA methods (r2 = 0.9851). The RAG analysis showed the Boditech i-CHROMA™ PSA method identified 30 reds, three ambers, and eight greens compared with 31 reds, two ambers, and eight greens identified Roche Cobas e411 PSA methods. Conclusion: The data showed that the Boditech i-CHROMA™ PSA method is comparable to the Roche Cobas c303/501/502/503, Roche Cobas e402/ e801 and Roche Cobas e411 PSA methods. This could effectively reduce the turnaround time to make prompt decisions on diagnosing, treating, and monitoring of patients with prostate-related disorders.

Glutathione-S-Transferase p1 Gene Promoter Methylation in Cell-Free DNA as a Diagnostic and Prognostic Tool for Prostate Cancer: A Systematic Review and Meta-Analysis.

Promoter methylation of glutathione-S-transferase p1 (GSTP1) is related to the occurrence of prostate cancer (PCa), but reports are inconsistent about the accuracy of GSTP1 promoter methylation in PCa diagnosis and prognosis. Therefore, we systematically evaluated the diagnostic and prognostic value of GSTP1 promoter methylation in PCa. The PubMed, EMBASE, Web of Science, and PMC databases were searched for all relevant studies from the date of inception to November 31, 2021. We compared differences in the incidence of GSTP1 promoter methylation in cfDNA between prostate cancer patients and controls. The odds ratio (OR) and hazard ratio (HR) were used as effect sizes, and the result of each effect size is expressed as a 95% confidence interval (95% CI). Our meta-analysis showed that the combined sensitivity and specificity of GSTP1 promoter methylation in cfDNA for the diagnosis of prostate cancer were 0.37 (95% CI = 0.23, 0.53) and 0.97 (95% CI = 0.88, 0.99), respectively. The area under the curve (AUC) with 95% CI was 0.78 (95% CI = 0.75, 0.82). For prognostic variables, hypermethylation of GSTP1 was associated with shorter survival in PCa (HR = 2.57, 95% CI = 1.30, 5.10), with statistical significance in between-study heterogeneity (I 2 = 72%, P=0.006). The results of the subgroup analysis indicated that the heterogeneity of studies may be due to differences in the observed indicators. The results of the meta-analysis substantiate the high specificity of promoter methylation of GSTP1 in cfDNA for the diagnosis of prostate cancer, and it may be used to more precisely evaluate the prognosis of patients with prostate cancer. It may be helpful for the early detection of prostate cancer, but it still must be combined with traditional prostate-specific antigen (PSA) or other methylated genes to accomplish this goal.

Cost-effectiveness of Prostate Cancer Screening Using Magnetic Resonance Imaging or Standard Biopsy Based on the STHLM3-MRI Study

The combination of prostate-specific antigen (PSA) testing with magnetic resonance imaging (MRI) for prostate cancer detection has rarely been evaluated in a screening context. The STHLM3-MRI screening-by-invitation study (NCT03377881) has reported the benefits of using MRI with subsequent combined targeted and standard biopsies compared with using standard biopsies alone. To investigate the cost-effectiveness of prostate cancer screening using MRI with combined targeted and standard biopsies compared with standard biopsies alone among men aged 55 to 69 years in Sweden, based on evidence from the STHLM3-MRI study. This economic evaluation study was conducted from a lifetime health care perspective using a microsimulation model to evaluate no screening and screening strategies among adult men in Sweden. Men aged 55 to 69 years in Sweden were simulated for no screening and screening strategies. Input parameters were obtained from the STHLM3-MRI study and recent reviews. One-way and probabilistic sensitivity analyses were performed in May 2022. No screening, quadrennial PSA screening using standard biopsies alone, and MRI-based screening using combined targeted and standard biopsies. The number of tests, incidence, deaths, costs, quality-adjusted life-years (QALY), and incremental cost-effectiveness ratios (ICERs) were estimated. A total 603 men were randomized to the standard arm, 165 of these participants (27.4%) did not undergo standard biopsy; 929 men were randomized to the experimental arm, 111 (11.9%) of whom did undergo MRI or any biopsy. Compared with no screening, the screening strategies were associated with reduced lifetime prostate cancer-related deaths by 6% to 9%. Screening with MRI and the combined biopsies resulted in an ICER of US $53 736, which is classified as a moderate cost per QALY gained in Sweden. Relative to screening with standard biopsies alone, MRI-based screening reduced the number of both lifetime biopsies and overdiagnosis by approximately 50% and had a high probability of being cost-effective than the traditional PSA screening. For prostate cancer screening, this economic evaluation study found that PSA testing followed by MRI with subsequent combined targeted and standard biopsies had a high probability to be more cost-effective compared with the traditional screening pathway using PSA and standard biopsy. MRI-based screening may be considered for early detection of prostate cancer in Sweden.

