Francisco Pina

INTERMEDIATE‐TERM RESULTS, UP TO 4 YEARS, OF A BONE‐ANCHORED MALE PERINEAL SLING FOR TREATING MALE STRESS URINARY INCONTINENCE AFTER PROSTATE SURGERY

To examine the intermediate‐term outcome (up to 4 years) of a bone‐anchored perineal sling (InVanceTM, American Medical Systems, Minnetonka, MN, USA) in men with stress urinary incontinence (SUI) after prostate surgery.

Genetic Polymorphism in EGF Is Associated with Prostate Cancer Aggressiveness and Progression-Free Interval in Androgen Blockade–Treated Patients

Purpose: Most prostate cancer patients develop resistance to androgen deprivation treatment, resulting in hormone resistance. Epidermal growth factor (EGF) activates several pro-oncogenic intracellular pathways inducing proliferation, differentiation, and tumorigenesis in epithelial cells. The EGF-EGF receptor pathway seems to be especially relevant in hormone-resistant prostate cancer stage. A single nucleotide polymorphism G>A in +61 locus of EGF gene has been described, in which A homozygous carriers express significantly less EGF protein compared with G allele carriers. Our purpose was to investigate the potential prognostic and predictive role of EGF functional genetic variant +61 G>A in prostate cancer patients submitted to androgen blockade therapy (ABT). Experimental Design: We conducted a case-control study in prostate cancer patients treated with ABT (n = 123) and in healthy controls without evidence of cancer (n = 152). Cumulatively, a follow-up study (median follow-up, 37 months) was undertaken to evaluate response to ABT therapy in prostate cancer patients. EGF +61 G>A genotypes were detected by PCR-RFLP. Results: We found increased risk in G carriers, after age-adjusted regression analysis, for being diagnosed with Gleason ≥7 and with metastatic disease compared with control group (CG; age-adjusted odds ratio, 3.37, P = 0.004 and age-adjusted odds ratio, 2.61, P = 0.043, respectively). Kaplan-Meier survival analysis and log-rank test showed an influence of EGF +61 G>A polymorphism in time to relapse during ABT (P = 0.018). Conclusions:EGF functional polymorphism may contribute to earlier relapse in ABT patients, supporting the involvement of EGF as an alternative pathway in hormone-resistant prostatic tumors. Furthermore, our results lend support to EGF-EGF receptor pathway as an additional therapeutic target during hormonal treatment.

Vegf and prostatic cancer: a systematic review

Elevated vascular endothelial growth factor (VEGF) blood concentration reflects its prostatic production, making this a potentially interesting tumour marker to support the decision of submitting a patient for prostatic biopsy. The objective was to review systematically the evidence on the role of VEGF blood concentration in prostate cancer detection. Published studies addressing the relation between serum or plasma VEGF levels and prostate cancer were identified by searching Pubmed, ISI Web of Knowledge, SCOPUS and LILACS up to January 2010, and reviewed following a standardized protocol. Three studies reported higher plasma VEGF (pg/ml) in patients with localized prostate cancer than in healthy controls (7.0 vs. 0.0, 9.9 vs. 2.2, and 210 vs. 26.5, P<0.01), and two showed higher serum VEGF (pg/ml) in prostate cancer patients than in patients with benign prostate hypertrophy (518.9 vs. 267.9, P<0.001; no specific values, P<0.05). In one study, serum VEGF was significantly lower in healthy controls than in patients with benign prostate hypertrophy, localized or metastatic prostate cancer. The three studies that used controls with previous suspicion of prostatic cancer but a negative biopsy reported non-statistically significant difference in VEGF serum levels (pg/ml) between controls and localized prostate cancer patients (241 vs. 206; 69.5 vs. 55; 215.2 vs. 266.4). Higher VEGF plasma levels are observed in prostatic cancer patients compared with healthy controls, but serum levels do not appear to be useful in differentiating benign from malignant prostatic disease using, as controls, individuals with high risk of prostate cancer and negative biopsy.

