Gray-zone Prostate-specific Antigen Research Articles

Evaporation-Induced rGO Coatings for Highly Sensitive and Non-Invasive Diagnosis of Prostate Cancer in the PSA Gray Zone.

The prostate-specific antigen (PSA) has been widely used for the early diagnosis of prostate cancer during routine check-ups. However, the low sensitivity of regular PSA tests in the PSA gray zone often means that patients are required to undergo further invasive needle biopsy for the diagnosis of prostate cancer, which may lead to potential overdiagnosis and overtreatment. In this study, a circulating tumor cell (CTC)-chip based on an evaporation-induced reduced graphene oxide (rGO) coating is presented, which enables a highly specific and non-invasive diagnosis of prostate cancer in the PSA gray zone. During the evaporation process of the rGO dispersion, the Marangoni effect induces the self-assembly of a hierarchical micro/nanowrinkled rGO coating, which can capture CTCs after subsequent surface modification of capture agents. Compared to the low diagnostic sensitivity (58.3%) of regular PSA tests, a combination of CTC detection and PSA-based hematological tests via machine-learning analysis can greatly upgrade the diagnostic sensitivity of this disease to 91.7% in clinical trial. Therefore, this study provides a non-invasive alternative with high sensitivity for the diagnosis of prostate cancer in the PSA gray zone.

Is PSA density of the peripheral zone as a useful predictor for prostate cancer in patients with gray zone PSA levels?

BackgroundSerum prostate-specific antigen (PSA) is widely used in screening tests for prostate cancer. As the low specificity of PSA results in unnecessary and invasive prostate biopsies, we evaluated the clinical significance of various PSAs and PSA density (PSAD) related to peripheral zones in patients with gray zone PSA level (4–10 ng/mL).MethodsA total of 1300 patients underwent transrectal ultrasonography-guided prostate biopsy from 2014 to 2019. Among them, 545 patients in the gray zone were divided into the prostate cancer diagnosis group and the non-prostate cancer diagnosis group, and PSA, relative extra transitional zone PSA (RETzPSA), estimated post holmium laser enucleation of the prostate PSA (EPHPSA), PSAD, peripheral zone PSA density (PZPSAD) and extra-transitional zone density (ETzD) were compared and analyzed using receiver-operating characteristics (ROC) analysis after 1:1 matching using propensity score.ResultsArea under the ROC curve values of PSA, EPHPSA, RETzPSA, PSA density, ETzD, and PZPSAD were 0.553 (95% CI: 0.495–0.610), 0.611 (95% CI: 0.554–0.666), 0.673 (95% CI: 0.617–0.725), 0.745 (95% CI: 0.693–0.793), 0.731 (95% CI: 0.677–0.780) and 0.677 (95% CI: 0.611–0.719), respectively. PSAD had 67.11% sensitivity, 71.71% specificity, and 70.34% positive predictive rate at 0.18 ng/mL/cc. ETzD had 69.08% sensitivity, 64.47% specificity, and 66.04% positive predictive rate at 0.04 ng/mL/cc. When the cut-off value of PSAD was increased to 0.18 ng/mL/cc, the best results were obtained with an odds ratio of 5.171 (95% CI: 3.171–8.432), followed by ETzD with 4.054 (95% CI: 2.513–6.540).ConclusionsThese results suggested that volume-adjusted parameters (ETzD and PSAD) might be more sensitive and accurate than various PSA in gray zone patients who required prostate biopsy to reduce unnecessary biopsy.

A Multivariate Diagnostic Model Based on Urinary EpCAM-CD9 Positive Extracellular Vesicles for Prostate Cancer Diagnosis