Prostate-specific antigen glycoprofiling as diagnostic and prognostic biomarker of prostate cancer.

The initial part of this review details the controversy behind the use of a serological level of prostate-specific antigen (PSA) for the diagnostics of prostate cancer (PCa). Novel biomarkers are in demand for PCa diagnostics, outperforming traditional PSA tests. The review provides a detailed and comprehensive summary that PSA glycoprofiling can effectively solve this problem, thereby considerably reducing the number of unnecessary biopsies. In addition, PSA glycoprofiling can serve as a prognostic PCa biomarker to identify PCa patients with an aggressive form of PCa, avoiding unnecessary further treatments which are significantly life altering (incontinence or impotence).

Abstract 5445: Inhibition of tumor suppressor function of RUNX3 by miR-301a facilitates the progression of castration resistant prostate cancer

Abstract Treatment of prostate cancer is still clinically challenging due to lack of reliable markers for diagnosis and prognosis. Serum prostate specific antigen (PSA) is of limited clinical utility due to poor sensitivity and specificity. A large number of false positives (50%) with traditional PSA testing lead many patients to undergoing unnecessary prostate biopsy and exposure to unnecessary risk of complications. So the goal of this study is to identify a reliable, non-invasive biomarker that can distinguish patients with benign, indolent and aggressive prostate cancer in various clinical settings. MicroRNAs (miRNAs) are small noncoding (18 to 28 nucleotides) RNA molecules that are present in all human cells, and their expression patterns are correlated with many cancer types, including CaP. In our results, we found a significant differential expression (p=0.013) of miR-301a in both tumor tissues (Gleason-6 and -7) and serum samples in comparison to benign prostatic hyperplasia (BPH) or adjacent benign samples. We observed a negative correlation between miR-301a and RUNX3 expression in human CaP samples suggesting tumor suppressive role RUNX3 might be compromised in CaP. To determine MiR-301a regulation on RUNX3, we evaluated miR-301a and RUNX3 protein in panel of prostate cancer cell lines, normal prostate epithelial cells and Benign Prostate Hyperplasia (BPH). Similar results such as inverse correlation between miR-301a and RUNX were found in cell culture models. Also, over expression of miR-301a down regulates RUNX3 activation in prostate cancer cell lines and silencing miR-301a expression reverts RUNX3 activation in BPH cells. While evaluating the reporter activity of RUNX3 either by co-transfecting with mimic or inhibitor of miR-301a in BPH and prostate cancer cells: over expression of miR-301a down regulated RUNX3 reporter activity which corresponded with RUNX3 protein expression. Similarly, silencing miR-301a reverted RUNX3 promoter activity and protein expression suggesting RUNX3 is a direct target of miR-301a in CaP cells. Silencing miR-301a reverted the pro-apoptotic function of RUNX3, results in reduced colony formation, adhesion, invasion and migration of CaP cells. Investigating the mechanistic link miR-301a and RUNX3 may explore whether it could facilitate clinical decision making such as the decision to proceed with early surgery rather than active surveillance for intermediate risk prostate cancer patients deemed to be at high risk of progression. Citation Format: Venkatesh Kolluru, Balaji Chandrasekhar, Collin McKenzie, Houda Alatassi, Murali Ankem, Chendil Damodaran. Inhibition of tumor suppressor function of RUNX3 by miR-301a facilitates the progression of castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5445. doi:10.1158/1538-7445.AM2017-5445

