Negative Digital Rectal Examination Research Articles

Thiosulfate in urine as a facilitator in the diagnosis of prostate cancer for patients with prostate-specific antigen less or equal 10 ng/mL

The aim of this study was to examine the level of thiosulfate in the urine of prostate cancer (PCa) patients and evaluate its usefulness in the diagnosis and monitoring of prostate malignant transformation. Thiosulfate is a naturally occurring product of hydrogen sulfide (H2S) metabolism. H2S is involved in many physiological and pathological processes including inflammation and tumorigenesis. The determination of thiosulfate in the urine of PCa patients and healthy controls was performed by reverse-phased liquid chromatography using 2-chloro-1-methylquinolinium tetrafluoroborate as a derivatization reagent. Thiosulfate concentrations were normalized to urinary creatinine levels to compensate for variable diuresis. In the urine samples of PCa patients, the mean thiosulfate level was almost 50 times higher than in the control groups and five times higher than in the benign prostatic hyperplasia group. The level of thiosulfate did not correlate with the serum prostate-specific antigen (PSA) level or PSA density. Neither tumor stage nor tumor grade was associated with thiosulfate level. The results suggest that thiosulfate concentration in urine may be a good facilitator in the diagnostics of PCa. The predictive accuracy of this method is particularly valuable for the diagnosis of patients with low serum PSA level and negative digital rectal examination and transrectal ultrasound results.

Histological chronic prostatitis and high-grade prostate intra-epithelial neoplasia do not influence urinary prostate cancer gene 3 score

What's known on the subject? and What does the study add? While the relationship between PCA3 score and clinical or histological prostatitis was quite proven even in small patient groups, conversely the relationship between PCA3 score and HG-PIN is still under debate. We demonstrated in a large series (432 patients) that histologically documented chronic prostatitis and HG-PIN have similar PCA3 scores to patients with BPH and/or normal parenchyma at biopsy. To determine whether histological chronic prostatitis and high-grade prostate intra-epithelial neoplasia (HG-PIN) influence the prostate cancer gene 3 (PCA3) score in Italian patients with an elevated prostate-specific antigen (PSA) level and a negative digital rectal examination (DRE) who were undergoing a first or repeat prostate biopsy. A urinary PCA3 test was prospectively performed in 432 consecutive patients who were admitted to Gradenigo Hospital (Turin, Italy) between January and December 2011 and scheduled for first or repeat prostate biopsy as a result of an elevated PSA level and negative DRE. A comparison of the PCA3 score and patients with a negative biopsy (normal parenchyma, benign prostatic hyperplasia, chronic prostatitis, HG-PIN) or positive biopsy was performed. PCA3 median (range) scores varied significantly (P < 0.001) in men with a negative vs positive biopsy: 33 (2-212) and 66 (5-324), respectively. By contrast, men with chronic prostatitis and HG-PIN showed no significant difference with respect to PCA3 score compared to other negative biopsy patients. No correlation was found between the number of positive cores for chronic prostatitis, HG-PIN and PCA3 score. Of all patients with a positive biopsy, 23 (20%) of 114 men had a PCA3 score ≤ 35. In total, 79 (40%) of 197 men with a negative biopsy (normal parenchyma and benign prostatic hyperplasia), 24 (37.5%) of 64 men with chronic prostatitis and 19 (39.6%) of 48 men with HG-PIN had a PCA3 score >35. At this early stage of clinical evaluation, cancer specificity of the urinary PCA3 test appears to be maintained in the face of chronic prostatitis and HG-PIN.

Effectiveness of antibiotic treatment given to patients for an abnormal prostate specific antigen before prostate biopsy