Background: Prostate cancer (PCa) is one of the most frequently diagnosed cancers and the leading cause of cancer death in males worldwide. However, current biomarkers used in the clinic such as prostate-specific antigen (PSA) are not satisfied for the resectable PCa due to its low specificity, unclear benefits for reducing PCa deaths and the harms of overdiagnosing indolent disease. Methods: We investigated the performance of uEVEpCAM-CD9 from urine samples of 193 participates ( 112 PCa, 55 BPH and 26 HD) to diagnose the prostate cancer using our laboratory-developed chemiluminescent immunoassay. We applied machine learning to training sets and subsequently evaluated the multivariate diagnostic model based on uEVEpCAM-CD9 in validation sets. Findings: Results showed uEVEpCAM-CD9 were able to distinguish PCa from controls and significant decrease of uEVEpCAM-CD9 were observed after prostatectomy. We further used a training set (N=116) and constructed an exclusive multivariate diagnostic model based on uEVEpCAM-CD9, PSA and other clinical parameters, which showed an enhanced diagnostic sensitivity and specificity and performed excellently to diagnose prostate cancer (AUC = 0.952). When applied to a validation test (N= 77), the model achieved an area under the curve of 0.947. Moreover, this diagnostic model also exhibited a superior diagnostic performance (AUC = 0.917) over PSA (AUC = 0.712) at the PSA gray zone. Interpretation: The multivariate model based on uEVEpCAM-CD9 achieved notable diagnostic performance to diagnose PCa. Funding: This study was funded by National Natural Science Foundation of China Youth Science Foundation Project (81902156) and Zhejiang Provincial Natural Science Foundation of China (LQ21H160016). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Approval was obtained from the Second Affiliated Hospital of Zhejiang University School of Medicine Ethical Committee before initiating the study, and the requirement for informed consent was waived due to the retrospective nature of this study. All methods were performed in accordance with the relevant guidelines and regulations.

A novel urinary mRNA signature using the droplet digital polymerase chain reaction platform improves discrimination between prostate cancer and benign prostatic hyperplasia within the prostate-specific antigen gray zone.

PurposeThe aim of this study was to identify a noninvasive urinary marker for prostate cancer (PCa) diagnosis and to validate the clinical performance of this novel urinary mRNA signature using the droplet digital polymerase chain reaction (ddPCR) approach.Materials and MethodsA gene expression microarray (HT-12, Illumina Inc., USA) was used to identify genes differentially expressed between 16 PCa and 8 benign prostatic hyperplasia (BPH) tissues; ddPCR (QX200; Bio-Rad Laboratories, USA) was carried out to quantify the expression of selected genes in urine. The urinary molecular PCa risk score (UMPCaRS) was calculated by using the sum of three upregulated genes as the numerator and the sum of three downregulated genes as the denominator. The diagnostic utility of the UMPCaRS was validated by using a screening set (10 PCa and 10 BPH samples) and a validation set (131 PCa and 105 BPH samples).ResultsThree upregulated genes (PDLIM5, GDF-15, THBS4) and three downregulated genes (UPK1A, SSTR3, NPFFR2) were selected from the microarray and subjected to ddPCR. The UMPCaRS for PCa in the screening and validation sets was significantly higher than that for BPH. For the validation set, the diagnostic accuracy of the UMPCaRS was comparable with that of prostate-specific antigen (PSA). Importantly, in the “PSA gray zone” (3–10 ng/mL), the AUC for the UMPCaRS was 0.843 and that for PSA was 0.628 (p<0.001).ConclusionsThe data demonstrate that the UMPCaRS is useful for discriminating between PCa and BPH in the “PSA gray zone”.

A Comparative Study: Has MRI-guided Fusion Prostate Biopsy Changed the Prostate-specific Antigen Gray-zone Range?

ObjectiveThe gray-zone prostate-specific antigen (PSA) range is accepted to be 4-10 ng/ml and is considered to vary according to age. We aimed to investigate whether fusion prostate biopsy (FPB), which has been reported to have relatively higher cancer detection rates, has an effect on gray-zone PSA cut-off value.Material and methodsThis retrospective study included patients that underwent standard prostate biopsy (SPB) or multiparametric magnetic resonance imaging (MpMRI)-guided FPB (SPB+ targeted biopsy). All the patients included in the study were detected with a Prostate Imaging Reporting and Data System (PI-RADS) ≥3 lesion on MpMRI (the FPB group only). The demographics, clinical characteristics, and histopathological diagnoses were recorded for each patient.ResultsA total of 1,628 patients comprising 1,208 patients in the SPB group and 420 patients in the FPB group were included in the study. The mean PSA level was 9.75±6.68 ng/ml in the FBP group and 10.46±6.46 ng/ml in the SPB group (p=0.053). Prostate cancer (PCa) detection rate was significantly higher in the FPB group as compared to the SPB group (42.4% vs. 36.4%). The PSA cut-off value for PCa was 9.75 ng/ml (sensitivity and specificity, 81%) in the SPB group and was 7.55 ng/ml (sensitivity and specificity, 81% and 84%, respectively) in the FPB group. In the FPB group, the cancer detection rate among the patients with a PSA level of 7.55-10.00 ng/ml was 56.1%.ConclusionThe results indicated that the introduction of FPB into clinical practice, which has relatively higher cancer detection rates, has further lowered the upper limit for gray-zone PSA.