Abstract 1297: Genetic reclassification of prostate-specific antigen levels for personalized prostate cancer screening

Abstract Background: Prostate-specific antigen (PSA) screening for prostate cancer results missed diagnoses as well as many unnecessary biopsies and their associated morbidities. Because PSA levels are heritable, traditional PSA screening may be improved by adjustment for constitutive germline genetics that influence PSA independently of prostate cancer. Methods: In a previous genome-wide association study in non-Hispanic white men without prostate cancer in the Kaiser Permanente Research Program on Genes, Environment and Health cohort, we identified 40 single nucleotide polymorphisms (SNP) independently and significantly associated with PSA levels. Among them, 24 were not associated with prostate cancer risk. To calculate genetically normalized PSA (i.e., PSA’), we multiplied each man’s most recent PSA measurement by a factor that adjusted for the amount by which his 24 PSA-specific SNPs may have increased his PSA level. We then compared how men without prostate cancer were classified based on their PSA and PSA’ levels with regard to decisions for diagnostic testing. Results: PSA and PSA’ were highly correlated among non-Hispanic white men without prostate cancer (r2: 0.959; 95% CI: 0.958-0.960). Still, 4.6% were reclassified from above to below a cutpoint of 2.5 ng/ml when using the PSA’ measure, and 2.7% were reclassified from below to above this cutpoint (4.6% - 2.7% = 1.9% net reclassified to below the cutoff). The reclassification was even more pronounced when restricting to controls with a negative prostate biopsy: 5.0% downward and 1.5% upward (3.5% net reclassified to below the cutoff). Conclusions: Normalizing PSA levels using germline PSA variants may reduce the number of subjects without prostate cancer receiving unnecessary biopsies. Citation Format: Rebecca E. Graff, Thomas J. Hoffmann, Michael N. Passarelli, Nima C. Emami, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Charles P. Quesenberry, Chun R. Chao, Nirupa R. Ghai, David Aaronson, Joseph Presti, Tobias Nordström, Zhaoming Wang, Sonja I. Berndt, Stephen J. Chanock, Jonathan D. Mosley, Robert J. Klein, Mridu Middha, Hans Lilja, Olle Melander, Mark N. Kvale, Pui-Yan Kwok, Catherine Schaefer, Neil Risch, Neil Risch, Stephen K. Van Den Eeden, John S. Witte. Genetic reclassification of prostate-specific antigen levels for personalized prostate cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2017-1297

An Evaluation of the Point-of-Care Test i-CHROMA Prostate-Specific Antigen Method for Screening in the Community

Background This study evaluated and compared the performance of the i-CHROMA point-of-care testing (POCT) method for the quantification of prostate-specific antigen (PSA) against a traditional laboratory PSA method (Abbott Architect assay). Materials and Method Blood samples (venous [143] serum [143]) and finger prick (55) were collected from volunteers at a PSA screening campaign. Both venous and finger-prick samples were analyzed using the i-CHROMA PSA method and serum samples using the Abbott Architect method. Results were compared using linear regression and Red Amber Green analysis, a scoring system based on volunteer's age and PSA level. Red indicated a raised PSA, amber indicated a slightly raised PSA, and green indicated a normal PSA. Results The data showed that both the i-CHROMA PSA results using the venous samples (r2 = 0.9841) and the finger-prick samples (r2 = 0.90845) showed a good correlation when compared with the serum samples using the laboratory method. The Red Amber Green analysis showed the i-CHROMA' venous PSA method identified 15 reds, 13 ambers, and 115 greens compared with 9 reds, 8 ambers, and 126 greens identified by Abbot Architect method. The i-CHROMA finger-prick PSA method identified 3 reds, 3 ambers, and 49 greens compared with 3 reds, 1 ambers, and 51 greens identified by Abbot Architect method. Conclusions The i-CHROMA POCT PSA method showed good correlation with the Abbott Architect PSA method. Higher numbers of raised and abnormal PSA were identified by the i-CHROMA POCT PSA method due to the positive bias observed. The i-CHROMA POCT PSA method is a reliable method for total PSA within its limitations.