Objective To analyze the effect of antibiotic treatment on prostate specific antigen (PSA) derivations in patients with and without prostate cancer and to further determine if the changes of PSA values after antibiotic treatment could help to exclude inflammation in the differential diagnosis of an abnormal PSA. Methods A total of 100 patients with lower urinary tract symptoms,a PSA level of 4 to 10 μg/L,free PSA/total PSA (fPSA/tPSA) ratio ＜ 0.25,and a negative digital rectal examination and transrectal ultrasonography were enrolled in this study.All patients received 500 mg of ciprofloxacin twice a day for 3 weeks.Free and total PSA values were measured before and after antibiotic treatment.All the patients were then scheduled for 12-core prostate biopsy. Results The mean tPSA value was (6.5 ± 1.2) and (5.1 ± 1.2) μg/L respectively before and after antibiotic treatment ( P ＜ 0.01 ).Ninety-one patients (91.0％) showed tPSA reduction after antibiotic therapy,of which 13 ( 14.3％ ) had prostate cancer on biopsy.In 17 cases (18.7％) post-treatment tPSA was less than 4 μg/L.Three of the 17 cases (17.6％)had prostate cancer on biopsy.In 6 of the 100 men post-treatment tPSA was between 4 and 10 μg/L and the fPSA/tPSA ratio was above 0.25.One of these cases had prostate cancer on biopsy.Seven cases had a ＞50％ reduction in PSA levels with no positive biopsy results.Although mean total PSA and PSAD decreased after treatment in both groups,the reductions within these parameters were not significantly different between patients with and without prostate cancer (P ＞ 0.05).Furthermore,no differences emerged in terms of the changes of other PSA derivations including fPSA and fPSA/tPSA ( P ＞ 0.05 ). Conclusions The PSA levels may change with long-term antibiotic treatment in patients with elevated PSA values.A decrease in PSA after antibiotic treatment does not rule out the presence of prostate cancer even if PSA decreases to a normal level.But a ＞ 50％ reduction in PSA levels may be associated with a decreasing risk of prostate cancer,which may allow a postponement of prostate biopsy in selected patients. Key words: Prostatic neoplasms; Carcinoma; Prostate specific antigen; Prostate biopsy; Antibiotic treatment

Magnetic Resonance Imaging/Ultrasound Fusion Guided Prostate Biopsy Improves Cancer Detection Following Transrectal Ultrasound Biopsy and Correlates With Multiparametric Magnetic Resonance Imaging

A novel platform was developed that fuses pre-biopsy magnetic resonance imaging with real-time transrectal ultrasound imaging to identify and biopsy lesions suspicious for prostate cancer. The cancer detection rates for the first 101 patients are reported. This prospective, single institution study was approved by the institutional review board. Patients underwent 3.0 T multiparametric magnetic resonance imaging with endorectal coil, which included T2-weighted, spectroscopic, dynamic contrast enhanced and diffusion weighted magnetic resonance imaging sequences. Lesions suspicious for cancer were graded according to the number of sequences suspicious for cancer as low (2 or less), moderate (3) and high (4) suspicion. Patients underwent standard 12-core transrectal ultrasound biopsy and magnetic resonance imaging/ultrasound fusion guided biopsy with electromagnetic tracking of magnetic resonance imaging lesions. Chi-square and within cluster resampling analyses were used to correlate suspicion on magnetic resonance imaging and the incidence of cancer detected on biopsy. Mean patient age was 63 years old. Median prostate specific antigen at biopsy was 5.8 ng/ml and 90.1% of patients had a negative digital rectal examination. Of patients with low, moderate and high suspicion on magnetic resonance imaging 27.9%, 66.7% and 89.5% were diagnosed with cancer, respectively (p <0.0001). Magnetic resonance imaging/ultrasound fusion guided biopsy detected more cancer per core than standard 12-core transrectal ultrasound biopsy for all levels of suspicion on magnetic resonance imaging. Prostate cancer localized on magnetic resonance imaging may be targeted using this novel magnetic resonance imaging/ultrasound fusion guided biopsy platform. Further research is needed to determine the role of this platform in cancer detection, active surveillance and focal therapy, and to determine which patients may benefit.

Colour Doppler and microbubble contrast agent ultrasonography do not improve cancer detection rate in transrectal systematic prostate biopsy sampling

What's known on the subject? and What does the study add? Transrectal gray-scale ultrasonography guided prostate biopsy sampling is the method for diagnosing prostate cancer (PC) in patients with an increased prostate specific antigen level and/or abnormal digital rectal examination. Several imaging strategies have been proposed to optimize the diagnostic value of biopsy sampling, although at the first biopsy nearly 10-30% of PC still remains undiagnosed. This study compares the PC detection rate when employing Colour Doppler ultransongraphy with or without the injection of SonoVue™ microbubble contrast agent, versus the transrectal ultrasongraphy-guided systematic biopsy sampling. The limited accuracy, sensitivity, specificity and the additional cost of using the contrast agent do not justify its routine application in PC detection. • To compare prostate cancer (PC) detection rate employing colour Doppler ultrasonography with or without SonoVue™ contrast agent with transrectal ultrasonography-guided systematic biopsy sampling. • A total of 300 patients with negative digital rectal examination and transrectal grey-scale ultrasonography, with PSA values ranging between 2.5 and 9.9 ng/mL, were randomized into three groups: 100 patients (group A) underwent transrectal ultrasonography-guided systematic bioptic sampling; 100 patients (group B) underwent colour Doppler ultrasonography, and 100 patients (group C) underwent colour Doppler ultrasonography before and during the injection of SonoVue™. • Contrast-enhanced targeted biopsies were sampled into hypervascularized areas of peripheral, transitional, apical or anterior prostate zones. • All the patients included in Groups B and C underwent a further 13 systematic prostate biopsies. The cancer detection rate was calculated for each group. • In 88 (29.3%) patients a histological diagnosis of PC was made, whereas 22 (7.4%) patients were diagnosed with high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. • No significant differences were found among the three groups for cancer detection rate (P= 0.329). • Additionally, low sensitivity, specificity and accuracy of colour Doppler with or without SonoVue™ contrast agent were found. • Prostate cancer detection rate does not significantly improve with the use of colour Doppler ultrasonography with or without SonoVue™. • Although no collateral effects have been highlighted, the combined use of colour Doppler ultrasonography and SonoVue™ determines adjunctive costs and increases the mean time for taking a single prostate biopsy.