Performance of a validated urine exosome gene expression test (EPI) in men within the USPSTF suggested age-group of 55 to 69 years at initial biopsy with a PSA 2-10 ng/mL.

53 Background: Prostate-specific antigen (PSA) plays a key-role in prostate cancer (PCa) risk stratification but leads to over-diagnosis of low grade PCa. Recently, the USPSTF recommended that the decision to undergo PSA-based screening for men aged 55 to 69 years should be an individual one. We have developed and validated a non-invasive diagnostic test (ExoDx Prostate(IntelliScore), EPI) as a decision aid to guide the initial prostate biopsy decision process for men in the PSA gray zone of 2-10 ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GG 2) from low-grade (GG 1) and benign disease, thereby reducing the number of unnecessary biopsies. Methods: Patient data from two clinical trials were merged and constrained by age (55-69) according to the USPSTF suggested age-group resulting in a cohort of 701 patients with PSA 2-10 ng/mL, scheduled for initial prostate needle biopsy. EPI test results as well as PCPT2.0 risk calculator, ERSPC risk calculator and PSA results are compared with biopsy outcomes. Performances are reported using the area under the receiver operating characteristic curve (AUC), Negative predictive value (NPV), Positive predictive value (PPV), Sensitivity, and Specificity for discriminating ≥GG2 from GG1 and benign disease. Results: EPI showed a superior AUC of 0.70 compared to PSA (AUC: 0.57), PCPT2.0 (AUC: 0.60) and ERSPC (AUC: 0.58) (all p-values &lt; 0.001) for discriminating ≥GG2 PCa from benign and GG1. The previously validated EPI cut-point of 15.6 would avoid 22% of all prostate biopsies and 29% of unnecessary biopsies, with an NPV of 93% and miss only 5.4% of ≥GG2, respectively. Conclusions: EPI is a non-invasive, easy to use urine exosome RNA expression assay to discriminate high-grade (GG2) from low-grade (GG1) PCa and benign disease. EPI significantly outperformed the other standard of care parameters tested and applying the EPI test for risk stratification of patients in the USPSTF suggested age group, should reduce the number of unnecessary biopsies.

Identification of Multisialylated LacdiNAc Structures as Highly Prostate Cancer Specific Glycan Signatures on PSA.

Serum prostate-specific antigen (PSA) test is the current gold standard for screening and diagnosis of prostate cancer (PCa), while overdiagnosis and overtreatment are social problems. In order to improve the specificity and exclude a false positive diagnosis in PSA test, PCa-specific glycosylation subtypes of PSA were explored using in-depth quantitative profiling of PSA glycoforms based on mass spectrometric oxonium ion monitoring technology. As a result of analysis using sera from 15 PCa or 15 benign prostate hyperplasia (BPH) patients whose PSA levels were in the "gray zone" (4.0-10.0 ng/mL), 52 glycan structures on PSA were quantitatively observed. We found that abundance of multisialylated LacdiNAc (GalNAcβ1-4GlcNAc) structures were significantly upregulated in the PCa group compared to the BPH group. A couple of those glycoforms were then extracted and subjected to establish a novel PCa-specific diagnosis model (PSA G-index). When the diagnostic power was assessed using an independent validation sample set (15 PCa and 15 BPH patients in the PSA gray zone), an AUC of PSA G-index was 1.00, while that of total PSA or PSA f/T ratio was 0.50 or 0.60, respectively. Moreover, both PSA glycoforms showed significant correlation with Gleason scores. Lectin histochemical staining analysis also showed that PCa cells overexpressed glycoproteins containing LacdiNAc and sialic acids moieties. Thus, PSA G-index could serve as not only an effective secondary screening method to exclude false positive diagnosis in PSA screening, but also a potential grading biomarker for PCa.