Racial variation in the reliability of prostate cancer indicators in men undergoing subsequent prostate biopsy.

115 Background: Many men with an initial negative prostate biopsy have a persistently elevated prostate specific antigen (PSA) prompting physicians to perform repeat biopsies. African American men (AA) are at particular risk as they have a greater prostate cancer (PCa) incidence and mortality, yet traditional PSA testing may be less reliable in this cohort. We sought to determine the predictors of PCa and PCa severity in a racially diverse population on subsequent biopsy following an initial benign biopsy. Methods: Upon receiving Institutional Review Board approval, a retrospective analysis was performed on men with repeat prostate biopsies at Tulane Medical Center and Southeast Louisiana Veterans Health Care Services in New Orleans, Louisiana from 2003-2015. Inclusion criteria included patients with a benign initial prostate biopsy and underwent subsequent repeat prostate biopsy within 5 years. Race, age, serum PSA, PSA density (PSAD), and prostate volume by transrectal ultrasound (TRUS) were evaluated to determine if they correlate with the presence and severity of PCa. Aggressive PCa was defined as Gleason score >6. Results: A total of 209 men were included; 127 (61%) were AA, and 82 (39%) were Caucasian American men (CA). The two groups were similar with respect to PSA, PSAD, and TRUS. More AA (25.2% vs. 17.1%) had a repeat biopsy showing any PCa. Of those with PCa, 28.1% of AA and 28.6% of CA had aggressive PCa. PSAD positively correlated with any PCa (p=.015). TRUS negatively correlated with any PCa (p=.008). PSA levels (p<.001) and PSAD (p<.001) positively correlated with aggressive PCa in CA but not in AA. Conclusions: The goal of prostate biopsy particularly for those with a prior negative biopsy is to detect aggressive PCa. PSA and PSAD positively correlated with finding any PCa in both AA and CA but not with aggressive PCa in AA. PSA and PSAD are less accurate predictors of aggressive PCa in AA, and novel biomarkers are needed. [Table: see text]

Longitudinal modeling of ultrasensitive and traditional prostate-specific antigen and prediction of biochemical recurrence after radical prostatectomy

Ultrasensitive prostate-specific antigen (u-PSA) remains controversial for follow-up after radical prostatectomy (RP). The aim of this study was to model PSA doubling times (PSADT) for predicting biochemical recurrence (BCR) and to capture possible discrepancies between u-PSA and traditional PSA (t-PSA) by utilizing advanced statistical modeling. 555 RP patients without neoadjuvant/adjuvant androgen deprivation from the Turku University Hospital were included in the study. BCR was defined as two consecutive PSA values >0.2 ng/mL and the PSA measurements were log2-transformed. One third of the data was reserved for independent validation. Models were first fitted to the post-surgery PSA measurements using cross-validation. Major trends were then captured using linear mixed-effect models and a predictive generalized linear model effectively identified early trends connected to BCR. The model generalized for BCR prediction to the validation set with ROC-AUC of 83.6% and 95.1% for the 1 and 3 year follow-up censoring, respectively. A web-based tool was developed to facilitate its use. Longitudinal trends of u-PSA did not display major discrepancies from those of t-PSA. The results support that u-PSA provides useful information for predicting BCR after RP. This can be beneficial to avoid unnecessary adjuvant treatments or to start them earlier for selected patients.