Results of Vardenafil Mediated Power Doppler Ultrasound, Contrast Enhanced Ultrasound and Systematic Random Biopsies to Detect Prostate Cancer

We evaluated the ability of the phosphodiesterase-5 inhibitor vardenafil to increase prostate microcirculation during power Doppler ultrasound. We also evaluated the results of contrast and vardenafil enhanced targeted biopsies compared to those of standard 12-core random biopsies to detect cancer. Between May 2008 and January 2010, 150 consecutive patients with prostate specific antigen more than 4 ng/ml at first diagnosis with negative digital rectal examination and transrectal ultrasound, and no clinical history of prostatitis underwent contrast enhanced power Doppler ultrasound (bolus injection of 2.4 ml SonoVue® contrast agent), followed by vardenafil enhanced power Doppler ultrasound (1 hour after oral administration of vardenafil 20 mg). All patients underwent standard 12-core transrectal ultrasound guided random prostate biopsy plus 1 further sampling from each suspected hypervascular lesion detected by contrast and vardenafil enhanced power Doppler ultrasound. Prostate cancer was detected in 44 patients (29.3%). Contrast and vardenafil enhanced power Doppler ultrasound detected suspicious, contrast enhanced and vardenafil enhanced areas in 112 (74.6%) and 110 patients (73.3%), and was diagnostic for cancer in 32 (28.5%) and 42 (38%), respectively. Analysis of standard technique, and contrast and vardenafil enhanced power Doppler ultrasound findings by biopsy core showed significantly higher detection using vardenafil vs contrast enhanced power Doppler ultrasound and standard technique (41.2% vs 22.7% and 8.1%, p <0.005 and <0.001, respectively). The detection rate of standard plus contrast or vardenafil enhanced power Doppler ultrasound was 10% and 11.7% (p not significant). Vardenafil enhanced power Doppler ultrasound enables excellent visualization of the microvasculature associated with cancer and can improve the detection rate compared to contrast enhanced power Doppler ultrasound and the random technique.

Prostate-Specific Antigen (PSA) Isoform p2PSA Significantly Improves the Prediction of Prostate Cancer at Initial Extended Prostate Biopsies in Patients with Total PSA Between 2.0 and 10 ng/ml: Results of a Prospective Study in a Clinical Setting

BackgroundTotal prostate-specific antigen (tPSA), ratio of free PSA (fPSA) to tPSA (%fPSA), and PSA density (PSAD) testing have a very low accuracy in the detection of prostate cancer (PCa). There is an urgent need for more accurate biomarkers. ObjectiveTo compare the diagnostic accuracy of PSA isoform p2PSA and its derivatives in determining the presence of PCa at initial biopsy with the accuracy of other predictors in patients with tPSA 2.0–10 ng/ml. Design, setting, and participantsWe conducted an observational prospective study in a real clinical setting of consecutive men with tPSA 2.0–10 ng/ml and negative digital rectal examination who were scheduled for prostate biopsy at a tertiary academic center. InterventionOutpatient transrectal ultrasound-guided prostate biopsies were performed according to a standardized institutional saturation scheme (18–22 cores). MeasurementsWe determined the diagnostic accuracy of serum tPSA, %fPSA, PSAD, p2PSA, %p2PSA [(p2PSA/fPSA)×100] and the Beckman Coulter Prostate Health Index (phi; [p2PSA/fPSA×√tPSA]). Results and limitationsOverall, 107 of 268 patients (39.9%) were diagnosed with PCa at extended prostate biopsies. Statistically significant differences between patients with and without PCa were observed for age, prostate and transition zone volume, PSAD, %p2PSA, and phi (all p values<0.05). In univariate accuracy analysis, phi and %p2PSA were the most accurate predictors of PCa (area under the curve: 75.6% and 75.7%, respectively), followed by transition zone volume (66%), prostate volume (65%), patient age (63%), PSAD (61%), %fPSA (58%), and tPSA (53%). In multivariate accuracy analyses, both phi (+11%) and %p2PSA (+10%) significantly improved the accuracy of established predictors in determining the presence of PCa at biopsy (p<0.001). Although %p2PSA and phi were significantly associated with Gleason score (Spearman ρ: 0.303 and 0.387, respectively; p ≤ 0.002), they did not improve the prediction of Gleason score ≥7 PCa in multivariable accuracy analyses (p > 0.05). ConclusionsIn patients with a tPSA between 2.0 and 10 ng/ml, %p2PSA and phi are the strongest predictors of PCa at initial extended biopsies and are significantly more accurate than the currently used tests (tPSA, %fPSA, and PSAD) in determining the presence of PCa at biopsy.