Combining Prostate-Specific Antigen Parameters With Prostate Imaging Reporting and Data System Score Version 2.0 to Improve Its Diagnostic Accuracy.

BackgroundAny non-invasive test that can predict the absence of prostate cancer (PCa) or absence of clinically significant PCa (CSPCa) is necessary, as it can reduce the number of unnecessary biopsies in patients with gray zone prostate-specific antigen (PSA, 4 - 10 ng/mL). This study evaluated the diagnostic performance of free PSA% and PSA density (PSAD), and Prostate Imaging Reporting and Data System (PIRADS) score (version 2.0) alone and combined in predicting CSPCa in patients with PSA between 4 and 10 ng/mL.MethodsThis prospective study included a total of 104 consecutive patients with lower urinary tract symptoms (LUTS) and serum PSA between 4 and 10 ng/mL, with or without abnormal digital rectal examination (DRE) findings or any hypoechoic lesion on ultrasound sonography of prostate and without prior transrectal ultrasound (TRUS) biopsy of prostate. PIRADS score was calculated using multi-parametric magnetic resonance imaging (mp-MRI) before TRUS biopsy of prostate. Relationships among PIRADS score, PSAD, free PSA% and presence of CSPCa in TRUS biopsy were statistically analyzed.ResultsIn patients with CSPCa, significantly higher median age (P = 0.001), PSA level (P < 0.001), PSAD (P < 0.001) and significantly lower prostate volume (P < 0.001) and free PSA% were observed as compared to patients with non-CSPCa. Significantly higher proportion of patients with CSPCa showed PIRADS positive test compared to those with non-CSPCa (86.4% vs. 53.3%, P < 0.001). Cut-off values for PSAD and free PSA% were 0.12 ng/mL2 and 25%, respectively. Age, PSAD and free PSA% were significant predictors of PCa, while age and PSAD were significant predictors of CSPCa. Criteria 2, 3 and 4 demonstrated higher specificity and positive predictive value (PPV) in predicting CSPCa as compared to criterion 1. The overall accuracies of criterion 1, 2, 3 and 4 were 64.42%, 85.58%, 80.77% and 79.81%, respectively. The area under the curve (AUC) values of criterion 2, 3 and 4 were higher (0.827, 0.732 and 0.792) than criterion 1 (0.665).ConclusionUsing PIRADS score for predicting CSPCa as a screening test, criteria 2, 3 and 4 have much higher diagnostic performance and present accuracy of mp-MRI to predict CSPCa can be increased with addition of PSAD and free PSA%.

Developing a nomogram based on multiparametric magnetic resonance imaging for forecasting high-grade prostate cancer to reduce unnecessary biopsies within the prostate-specific antigen gray zone

BackgroundSince 1980s the application of Prostate specific antigen (PSA) brought the revolution in prostate cancer diagnosis. However, it is important to underline that PSA is not the ideal screening tool due to its low specificity, which leads to the possible biopsy for the patient without High-grade prostate cancer (HGPCa). Therefore, the aim of this study was to establish a predictive nomogram for HGPCa in patients with PSA 4–10 ng/ml based on Prostate Imaging Reporting and Data System version 2 (PI-RADS v2), MRI-based prostate volume (PV), MRI-based PV-adjusted Prostate Specific Antigen Density (adjusted-PSAD) and other traditional classical parameters.MethodsBetween January 2014 and September 2015, Of 151 men who were eligible for analysis were formed the training cohort. A prediction model for HGPCa was built by using backward logistic regression and was presented on a nomogram. The prediction model was evaluated by a validation cohort between October 2015 and October 2016 (n = 74). The relationship between the nomogram-based risk-score as well as other parameters with Gleason score (GS) was evaluated. All patients underwent 12-core systematic biopsy and at least one core targeted biopsy with transrectal ultrasonographic guidance.ResultsThe multivariate analysis revealed that patient age, PI-RADS v2 score and adjusted-PSAD were independent predictors for HGPCa. Logistic regression (LR) model had a larger AUC as compared with other parameters alone. The most discriminative cutoff value for LR model was 0.36, the sensitivity, specificity, positive predictive value and negative predictive value were 87.3, 78.4, 76.3, and 90.4%, respectively and the diagnostic performance measures retained similar values in the validation cohort (AUC 0.82 [95% CI, 0.76–0.89]). For all patients with HGPCa (n = 50), adjusted-PSAD and nomogram-based risk-score were positively correlated with the GS of HGPCa in PSA gray zone (r = 0.455, P = 0.002 and r = 0.509, P = 0.001, respectively).ConclusionThe nomogram based on multiparametric magnetic resonance imaging (mp-MRI) for forecasting HGPCa is effective, which could reduce unnecessary prostate biopsies in patients with PSA 4–10 ng/ml and nomogram-based risk-score could provide a more robust parameter of assessing the aggressiveness of HGPCa in PSA gray zone.