Ultrasensitive Electrochemical Detection of Prostate-Specific Antigen by Using Antibodies Anchored on a DNA Nanostructural Scaffold

The high occurrence of prostate cancer in men makes the prostate-specific antigen (PSA) screening test really important. More importantly, the recurrence rate after radical prostatectomy is high, whereas the traditional PSA immunoassay does not possess the sufficient high sensitivity for post-treatment PSA detection. In these assays, uncontrolled and random orientation of capture antibodies on the surface largely reduces their activity. Here, by exploiting the rapidly emerging DNA nanotechnology, we developed a DNA nanostructure based scaffold to precisely control the assembly of antibody monolayer. We demonstrated that the detection sensitivity was critically dependent on the nanoscale-spacing (nanospacing) of immobilized antibodies. In addition to the controlled assembly, we further amplified the sensing signal by using the gold nanoparticles, resulting in extremely high sensitivity and a low detection limit of 1 pg/mL. To test the real-world applicability of our nanoengineered electrochemical sensor, we evaluated the performance with 11 patients' serum samples and obtained consistent results with the "gold-standard" assays.

MP74-07 USE OF ULTRASENTIVE PSA DOUBLING TIME TO ESTIMATE PROGRESSION RISK OF PROSTATE CANCER AFTER RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 2014MP74-07 USE OF ULTRASENTIVE PSA DOUBLING TIME TO ESTIMATE PROGRESSION RISK OF PROSTATE CANCER AFTER RADICAL PROSTATECTOMY Heikki Seikkula, Samu Kurki, Kari Syvänen, Peter Boström, and Matti Laato Heikki SeikkulaHeikki Seikkula More articles by this author , Samu KurkiSamu Kurki More articles by this author , Kari SyvänenKari Syvänen More articles by this author , Peter BoströmPeter Boström More articles by this author , and Matti LaatoMatti Laato More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2340AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate specific antigen (PSA) is the single most important tool in follow up of prostate cancer (PC) after radical prostatectomy (RP). Biochemical relapse (BCR) is defined by two consecutive PSA values of > 0.2 ng/mL. The role of ultrasensitive PSA(uPSA) in follow-up after RP is not well defined. The objective of this study was to investigate two questions: 1) Is there a definitive value for biochemical relapse (BCR) in ultrasensitive areas, and 2) is uPSA doubling time (DT) in ultrasensitive area (uDT) a useful prognostic tool and whether it correlates with doubling time in traditional PSA (tDT) area. METHODS A total of 604 patients underwent open RPs in Turku university hospital during 2004-2008. After exclusion of patients with neoadjuvant or adjuvant androgen deprivation therapy, 548 patients were available for analysis. Median age was 61.8 years ( ± 5.8). Of these men 272 (50%) had Gleason score 6 or less, 227 (41%) Gleason 7 and 49 (9%) 8 or more. Positive margin was found in 207 (38%) patient. Local lymph nodes were positive in two men. Median follow up time was 5.6 years (±2.4). During follow-up 71 of 548 (13%) patient had BCR and 18 men received salvage radiation before psa level 0.2 The total amount of psa failures was 89 (16.2%). To analyze upper limit of uPSA in patients without BCR patients with at least two years of follow up and no tPSA relapse were analyzed. We used a Scatterplot-table to evaluate biological reflection of uPSA. To answer our second question we analyzed every man with BCR (PSA ≥0.2ng/ml). Patients with at least two uPSA and two tPSA measurements were included to calculate uDT and tDT. We excluded subjects with salvage treatment. 47 patients met these criteria. uDT was calculated using all nonzero values under 0.2 ng/ml. These two DTs were compared. To compare uDT and tDT a weighted Cohen`s kappa statistic was used to test agreement across the categories. RESULTS There were 229 patients without BCR who had three rising PSA values after nadir. Their highest PSA value was between 0.003-0.1 ng/ml. In 97.4% of patients highest PSA value was under 0.03 and in 89% under 0.02. The median DT in uPSA was 10.2 months and tPSA11.4 months. The weighted Cohen's kappa statistic between these two groups was 0.30. This demonstrates a poor agreement of PSADT across categories. CONCLUSIONS uPSA values under 0.03 should be considered non-significant and may be normal variation without risk of BCR. In current study a poor agreement between tDT and uDT was found. Accuracy of uDT improves when it is nearing threshold 0.1 ng/ml. More studies are needed to define the optimal use of uPSA. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e858 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Heikki Seikkula More articles by this author Samu Kurki More articles by this author Kari Syvänen More articles by this author Peter Boström More articles by this author Matti Laato More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Poor Agreement of Prostate Specific Antigen Doubling Times Calculated Using Ultrasensitive Versus Standard Prostate Specific Antigen Values: Important Impact on Risk Assessment