A Multicenter Study of [-2]Pro-Prostate Specific Antigen Combined With Prostate Specific Antigen and Free Prostate Specific Antigen for Prostate Cancer Detection in the 2.0 to 10.0 ng/ml Prostate Specific Antigen Range

Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer. We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

D'Amico Risk Stratification Correlates With Degree of Suspicion of Prostate Cancer on Multiparametric Magnetic Resonance Imaging

We determined whether there is a correlation between D'Amico risk stratification and the degree of suspicion of prostate cancer on multiparametric magnetic resonance imaging based on targeted biopsies done with our electromagnetically tracked magnetic resonance imaging/ultrasound fusion platform. A total of 101 patients underwent 3 Tesla multiparametric magnetic resonance imaging of the prostate, consisting of T2, dynamic contrast enhanced, diffusion weighted and spectroscopy images in cases suspicious for or with a diagnosis of prostate cancer. All prostate magnetic resonance imaging lesions were then identified and graded by the number of positive modalities, including low-2 or fewer, moderate-3 and high-4 showing suspicion on multiparametric magnetic resonance imaging. The biopsy protocol included standard 12-core biopsy, followed by real-time magnetic resonance imaging/ultrasound fusion targeted biopsies of the suspicious magnetic resonance lesions. Cases and lesions were stratified by the D'Amico risk stratification. In this screening population 90.1% of men had a negative digital rectal examination. Mean±SD age was 62.7±8.3 years and median prostate specific antigen was 5.8 ng/ml. Of the cases 54.5% were positive for cancer on protocol biopsy. Chi-square analysis revealed a statistically significant correlation between magnetic resonance suspicion and D'Amico risk stratification (p<0.0001). Within cluster resampling demonstrated a statistically significant correlation between magnetic resonance suspicion and D'Amico risk stratification for magnetic resonance targeted core biopsies and magnetic resonance lesions (p<0.01) Our data support the notion that using multiparametric magnetic resonance prostate imaging one may assess the degree of risk associated with magnetic resonance visible lesions in the prostate.

Prostate cancer risk alleles significantly improve disease detection and are associated with aggressive features in patients with a “normal” prostate specific antigen and digital rectal examination

Several reports suggest that a combination of risk alleles may be associated with prostate cancer (CaP) risk and tumor features. However, their ability to detect CaP and tumor characteristics in patients with a "normal" PSA (<4 ng/ml) and non-suspicious digital rectal examination (DRE) remains to be determined. We examined 203 men of European ancestry with clinical stage T1c CaP diagnosed at a "normal" PSA and 611 healthy volunteer controls. The genotypes for 17 different risk alleles were compared between CaP cases and controls. Additional analyses were used to compare the pathologic features between carriers and non-carriers (defined using best-fit genetic model) of these variants. All risk alleles were present at an increased frequency in cases with "normal" PSA values and DRE compared to controls. Amongst CaP patients, carriers of an increasing number of genetic risk factors (i.e., alleles and positive family history) were at a significantly increased risk of CaP (P-trend <0.001). Specifically, men with >10 genetic risk factors had an 11.2-fold risk (95% CI 4.3-29.2) of having the disease compared to men with ≤5 variants. There also was a higher frequency of many the variants amongst men with adverse pathologic features. A substantial proportion of biopsy-detectable CaP occurs in men with "normal" PSA levels and negative DRE. In this population, CaP risk alleles and family history are significantly associated with CaP risk and may help predict aggressive disease. Future studies are warranted to determine the utility of incorporating these variants into CaP screening programs.