Prostate cancer detection in patients with total serum prostate-specific antigen levels of 4–10 ng/mL: Diagnostic efficacy of MicroRNA-141

Objective: The purpose of this small pilot study was to evaluate the utility of microRNA-141 (miR-141) as a biomarker for detecting prostate cancer (PCa) in patients with total serum prostate-specific antigen (PSA) levels of 4–10 ng/mL, which is referred to as the “gray zone.” Materials and Methods: Eleven PCa patients, 23 benign prostatic hyperplasia (BPH) patients with PSA levels of 4–10 ng/mL, and 16 healthy controls were enrolled in this study. Total RNA was extracted from serum samples, and the level of miR-141 was analyzed by quantitative reverse transcription polymerase chain reaction. Results: The circulating miR-141 level was significantly higher in PCa patients than in BPH patients and healthy controls (fold change [mean ± standard deviation], 0.528 ± 0.083 for PCa, 0.297 ± 0.038 for BPH, and 0.262 ± 0.025 for controls; P< 0.05). Receiver operating characteristic curve revealed that the serum miR-141 yielded an area under the curve of 0.751, with 72% sensitivity and 92% specificity in discriminating patients with PCa from BPH patients with total serum PSA levels in the gray zone. Conclusion: The present results indicate that miR-141 expression is significantly increased in the peripheral blood of patients with PCa compared with BPH patients and healthy individuals. We think that miR-141 may guide clinicians during the decision phase of patients with PCa and BPH in the PSA gray zone.

S&T-58 WHY DO SOME PATIENTS MAKE PRIMARILY CALCIUM OXALATE MONOHYDRATE VERSUS DIHYDRATE STONES?

INTRODUCTION AND OBJECTIVES: A major concern with transrectal biopsy (TRBx) is that the anterior portion of the prostate gland, including the anterior peripheral and transition zones is difficult to target by standard TRBx, particularly for larger glands. A recent study has assessed simulated biopsy schemes using threedimensional reconstructions of actual prostate cancer (PCa) specimens, and suggested that nearly all PCas with a tumor volume of >0.5 ml can be detected by 14-18 TRBx cores using needle with longer cutting length. The purpose of this study is to compare the detection rate of PCa using a novel Tru-Cut needle with 25 mm cutting length with that of a conventional needle with 17 mm cutting length in TRBx. METHODS: We cooperated with biopsy maker, TSK company, and developed a novel Tru-Cut biopsy needle with a 25 mm cutting length. A total of 426 patients underwent TRBx by the novel needle (group 25 mm). Complications that occurred (hematuria, urinary retention, rectal bleeding, and fever) were evaluated, and pain during biopsy was assessed using the Face scale. The biopsy tissue on the slides was scanned into a computer, and the length of the tissue was measured using the software ImageJ. The complications, pain on biopsy, tissue length, and detection rate of PCa were compared to those of 288 patients who underwent TRBx by a conventional needle with 17 mm cutting length (group 17 mm). RESULTS: Complications and values on the pain scale did not differ significantly between the groups. The length of tissue taken from the mid-portion of the prostate was significantly longer in group 25 mm than in group 17 mm (16.30 mm vs 18.53 mm, P < 0.001). The detection rate of PCa within the prostate-specific antigen (PSA) gray zone was significantly higher in group 25 mm than in group 17 mm (49.48% vs 39.77%, p1⁄40.044). CONCLUSIONS: The novel Tru-Cut biopsy needle is safe, and can be used to acquire a longer prostate tissue specimen. Use of the novel Tru-Cut needle with 25 mm cutting length in transrectal prostate biopsy significantly improved the detection rate of PCa within the PSA gray zone.