In men with biochemical recurrence after radical prostatectomy, a rapid prostate specific antigen doubling time is associated with adverse outcomes, and is often used to guide the type and timing of salvage therapy. It is unknown whether prostate specific antigen doubling time calculated in the ultrasensitive range (prostate specific antigen less than 0.2 ng/ml) accurately reflects measures performed in the traditional range (prostate specific antigen greater than 0.2 ng/ml). We studied 394 men in a national disease registry of men with prostate cancer (CaPSURE™) who underwent radical prostatectomy, experienced biochemical failure, and had prostate specific antigen doubling time assessed using ultrasensitive and traditional prostate specific antigen values. Agreement between these measurements was assessed using Cohen's kappa score. Median ultrasensitive prostate specific antigen doubling time was 11.9 months (IQR 6-29) and median traditional prostate specific antigen doubling time was 240 months (IQR 18-240). Agreement between ultrasensitive and traditional prostate specific antigen doubling time was poor, with a weighted Cohen's kappa score of 0.04 (95% CI -0.02-0.10). Using a dichotomous prostate specific antigen doubling time cutoff of 9 months, there was a statistically significant difference between ultrasensitive and standard prostate specific antigen doubling time (exact McNemar p <0.01). Ultrasensitive prostate specific antigen doubling time was more or less rapid than traditional prostate specific antigen doubling time by more than 15 months in 244 (62%) and 35 (9%) patients, respectively. Agreement between prostate specific antigen doubling time calculated using ultrasensitive vs traditional prostate specific antigen values is poor. Ultrasensitive prostate specific antigen doubling time is often significantly more rapid than traditional prostate specific antigen doubling time, potentially overestimating the risk of clinical recurrence. Until the significance of ultrasensitive prostate specific antigen doubling time is better characterized, the decision to proceed with salvage therapy should not be based on prostate specific antigen doubling time calculated using ultrasensitive prostate specific antigen values.

Is there an optimal prostate-specific antigen threshold for prostate biopsy?

Prostate-specific antigen (PSA) remains the best biomarker available for early prostate cancer (PCa) detection. Increasing PSA values are associated with increasing PCa risk. The traditional PSA cut-off of 4 µg/l was lowered because the PCa detection rates are similar in the PSA ranges 2–4 and 4–10 µg/l. This approach increases sensitivity, but also lets the numbers of ‘insignificant cancers’ rise. Thus far, the used PSA cut-offs 2.5, 3 or 4 µg/l provide a reasonable balance between excessive detection rates and the risk of missing relevant PCa. Specificity of PSA has been enhanced by using PSA derivatives, PSA isoforms, new biomarkers and multivariate models. PSA should be used intelligently and several other factors should be considered for a final biopsy decision.