Prospective comparison of T2w-MRI and dynamic-contrast-enhanced MRI, 3D-MR spectroscopic imaging or diffusion-weighted MRI in repeat TRUS-guided biopsies

To compare T2-weighted MRI and functional MRI techniques in guiding repeat prostate biopsies. Sixty-eight patients with a history of negative biopsies, negative digital rectal examination and elevated PSA were imaged before repeat biopsies. Dichotomous criteria were used with visual validation of T2-weighted MRI, dynamic contrast-enhanced MRI and literature-derived cut-offs for 3D-spectroscopy MRI (choline-creatine-to-citrate ratio >0.86) and diffusion-weighted imaging (ADC × 10(3) mm(2)/s < 1.24). For each segment and MRI technique, results were rendered as being suspicious/non-suspicious for malignancy. Sextant biopsies, transition zone biopsies and at least two additional biopsies of suspicious areas were taken. In the peripheral zones, 105/408 segments and in the transition zones 19/136 segments were suspicious according to at least one MRI technique. A total of 28/68 (41.2%) patients were found to have cancer. Diffusion-weighted imaging exhibited the highest positive predictive value (0.52) compared with T2-weighted MRI (0.29), dynamic contrast-enhanced MRI (0.33) and 3D-spectroscopy MRI (0.25). Logistic regression showed the probability of cancer in a segment increasing 12-fold when T2-weighted and diffusion-weighted imaging MRI were both suspicious (63.4%) compared with both being non-suspicious (5.2%). The proposed system of analysis and reporting could prove clinically relevant in the decision whether to repeat targeted biopsies.

Community‐based prostate cancer screening in Japan: Predicting factors for positive repeat biopsy

To assess possible predictors in determining criteria for repeat biopsy in a prostate cancer screening population. A total of 50 207 men over 55 years-of-age have participated in a prostate cancer screening program in Otokuni, Kyoto, Japan for 12 years. Transperineal systematic biopsy was carried out in case of positive digital rectal examination (DRE) or positive transrectal ultrasonography (TRUS) or a prostate-specific antigen (PSA) value greater than 10.0 ng/mL. For those with a PSA level from 4.1 to 10.0 ng/mL, and negative DRE and TRUS findings, biopsy was indicated only when PSA density (PSAD) was greater than 0.15. The same indication was applied for the repeat biopsy. A repeat biopsy after an interval of more than 2 years was carried out in 140 patients and was positive in 50 (36%) patients. The PSA value at the diagnosis of cancer declined from the initial value in six (12%) patients. On multivariate logistic regression analysis, PSA velocity (PSAV) as well as PSAD and DRE findings at latest screening were independent predictors for positive repeat-biopsy outcome. The odds ratio (95% confidence intervals) of PSAV >0.48, latest PSAD >0.33 and positive latest DRE were 4.17 (1.05-18.5), 4.15 (1.31-14.0), and 3.62 (1.06-13.2), respectively. A combination of three variables defined as positive if any of these were positive, reduced 31% of unnecessary biopsies while missing 8% of low volume, low grade cancers. A combination of latest PSAD, PSAV and positive DRE at latest screening might help to reduce unnecessary repeat biopsies in high-risk patients with an initial negative biopsy.

123 GENETIC VARIANTS SIGNIFICANTLY IMPROVE DETECTION OF PROSTATE CANCER AND ARE ASSOCIATED WITH AGGRESSIVE FEATURES IN PATIENTS WITH A “NORMAL” PSA AND DRE