The optimal number of initial prostate biopsy cores in daily practice: a prospective study using the Nara Urological Research and Treatment Group nomogram.

BackgroundTo elucidate the optimal number of prostate biopsy cores using a nomogram allocating 6–12 biopsy cores, the number generally used in daily practice, based on age and prostate volume (PV).MethodsWe enrolled 936 patients who received an initial prostate biopsy from April 2006 to January 2009. A number of 6–12 biopsy cores was allocated based on age and PV Nara Urological Research and Treatment Group (NURTG) nomogram. To elucidate the predictive parameters of cancer detection in patients with a prostate specific antigen (PSA) value in the gray zone, univariate and multivariate logistic regression analysis were carried out.ResultsThe total cancer detection rate and the cancer detection rate in the PSA gray zone (4.1–10.0 ng/mL) were 48.0 and 37.6 %, respectively. The cancer detection rates in the gray zone stratified by patient age of ≤59, 60–64, 65–69, 70–74, 75–79, and ≥80 years were 28.4, 35.0, 26.9, 37.9, 45.7, and 54.8 %, respectively. The significant predictive parameters of cancer detection in the gray zone were age, volume biopsy ratio (VBR: PV divided by number of biopsy cores), PSA density (PSAD), digital rectal examination findings, and transrectal ultrasound findings in univariate analyses. Finally, age, VBR, and PSAD were independent parameters to predict cancer detection in the gray zone. The adverse event profile was acceptable.ConclusionsOur present study revealed that the cancer detection rate using the NURTG nomogram allocating 6–12 biopsy cores, the number generally used in daily practice, based on age and PV, could provide similar efficacy as previous studies involving more biopsy cores. In older patients the number of biopsy cores could be reduced.

Additional Midline Biopsies of the Peripheral Zone Associated with the First Endorectal Standard Sextant Pattern Improves the Accuracy of Prostate Cancer Detection in Japanese Patients

Objectives: This study was designed to estimate the improved accuracy of prostate cancer (PCa) detection resulting from additional midline biopsies of the peripheral zone in first standard biopsy. Patients and Methods: Patients were classified into 3 groups: 402 cases of sextant biopsies (1995-2002), 488 cases of 8-core biopsies with 2 additional midline biopsies (2003-2006), and 391 cases of 10-core biopsies with 4 additional midline biopsies (2007-2012). The positive rate of each number of biopsies and changes in positive rates associated with prostate specific antigen (PSA) ranges were estimated. Results: The positive rate of core biopsy significantly improved with increasing numbers of core biopsies (30.1% for sextant, 43.4% for 8-core biopsies, and 53.1% for 10-core biopsies). The accuracy of biopsies for each PSA range also significantly improved (22.3% for sextant, 30.0% for 8-core biopsies, and 43.2% for 10-core biopsies in the PSA gray zone [4.01-10 ng/ml]; and 26.5% for sextant, 52.9% for 8-core biopsies, and 71.8% for 10-core biopsies in the intermediate PSA range [10.1-20 ng/ml]). In the 208 cases with positive results using the 10-core biopsy method, the distribution of Gleason scores did not differ between the sextant only group and the midline site only group. Conclusions: Additional midline biopsy was associated with improved accuracy of positive core biopsies in Japanese patients with a PSA range of 4.01-20 ng/ml.

Urinary MicroRNAs of Prostate Cancer: Virus-Encoded hsv1-miRH18 and hsv2-miR-H9-5p Could Be Valuable Diagnostic Markers.