Prostate-specific antigen test result interpretation when combined with risk factors for recommendation of biopsy: a survey of urologist’s practice patterns

Recent data have suggested historical cutoff levels for prostate cancer (PC) screening using a prostate-specific antigen (PSA) level≤4ng/ml may no longer be appropriate with cancer detected at lower levels, particularly in younger men. Our aim was to conduct a contemporary survey of urologist's practice patterns toward PC detection, specifically focusing on factors determining the decision to recommend ultrasound-guided biopsy (TRUS-BX). Three hundred and sixty active urologists from the Canadian Urological Association were requested to complete an online questionnaire focusing on scenarios of varying age, family history, ethnicity and PSA. Urologists indicated when to TRUS-BX. Of 360 urologists, 125 (35%) completed the questionnaire. Sixty-seven percent indicated men should be screened for PC aged 50-60 with 27% preferring 40-50years. Seventy-seven percent would continue screening >75. Considering a 65-year-old man with no risk factors and a normal digital rectal exam 56% would offer TRUS-BX at PSA 4.5; 35% at 3.5 and 10% at 2.5ng/ml. Considering a similar 45-year-old man, 94% would at PSA 4.5; 77% at 3.5 and 33% at 2.5ng/ml. On multivariate analysis, offering TRUS-BX appears driven significantly (P<0.0001) more by younger age and higher PSA (OR 4.3-20.6 and 4.4-34.9, respectively) rather than family history or ethnicity (OR 3.3 and 1.8, respectively). Age and PSA appear the driving factors in obtaining TRUS-BX. Also, a significant proportion of urologists would still not offer TRUS-BX at the traditional PSA cutoff of 4ng/ml for men with no risk factors. Further studies are required to ascertain whether this relates to a lack of dissemination of studies into practice.

20–25% Lower Concentrations of Total and Free Prostate-Specific Antigen (PSA) after Calibration of PSA Assays to the WHO Reference Materials – Analysis of 1098 Patients in Four Centers

Aim To examine the potential clinical implications of the recalibration of total prostate-specific antigen (PSA) and free PSA (fPSA) assays to the World Health Organization (WHO) standard materials. Material and methods Data from 1098 patients with or without clinically detected prostate cancer (PCa) from four independent cohort studies were compared using commercial assays calibrated to the traditional Hybritech® PSA (PSA-Hyb) and fPSA (fPSA-Hyb) standards and to the WHO 96/670 (PSA-WHO) and 96/668 (fPSA-WHO) standards. The Access® Immunoassay System (Beckman Coulter, Inc.) was used in all studies. Results All studies showed 20% to 25% lower PSA and fPSA test results with the WHO-standardized assays. No significant change in %fPSA (fPSA/PSA × 100) was observed. Continuing to use the traditional clinical PSA cutoffs obtained with the Hybritech standard after changing to the PSA-WHO standard could result in up to one-third of prostate cancer cases being missed. Conclusions: Manufacturers should fully inform laboratories about a calibration change and its clinical impact. Laboratory reports for PSA measurements should indicate the assay's manufacturer and which calibration standard was used to avoid misleading information concerning PCa risk

20-25% lower concentrations of total and free prostate-specific antigen (PSA) after calibration of PSA assays to the WHO reference materials – analysis of 1098 patients in four centers

To examine the potential clinical implications of the recalibration of total prostate-specific antigen (PSA) and free PSA (fPSA) assays to the World Health Organization (WHO) standard materials. Data from 1098 patients with or without clinically detected prostate cancer (PCa) from four independent cohort studies were compared using commercial assays calibrated to the traditional Hybritech PSA (PSA-Hyb) and fPSA (fPSA-Hyb) standards and to the WHO 96/670 (PSA-WHO) and 96/668 (fPSA-WHO) standards. The Access Immunoassay System (Beckman Coulter, Inc.) was used in all studies. All studies showed 20% to 25% lower PSA and fPSA test results with the WHO-standardized assays. No significant change in %fPSA (fPSA/PSA x 100) was observed. Continuing to use the traditional clinical PSA cutoffs obtained with the Hybritech standard after changing to the PSA-WHO standard could result in up to one-third of prostate cancer cases being missed. Manufacturers should fully inform laboratories about a calibration change and its clinical impact. Laboratory reports for PSA measurements should indicate the assay's manufacturer and which calibration standard was used to avoid misleading information concerning PCa risk.

