Biomarkers for the diagnosis of prostatic inflammation in benign prostatic hyperplasia.

BACKGROUND: Chronic prostatic inflammation could be a central mechanism in benign prostatic hyperplasia (BPH) progression. Currently, the histological examination of prostate biopsies remains the only way to diagnose prostatic inflammation. Our objective was to find new noninvasive biomarkers for the diagnosis of prostatic inflammation. METHODS: Ninety BPH samples were investigated in two steps. First, a hypothesis was generated using a profiling procedure with a panel of 96 genes on an initial set of 30 samples. Then, the candidate biomarkers were validated on a large number of samples (n = 90). Gene expression was compared with the histological prostatic inflammation score based on the density and the confluence of lymphoid nodules. Finally, protein transcripts of the candidate biomarkers were investigated in urine samples and compared with clinical data. RESULTS: Of the 96 genes, nine were significantly correlated with the inflammation score on the initial set of patients. Four of them were validated on the complete set of patients: CCR7, CD40LG, CTLA4, and ICOS. ICOS and CTLA4 protein levels were readily measured in urine samples using a conventional ELISA procedure. High-ICOS expression in urine was associated with a higher post-void residual and a lower maximum urinary flow rate. CONCLUSIONS: Four genes were significantly upregulated at the mRNA level in the prostate tissue of patients with severe inflammation score. Two proteins were measured in urine samples, and were associated with maximum uroflowmetry and post-void residual. A prospective clinical study is needed to confirm their clinical relevance.

Body mass index is not a predictor of biochemical recurrence after radical prostatectomy in Dutch men diagnosed with prostate cancer.

PURPOSE: To determine the effect of body mass index (BMI) on clinical and pathological characteristics at time of diagnosis and on risk of biochemical recurrence after radical prostatectomy among Dutch men diagnosed with prostate cancer. METHODS: In total, 1,116 prostate cancer patients with known BMI, diagnosed between 2003 and 2006, were identified from the population-based cancer registry held by the Comprehensive Cancer Centre East, The Netherlands. Of these, 504 patients underwent a radical prostatectomy. Patients were categorized as normal weight (BMI < 25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI ≥ 30 kg/m(2)). Multivariable proportional hazards regression models, adjusted for age, prediagnostic PSA levels, and pathological characteristics were used to evaluate BMI as a prognostic factor for biochemical recurrence after radical prostatectomy. RESULTS: Overall, clinical and biopsy characteristics did not significantly differ among BMI groups. Pathological characteristics after radical prostatectomy did not significantly differ among BMI groups, except for tumor stage, which was highest in obese patients (P = 0.017). For patients treated with radical prostatectomy, 5-year risk (95% Confidence Intervals) of biochemical recurrence was 30% (23-37%) for normal weight, 32% (25-39%) for overweight, and 25% (9-41%) for obese patients (log rank P = 0.810). BMI was not an independent prognostic factor for biochemical recurrence in multivariable proportional hazards regression analyses (HR 0.99 per kg/m(2), 95% CI: 0.93-1.06). CONCLUSIONS: Compared with non-obese men, pathological tumor stage tended to be higher in obese men. Clinical relevance of this finding is unclear, because BMI was not an independent predictor of biochemical recurrence after radical prostatectomy.

Impact of obesity on surgical outcomes following open radical prostatectomy.

OBJECTIVE: The increasing incidence of both obesity and prostate cancer (PCa) detection will confront the urologist more often with obese men having PCa. It is unknown whether obesity affects the surgical and oncological outcomes following open radical retropubic prostatectomy (RRP). Knowledge concerning this issue is relevant when counselling obese patients with PCa for RRP. PATIENTS AND METHODS: A single institution cohort study was performed including 252 men who underwent a RRP between 1992 and 2003. The surgical complications (perioperative complications, post-RRP urinary incontinence, urethral strictures) were compared between obese (BMI >30) and nonobese (BMI

Allelic imbalance analysis using a single-nucleotide polymorphism microarray for the detection of bladder cancer recurrence.

PURPOSE: Non-muscle-invasive bladder cancer is a frequently occurring cancer, with an extremely high recurrence risk. Recurrence detection is based on cytology and urethrocystoscopy. A previous study suggested that a single-nucleotide polymorphism (SNP) array may be effective for noninvasive detection of allelic imbalances in urine. We investigated whether this method is suitable to detect allelic imbalance as an indicator of recurrences in non-muscle-invasive bladder cancer follow-up. EXPERIMENTAL DESIGN: DNA from blood and urine from 158 patients (113 with and 45 without recurrence) was hybridized to the Affymetrix GeneChip Mapping 10K 2.0. Allelic imbalance detection was based on SNPs showing changes from heterozygosity in blood to homozygosity in urine and on automatic analysis of copy number changes using Copy Number Analyser for GeneChip. RESULTS: Urine samples with tumor showed allelic imbalance at 0.4% of all informative SNPs. In samples without tumors, 0.04% of these SNPs were affected (P = 0.07). In addition, Copy Number Analyser for GeneChip analysis showed more copy number changes in samples with a tumor (P = 0.001). Losses and gains of chromosomal regions showed clustering, overlapping with known bladder cancer loci. However, 25 (22%) patients with a tumor recurrence did not display any regions with copy number changes, whereas 24 (53%) individuals without a recurrence did. Receiver operating characteristic curve analysis using the number of SNPs displaying copy number changes from the Copy Number Analyser for GeneChip analysis resulted in an area under the curve of only 0.67 (95% confidence interval, 0.58-0.76). CONCLUSION: Single-nucleotide polymorphism microarray analysis of allelic imbalance in urine cannot replace urethrocystoscopy and cytology for the detection of recurrences in non-muscle-invasive bladder cancer follow-up.