Purpose:MicroRNAs (miRNAs) in biological fluids are potential biomarkers for the diagnosis and assessment of urological diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The aim of the study was to identify and validate urinary cell-free miRNAs that can segregate patients with PCa from those with BPH. Methods:In total, 1,052 urine, 150 serum, and 150 prostate tissue samples from patients with PCa or BPH were used in the study. A urine-based miRNA microarray analysis suggested the presence of differentially expressed urinary miRNAs in patients with PCa, and these were further validated in three independent PCa cohorts, using a quantitative reverse transcriptionpolymerase chain reaction analysis. Results:The expression levels of hsa-miR-615-3p, hsv1-miR-H18, hsv2-miR-H9-5p, and hsa-miR-4316 were significantly higher in urine samples of patients with PCa than in those of BPH controls. In particular, herpes simplex virus (hsv)-derived hsv1-miR-H18 and hsv2-miR-H9-5p showed better diagnostic performance than did the serum prostate-specific antigen (PSA) test for patients in the PSA gray zone. Furthermore, a combination of urinary hsv2-miR-H9-5p with serum PSA showed high sensitivity and specificity, providing a potential clinical benefit by reducing unnecessary biopsies. Conclusions:Our findings showed that hsv-encoded hsv1-miR-H18 and hsv2-miR-H9-5p are significantly associated with PCa and can facilitate early diagnosis of PCa for patients within the serum PSA gray zone.

Carbonic Anhydrase I as a New Plasma Biomarker for Prostate Cancer

Serum prostate-specific antigen (PSA) levels ranging from 4 to 10 ng/mL is considered a diagnostic gray zone for detecting prostate cancer because biopsies reveal no evidence of cancer in 75% of these subjects. Our goal was to discover a new highly specific biomarker for prostate cancer by analyzing plasma proteins using a proteomic technique. Enriched plasma proteins from 25 prostate cancer patients and 15 healthy controls were analyzed using a label-free quantitative shotgun proteomics platform called 2DICAL (2-dimensional image converted analysis of liquid chromatography and mass spectrometry) and candidate biomarkers were searched. Among the 40,678 identified mass spectrum (MS) peaks, 117 peaks significantly differed between prostate cancer patients and healthy controls. Ten peaks matched carbonic anhydrase I (CAI) by tandem MS. Independent immunological assays revealed that plasma CAI levels in 54 prostate cancer patients were significantly higher than those in 60 healthy controls (P = 0.022, Mann-Whitney U test). In the PSA gray-zone group, the discrimination rate of prostate cancer patients increased by considering plasma CAI levels. CAI can potentially serve as a valuable plasma biomarker and the combination of PSA and CAI may have great advantages for diagnosing prostate cancer in patients with gray-zone PSA level.

Reproducibility, Performance, and Clinical Utility of a Genetic Risk Prediction Model for Prostate Cancer in Japanese

Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1–10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.

Effect of Diabetes Mellitus on High-grade Prostate Cancer Detection Among Japanese Obese Patients With Prostate-specific Antigen Less Than 10 ng/mL

To investigate the association of diabetes mellitus (DM) with prostate cancer (PCa) risk and grade among Japanese patients undergoing extended biopsy and to investigate how obesity modifies these relationships. We retrospectively evaluated the data from 2038 patients with a prostate-specific antigen (PSA) level <10 ng/mL undergoing initial extended biopsy at our institutions. The DM history was determined by self-report and medication use. Multivariate analyses of DM for PCa risk and grade were done using logistic regression. Moreover, we examined whether these associations were modified by the body mass index using subgroup analyses (nonobese <25 kg/m(2) or obese ≥25 kg/m(2)) and interaction tests. Cancer grade was classified according to the Gleason score (GS): low-grade (GS ≤6), intermediate-grade (GS 7), and high-grade (GS 8-10). Of 2038 patients, obesity and DM was observed in 606 (30%) and 213 (11%), respectively. Also, 836 patients (41%) had positive biopsy findings. On multivariate analysis, we found no significant association of DM with the risk of overall PCa (P = .106) or the risk of low-grade (P = .735), intermediate-grade (P = .119), or high-grade (P = .110) disease. When stratified by obesity, the relative risk (RR) of PCa detection for diabetic men apparently increased with higher cancer grade (low grade, RR = 1.19, P = .71; intermediate grade, RR = 2.01, P = .099; high-grade, RR = 4.03, P = .025). However, in the nonobese men, no association was noted between DM and PCa risk, irrespective of grade. Obesity modified the effect of DM on high-grade disease risk with a trend (P for interaction = .087). DM was associated with more aggressive PCa detection among Japanese obese patients with gray-zone PSA levels undergoing extended biopsy.