Prostate Specific Antigen Velocity in Men With Total Prostate Specific Antigen Less Than 4 ng/ml

A prostate specific antigen velocity threshold of 0.75 ng/ml per year has commonly been used to distinguish men with prostate cancer from those with benign prostate conditions. In addition, a prostate specific antigen velocity greater than 2 ng/ml per year has been linked to an increased prostate cancer specific mortality rate after radical prostatectomy and after radiation therapy. However, both of these frequently cited thresholds were determined largely in groups of men with a prostate specific antigen greater than 4 ng/ml. Of approximately 26,000 men who participated in a prostate cancer screening study 22,019 had a prostate specific antigen of 4 ng/ml or less. Of these men 501 were diagnosed with prostate cancer and had sufficient data for a prostate specific antigen velocity calculation. We performed univariate and multivariate analyses to compare cancer detection rates and performance characteristics using various prostate specific antigen velocity thresholds in these men. In men with a prostate specific antigen less than 4 ng/ml, a prostate specific antigen velocity threshold of 0.4 ng/ml per year was most useful for recommending prostate biopsy. Overall prostate cancer was diagnosed in 223 (2%) men with a prostate specific antigen velocity less than 0.4 ng/ml per year compared to 278 (13%) men with a prostate specific antigen velocity greater than 0.4 ng/ml per year (p <0.0001). On multivariate analysis a prostate specific antigen velocity greater than 0.4 ng/ml per year was a stronger independent predictor of prostate cancer diagnosis than age, race or a family history of prostate cancer. The traditional prostate specific antigen threshold of 0.75 ng/ml per year was determined largely in men with a total prostate specific antigen of 4 to 10 ng/ml. Prostate specific antigen velocity thresholds in the range of 0.4 ng/ml per year should be used to help guide the need for biopsy in men with a total prostate specific antigen less than 4 ng/ml.

Prostate Specific Antigen Velocity Threshold for Predicting Prostate Cancer in Young Men

Longitudinal changes in prostate specific antigen are increasingly used to guide the recommendation for biopsy. Prostate specific antigen velocity 0.75 ng/ml yearly has been proposed to distinguish prostate cancer from benign prostate conditions. However, this threshold might be too high in young men with lower total prostate specific antigen. In a large prostate cancer screening study 6,844 men were 60 years or younger at study entry and prostate specific antigen velocity calculation was possible. Of these men 346 (5%) were subsequently diagnosed with prostate cancer and various prostate specific antigen velocity thresholds were examined for prediction of prostate cancer risk. Multivariate analysis was performed to determine whether prostate specific antigen velocity is an independent predictor of prostate cancer in men younger than 60 years. Median prostate specific antigen velocity was significantly higher in men who were later diagnosed with prostate cancer than in those who were not (0.840 vs 0.094 ng/ml yearly, p<0.0001). On multivariate analysis prostate specific antigen velocity greater than 0.4 ng/ml yearly was more predictive of prostate cancer than age, total prostate specific antigen, family history or race. Multivariate analysis in the subgroup of men with total prostate specific antigen less than 2.5 ng/ml had similar results. Overall a cutoff of 0.4 ng/ml yearly was associated with 67.3% sensitivity, 81.2% specificity, 16% positive predictive value and 98% negative predictive value for prostate cancer detection in young men. The traditional prostate specific antigen velocity threshold of 0.75 ng/ml yearly is too high for men younger than 60 years and it misses 48% of prostate cancers. Young men with prostate specific antigen velocity greater than 0.4 ng/ml yearly are at significantly greater risk for prostate cancer and close followup is warranted.