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History I1 Apr 2010123 GENETIC VARIANTS SIGNIFICANTLY IMPROVE DETECTION OF PROSTATE CANCER AND ARE ASSOCIATED WITH AGGRESSIVE FEATURES IN PATIENTS WITH A “NORMAL” PSA AND DRE Brian T. Helfand, Stacy Loeb, Matthias D. Hofer, Ronald Kim, Phillip R. Cooper, Donghui Kan, and William J. Catalona Brian T. HelfandBrian T. Helfand Chicago, IL More articles by this author , Stacy LoebStacy Loeb Baltimore, MD More articles by this author , Matthias D. HoferMatthias D. Hofer Chicago, IL More articles by this author , Ronald KimRonald Kim Chicago, IL More articles by this author , Phillip R. CooperPhillip R. Cooper Chicago, IL More articles by this author , Donghui KanDonghui Kan Chicago, IL More articles by this author , and William J. CatalonaWilliam J. Catalona Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.174AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Several reports suggest that a combination of genetic prostate cancer (CaP) susceptibility variants may independently predict CaP risk and tumor features. However, the ability to detect CaP in patients with a “normal” PSA and non-suspicious digital rectal examination (DRE) remains to be determined. Therefore, the present study examined the performance of genetic variants in prediction models for CaP risk and aggressiveness. METHODS From June 2002-May 2008, we examined 79 Caucasian men with clinical stage T1c prostate cancer diagnosed at a PSA <4.0 ng/mL and 595 controls with negative DRE and PSA <4.0 ng/mL. The genotypes for 14 CaP risk alleles (on chromosomes 2p15, 3q21, 5p15, 8q24, 10q11, 11q13, 17q12, 17q24, 19q13, and Xp11) were compared between CaP cases and controls. Additional analyses were used to compare the pathologic features between carriers and non-carriers of the variants. RESULTS 12 of the variants were over-represented in CaP patients with “normal” PSA values compared to controls. Among Caucasian men with “normal” PSA values, carriers of an increasing number of genetic variants were at a significantly increased risk of CaP (p-trend<0.001). Men with ≥9 genetic variants had an OR of 6.7 (95% CI 2.0-23.7) compared to men with ≤4 variants (Table 1). On multivariate analysis with age, the genetic variants remained significant predictors of CaP risk in this population (OR 2.3, 95% CI 1.5-3.8, p=0.0005). There also was an increase in the frequency of high Gleason grade (≥7) disease in carriers of 11 variants. Specifically, a statistically significant difference was observed for the frequency of both high-grade cancer (p=0.03) and seminal vesicle invasion (p=0.02) in carriers of the 8q24 rs16901979 variant. Table 1. Cumulative Model Comparing Frequency of Genetic Variants in Patients with “Normal” PSA and DRE Carrier of Variants # Case N=(%) Control N=(%) OR (95% C.I.) p-value 0-4 9(11.4) 145(24.4) — — 5 19(24.0) 158(26.5) 1.9(0.8-4.4) 0.12 6 14(17.8) 129(21.7) 1.7(0.7-4.2) 0.21 7 19(24.0) 108(18.2) 2.8(1.2-6.5) 0.14 8 13(16.5) 43(7.2) 4.9(2.0-12.2) 0.0007 ≥9 5(6.3) 12(2.0) 6.7(1.9-23.2) 0.0026 CONCLUSIONS A substantial proportion of biopsy-detectable CaP occurs in men with PSA levels >4 ng/mL and negative DRE. In this population, genetic risk variants are significantly associated with CaP risk and may guide in the prediction of aggressive disease. Future studies are warranted to determine the utility of incorporating genetic risk alleles into CaP screening programs. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e50 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brian T. Helfand Chicago, IL More articles by this author Stacy Loeb Baltimore, MD More articles by this author Matthias D. Hofer Chicago, IL More articles by this author Ronald Kim Chicago, IL More articles by this author Phillip R. Cooper Chicago, IL More articles by this author Donghui Kan Chicago, IL More articles by this author William J. Catalona Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1722 USE OF PSA DERIVATIVES TO DETERMINE THE NEED FOR REPEAT BIOPSY

You have accessJournal of UrologyProstate Cancer: Detection and Screening I1 Apr 20101722 USE OF PSA DERIVATIVES TO DETERMINE THE NEED FOR REPEAT BIOPSY Donghui Kan, Stacy Loeb, Phillip R. Cooper, and William Catalona Donghui KanDonghui Kan Chicago, IL More articles by this author , Stacy LoebStacy Loeb Baltimore, MD More articles by this author , Phillip R. CooperPhillip R. Cooper Chicago, IL More articles by this author , and William CatalonaWilliam Catalona Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1570AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES For men with a negative initial prostate biopsy, there is considerable variation in practice patterns regarding the decision for repeat biopsy. The 2010 NCCN Guidelines recommend the use of PSA derivatives to evaluate the need for repeat biopsy. We examined the joint use of %fPSA, PSA velocity (PSAV), and PSA density (PSAD) to predict repeat biopsy results following an initial negative biopsy. METHODS We identified 650 men from a large prostate cancer (CaP) screening study with a PSA of 2.5 to 10 ng/mL and negative digital rectal examination, who had an initial negative prostate biopsy and underwent at least one additional biopsy. In the 241 men with subsequent measurements of all PSA derivatives, we examined the use %fPSA, PSAV, and PSAD to predict the results of the next repeat biopsy and to predict an eventual diagnosis of CaP at any point during the study interval. RESULTS In the 241 men with an initial negative biopsy, 36 (14.9%) were diagnosed with CaP on the second biopsy, and an additional 11 (4.6%) were diagnosed with CaP on a subsequent repeat biopsy. Men with a %fPSA <10, PSAD >0.10, and PSAV >0.35 ng/mL/year were significantly more likely to be diagnosed with prostate cancer on the second biopsy (45.5% vs. 13.5%, p=0.013) or at any point during follow-up (54.6% vs. 17.8%, p=0.009), compared to men who did not. CONCLUSIONS PSA derivatives are useful for risk stratification following an initial negative prostate biopsy. Men with a %fPSA <10, PSAD >0.10, and PSAV >0.35 ng/mL/year are at significantly greater risk of subsequent prostate cancer detection. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e665 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Donghui Kan Chicago, IL More articles by this author Stacy Loeb Baltimore, MD More articles by this author Phillip R. Cooper Chicago, IL More articles by this author William Catalona Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