The time-resolved fluorescence-based PCA3 test on urinary sediments after digital rectal examination; a Dutch multicenter validation of the diagnostic performance.

PURPOSE: To improve the specificity in prostate cancer diagnosis and to prevent unnecessary prostate biopsies, especially in the serum prostate-specific antigen (PSA) "gray zone" between 3 and 15 ng/mL, the implementation of prostate cancer-specific markers is urgently needed. The recently discovered prostate cancer antigen 3 (PCA3) is such a promising prostate cancer marker. In a previous single institution study, the PCA3 urine test clearly proved to be of diagnostic value. Therefore, the diagnostic performance of the PCA3 urine test was validated in a multicenter study. EXPERIMENTAL DESIGN: The first voided urine after digital rectal examination was collected from a total of 583 men with serum PSA levels between 3 and 15 ng/mL who were to undergo prostate biopsies. We determined the PCA3 score in these samples and correlated the results with the results of the prostate biopsies. RESULTS: A total of 534 men (92%) had an informative sample. The area under the receiver-operating characteristic curve, a measure of the diagnostic accuracy of a test, was 0.66 for the PCA3 urine test and 0.57 for serum PSA. The sensitivity for the PCA3 urine test was 65%, the specificity was 66% (versus 47% for serum PSA), and the negative predictive value was 80%. CONCLUSIONS: In this multicenter study, we validated the diagnostic performance of the PCA3 urine test in the largest group studied thus far using a PCA3 gene-based test. This study shows that the PCA3 urine test, when used as a reflex test, can improve the specificity in prostate cancer diagnosis and could prevent many unnecessary prostate biopsies.

UroVysion compared with cytology and quantitative cytology in the surveillance of non-muscle-invasive bladder cancer.

OBJECTIVES: The multitarget fluorescence in situ hybridization probe set Vysis UroVysion, consisting of probes for chromosomes 3, 7, and 17 and for the 9p21 band, was studied to evaluate its value in the follow-up of patients with bladder cancer. The results were compared with conventional cytology and quantitative cytology (Quanticyt). The aim of this study was to evaluate whether UroVysion is a better adjunct to urethrocystoscopy than cytology and quantitative cytology. METHODS: UroVysion, cytology, and quantitative cytology were performed on 113 voided urinary samples of 105 patients under surveillance for non-muscle-invasive bladder cancer. Before urethrocystoscopy or transurethral resection of the bladder, a voided urinary sample was obtained. Results of all tests were compared to evaluate the value of UroVysion. RESULTS: Sixty-four patients had biopsy-proven urothelial cell carcinoma. Sensitivity and specificity were, respectively, 39.1% and 89.7% for UroVysion, 40.6% and 89.7% for cytology, and 42.1% and 67.9% for quantitative cytology. When the UroVysion test and cytology were combined, sensitivity increased to 53.1%, but specificity decreased to 79.5%. Detection of Ta tumours was equal for cytology and UroVysion (26.7%), detection of T1 and T2-T4 samples by UroVysion was 60% and 50%, respectively. Detection of grade 1, 2, and 3 tumours by UroVysion was 21.4%, 36.8%, and 66.7%, respectively. In four cases the UroVysion test was positive, but no abnormalities were seen at cystoscopy. CONCLUSIONS: Our data suggest that the use of UroVysion provides no improvement over cytology or quantitative cytology in the diagnosis of recurrent non-muscle-invasive bladder tumours.

DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer.

BACKGROUND: DD3(PCA3) is the most prostate cancer-specific gene described to date. To assess the clinical utility of DD3(PCA3) a time-resolved fluorescence-based, quantitative RT-PCR analysis for DD3(PCA3) was developed. METHODS: The diagnostic potential of DD3(PCA3) was determined by quantitative measurement of DD3(PCA3) transcripts in non-malignant and malignant prostate specimens. Moreover, DD3(PCA3) transcripts were determined quantitatively in urine sediments obtained after prostatic massage. A cohort of 108 men, admitted for prostate biopsies based on a PSA of >3ng/ml, was studied. RESULTS: Prostate tumors showed a 66-fold up-regulation of DD3(PCA3) (median 158.4.10(5) copies/microg tissue RNA) when compared to benign prostate tissue (median 2.4.10(5) copies/microg tissue RNA). This up-regulation was found in more than 95% of prostate cancer specimens studied. These data revealed that specimens with less than 10% of cancer cells could be accurately discriminated from non-cancer tissues. Hence, detection of a small fraction of prostate cancer cells in a background of normal cells seemed feasible. Therefore, this DD3(PCA3)-based RT-PCR assay was used for the identification of prostate cancer in urine sediments obtained after prostatic massage. From 108 men with a serum PSA value >3ng/ml, 24 men were shown to have prostate cancer upon biopsy. Of these 24 men, 16 were shown to be positive for DD3(PCA3), indicating a sensitivity of the assay of 67%. Furthermore, a negative predictive value of 90% was calculated. CONCLUSION: The quantitative RT-PCR assay for DD3(PCA3) described, bears great promise as a tool for molecular urine analysis. It has great potential in reducing the number of unnecessary biopsies. A multi-center study using this DD3(PCA3) assay can provide the basis for the utility of molecular diagnostics in clinical urological practice.