Reproducibility, performance, and clinical utility of a genetic risk prediction model for prostate cancer in Japanese patients.

10520 Background: Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model and estimate its utility as a diagnostic biomarker in a clinical scenario. Methods: We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of the Japanese. The model was validated by two independent sets of samples comprising 3,294 cases and 6,281 controls. Various cut offs were evaluated to be used in a clinical scenario. Results: The area under a curve (AUC) of the model was 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation respectively. The AUC of the model was not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio &lt;0.5 (low risk) or &gt;2 (high risk) in the model, and assuming the overall positive rate of prostate needle biopsies to be 20% in PSA gray zone (PSA 2-10 ng/ml), the positive biopsy rates were 10.7% and 42.4% respectively for the two genetic risk groups. Conclusions: The genetic risk prediction model was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.

Is extended biopsy protocol justified in all patients with suspected prostate cancer?

To determine the significance of an extended 10-core transrectal biopsy protocol in different categories of patients with suspected prostate cancer using digital guidance. We studied 125 men who were being evaluated for prostate cancer. They all had an extended 10-core digitally guided transrectal prostatic biopsy done for either an elevated serum prostate-specific antigen (PSA) or an abnormal digital rectal examination finding or both. Sextant biopsy samples were collected first, followed by additional four lateral biopsies in all patients. Both groups of specimens were analyzed separately. The cancer detection rates of both sextant and extended 10-core biopsy protocols at different PSA levels and digital rectal examination (DRE) findings were determined and compared. The level of significance of difference in cancer detection was determined using Pearson's Chi square test with level of significance set at <0.05. The overall cancer detection by the extended technique was 61 (48.8%) cases while the sextant protocol detected cancer in 52 cases. The 10-core extended protocol yielded an increase in cancer detection rate of 14.8% but the improvement in detection rate was only statistically significant in the sub-set of patients with PSA between 4.1 and 10 ng/mL, with or without abnormality on DRE, with an overall increase detection rate of 33%.(P=0.04) Our study has shown that a 10-core prostate biopsy protocol significantly improves cancer detection in patients with suspected early cancer. It should therefore be the optimum biopsy protocol for patients with gray-zone PSA value, with or without abnormal DRE.

Prostate Cancer Detection in Patients With Total Serum Prostate-Specific Antigen Levels of 4–10 ng/mL: Diagnostic Efficacy of Diffusion-Weighted Imaging, Dynamic Contrast-Enhanced MRI, and T2-Weighted Imaging

The purpose of this study is to evaluate the utility of T2-weighted imaging, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted imaging (DWI) for detecting prostate cancer in patients with total serum prostate-specific antigen (PSA) levels of 4-10 ng/mL, which is referred to as the "gray zone." Fifty patients with gray-zone PSA levels underwent MRI before biopsy. According to the sites of biopsy, the prostate was divided into eight regions on MRI scans. These regions were evaluated individually for the following features: detectability of prostate cancer on per-region and per-patient bases, and relationship between tumor size and positive or negative MRI findings for tumor detection. On a per-region basis, the sensitivity and specificity of tumor detection were 36% and 97% for T2-weighted imaging, 43% and 95% for DCE-MRI, 38% and 96% for DWI, and 53% and 93% for the combined method of MRI, respectively. The sensitivity of combined MRI to detect tumor was significantly higher than those of the individual methods (p < 0.001 to p = 0.001). Tumor size was significantly larger in regions with positive MRI findings than in regions with negative MRI findings (p = 0.004). On a per-patient basis, sensitivity and specificity of combined MRI to detect prostate cancer were 83% and 80%, respectively. Combined T2-weighted imaging, DWI, and DCE-MRI findings appear to be potentially useful for detecting and managing prostate cancer, even when performed for patients with gray-zone PSA levels.