-2]Proenzyme Prostate Specific Antigen is More Accurate Than Total and Free Prostate Specific Antigen in Differentiating Prostate Cancer From Benign Disease in a Prospective Prostate Cancer Screening Study

Due to the limited specificity of prostate specific antigen for prostate cancer screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme prostate specific antigen called [-2]proenzyme prostate specific antigen may enhance the specificity of prostate specific antigen based screening. We examined the usefulness of this isoform in a prospective prostate cancer screening study. From a population of 2,034 men undergoing prostate cancer screening we examined the relationship between the measurement of the [-2]isoform of proenzyme prostate specific antigen (p2PSA) and prostate cancer detection. Specifically we compared the usefulness of total prostate specific antigen, the ratio of free-to-total prostate specific antigen, the ratio of p2PSA-to-free prostate specific antigen, and a formula combining prostate specific antigen, free prostate specific antigen and p2PSA (the Beckman Coulter prostate health index or phi) to predict prostate cancer in men from the study undergoing prostate biopsy with a prostate specific antigen of 2.5 to 10 ng/ml and nonsuspicious digital rectal examination. Despite similar total prostate specific antigen (p = 0.88), percent free prostate specific antigen (p = 0.02) and %p2PSA (p = 0.0006) distinguished between positive and negative biopsy results. On ROC analysis %p2PSA (AUC 0.76) outperformed prostate specific antigen (AUC 0.50) and percent free prostate specific antigen (AUC 0.68) for differentiating between prostate cancer and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity as well as positive and negative predictive values. The Beckman Coulter prostate health index (AUC 0.77) had the best overall performance characteristics. This is the first prospective study to our knowledge to demonstrate that p2PSA provides improved discrimination between prostate cancer and benign disease in screened men with a prostate specific antigen of 2.5 to 10 ng/ml and a negative digital rectal examination.

PSA levels of 4.0 - 10 ng/ml and negative digital rectal examination: antibiotic therapy versus immediate prostate biopsy

The management of mildly elevated (4.0-10.0 ng/ml) prostate specific antigen (PSA) is uncertain. Immediate prostate biopsy, antibiotic treatment, or short term monitoring PSA level for 1-3 months is still in controversy. We conducted a retrospective chart review of patients in a large community practice (2003 - 2007) who had PSA levels between 4.0-10 ng/mL without any further evidence of infection. Data was gathered regarding patient's age, whether standard antibiotic therapy (10-14 days of ofloxacin or ciprofloxacin) had been administered before the second PSA measurement, results of a second PSA test performed at 1- to 2-month intervals, whether a prostate biopsy was performed and its result. One-hundred and thirty-five men met the study inclusion criteria with 65 (48.1%) having received antibiotics (group 1); the PSA levels decreased in 39 (60%) of which, sixteen underwent a biopsy which demonstrated prostate cancer in 4 (25%). Twenty-six (40%) patients of group 1 exhibited no decrease in PSA levels; seventeen of them underwent a biopsy that demonstrated cancer in 2 (12%). The other 70 (51.9%) patients were not treated with antibiotics (group 2); the PSA levels decreased in 42 (60%) of which, thirteen underwent a biopsy which demonstrated prostate cancer in 4 (31%). In the other 28 (40%) patients of group 2 there was no demonstrated decrease in PSA, nineteen of these subjects underwent a biopsy that demonstrated cancer in 8 (42%). There appears to be no advantage for administration of antibacterial therapy with initial PSA levels between 4-10 ng/mL without overt evidence of inflammation.

S28 The prognostic role of PSA Density in the detection of prostate cancer in men with PSA 4–10 ng/ml and negative both digital rectal examination and transrectal ultrasound

S28 The prognostic role of PSA Density in the detection of prostate cancer in men with PSA 4–10 ng/ml and negative both digital rectal examination and transrectal ultrasound

The f/t-PSA ratio in diagnosis of in-patients and out-patients: a unitary cutoff value is not useful!

In the prostate specific antigen (PSA) range of 4-10 ng/ml after a negative digital rectal examination, the PSA value indicates a lack of specificity with a carcinoma detection rate of roughly 20%. To improve the biopsy/carcinoma ratio, the interdisciplinary consensus recommends free PSA (fPSA) measurement. This does not take into account the pre-analysis when the cutoff value is established for biopsy indication. In the present study, an in-patient cohort whose blood samples were immediately analysed was compared with an out-patient cohort whose sample processing was delayed by between 24 and 48 h. The in-patient cohort comprises 382 patients with 99 prostate carcinomas, the out-patient cohort 987 patients with 235 carcinomas. In the in-patient cohort a sensitivity of 90% with a cutoff value of 25% for the f/t-PSA ratios is achieved with the theoretical possibility of reducing the number of punch biopsies by 34.6%. A sensitivity of 90% in the out-patient cohort necessitates a cutoff value of 18% for the f/t-PSA ratios. The specificity is 35.3% with a possible biopsy reduction of 29.1%. The cutoff values from cohorts with an immediate fPSA measurement cannot be adopted for a typical out-patient cohort whose analyses are delayed. On the contrary, an individual adjustment is necessary which corresponds to the pre-analysis.

Annexin A3 in Urine: A Highly Specific Noninvasive Marker for Prostate Cancer Early Detection

In prostate cancer cases the early diagnosis of tumors carrying a high risk of progression is of the utmost importance. There is an urgent clinical need to avoid unnecessary biopsies and subsequent overtreatment. We validated annexin A3 as a diagnostic marker for prostatic disease in typical clinical populations and relevant segments, such as patients with a negative digital rectal examination and low prostate specific antigen. We performed a blinded clinical study (ClinicalTrials.gov Identifier NCT00400894) from September 2005 to January 2007 in 591 patients who were continuously recruited from 4 European urological clinics. Urine was obtained directly after digital rectal examination and the annexin A3 concentration in urine was quantified by Western blot. Statistical analysis included combinations of annexin A3 with total, percent free, complexed and percent complexed prostate specific antigen. Combined readouts of prostate specific antigen and urinary annexin A3 were superior to all others with an area under the ROC curve of 0.82 for a total prostate specific antigen range of 2 to 6 ng/ml, 0.83 for a total prostate specific antigen range of 4 to 10 ng/ml and 0.81 in all patients. The best performing prostate specific antigen derivative was percent free prostate specific antigen with an area under the ROC curve of 0.68 for a total prostate specific antigen range of 2 to 6 ng/ml, 0.72 for a total prostate specific antigen range of 4 to 10 ng/ml and 0.73 in all patients. Annexin A3 has an inverse relationship to cancer and, therefore, its specificity was much better than that of prostate specific antigen. Annexin A3 quantification in urine provides a novel noninvasive biomarker with high specificity. Annexin A3 is complementary to prostate specific antigen or to any other cancer marker. It has a huge potential to avoid unnecessary biopsies with a particular strength in the clinically relevant large group of patients who have a negative digital rectal examination and prostate specific antigen in the lower range of values (2 to 10 ng/ml).

PSA Doubling Time as a Predictor of the Outcome of Random Prostate Biopsies Prompted by Isolated PSA Elevation in Subjects Referred to an Outpatient Biopsy Facility in a Routine Clinical Scenario

To assess the validity of PSA doubling time (PSADT) as a predictor of prostate sextant biopsy outcome in patients with PSA levels in the 4-10 ng/mL range. A consecutive series of 355 sextant biopsies performed during 2001-2007 in subjects with negative digital rectal examination and transrectal ultrasonography was considered. Variables tested as possible predictors were age, total and free/total PSA value, PSA velocity and PSA doubling time. While PSA at time of biopsy and free/total PSA were determined with a standardized method undergoing strict quality control, previous PSA values used to assess velocity/doubling time came from other labs using different assays over widely varying intervals of time. The association with biopsy outcome (cancer vs non-cancer) was investigated by univariate and multivariate analysis. Apart from free/total PSA ratio, no other studied variable showed a statistically significant and independent association with biopsy outcome, either at univariate or multivariate analysis. No studied variable had a good performance as a biopsy indicator. Depending on the variable considered, 1.17 to 1.97 cancers would be missed to spare 10 benign biopsies. When based on PSA data determined with different assays over widely varying intervals and in the absence of an underlying protocol for PSA surveillance, PSA velocity and doubling time should never discount a biopsy prompted by total PSA elevation.