Combined analysis of EGF+61G>A and TGFB1+869T>C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility.

Proliferative mechanisms involving the epidermal growth factor (EGF) and transforming growth factor beta (TGF-β1) ligands are potential alternative pathways for prostate cancer (PC) progression to androgen independence (AI). Thus, the combined effect of EGF and TGFB1 functional polymorphisms might modulate tumor microenvironment and consequently its development. We studied EGF+61G>A and TGFB1+869T>C functional polymorphisms in 234 patients with PC and 243 healthy individuals. Intermediate- and high-proliferation genetic profile carriers have increased risk for PC (odds ratio (OR)=3.76, P=0.007 and OR=3.98, P=0.004, respectively), when compared with low proliferation individuals. Multivariate analysis showed a significantly lower time to AI in the high proliferation group, compared with the low/intermediate proliferation genetic profile carriers (HR=2.67, P=0.039), after adjustment for age, metastasis and stage. Results suggest that combined analysis of target genetic polymorphisms may contribute to the definition of cancer susceptibility and pharmacogenomic profiles. Combined blockage of key molecules in proliferation signaling pathways could be one of the most promising strategies for androgen-independent prostate cancer.

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration.

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

Does baseline total testosterone improve the yielding of prostate cancer screening

Previous studies suggest an association between total testosterone (tT) and prostate cancer, but results are conflicting and it is not clear if accounting for the tT levels improves the yielding of patient selection for prostatic biopsy. We evaluated the potential for tT levels and the tT/total PSA (tPSA) ratio to be used as diagnostic tools for prostate cancer and its relation with cancer aggressiveness. We measured tT, tPSA and free PSA (fPSA) in fasting blood samples of 1570 subjects consecutively referred for prostate biopsy due to abnormal digital rectal examination and/or elevated tPSA levels. These values were compared between groups defined according to the pathological results of the biopsy. No significant difference was observed in tT levels when comparing cases with prostate cancer, high grade prostate intraepithelial neoplasia, pathological prostatitis, benign prostatic hyperplasia or no alteration (median: 4.26 versus 4.44 versus 4.31 versus 4.16 pg/mL, respectively; p=0.643). The tT/tPSA ratio had a better area under the curve than tT alone (0.62, 95% CI, 0.59-0.65 versus 0.50, 95% CI, 0.47-0.53), but worse than the f/tPSA ratio (0.70, 95% CI, 0.67-0.73). In multivariate analysis, using the median of distribution as cut-off no significant association was observed between tT or tT/tPSA and prostate cancer (OR=1.06, 95% CI, 0.84-1.33; OR=0.94, 95% CI, 0.70-1.27, respectively). The tT levels were not significantly different across Gleason score groups (p=0.553). In patients suspected of having prostate cancer the tT levels are not useful to improve the yielding of patient selection for prostatic biopsy or to predict cancer aggressiveness.

Performance of an Adipokine Pathway-Based Multilocus Genetic Risk Score for Prostate Cancer Risk Prediction

Few biomarkers are available to predict prostate cancer risk. Single nucleotide polymorphisms (SNPs) tend to have weak individual effects but, in combination, they have stronger predictive value. Adipokine pathways have been implicated in the pathogenesis. We used a candidate pathway approach to investigate 29 functional SNPs in key genes from relevant adipokine pathways in a sample of 1006 men eligible for prostate biopsy. We used stepwise multivariate logistic regression and bootstrapping to develop a multilocus genetic risk score by weighting each risk SNP empirically based on its association with disease. Seven common functional polymorphisms were associated with overall and high-grade prostate cancer (Gleason≥7), whereas three variants were associated with high metastatic-risk prostate cancer (PSA≥20 ng/mL and/or Gleason≥8). The addition of genetic variants to age and PSA improved the predictive accuracy for overall and high-grade prostate cancer, using either the area under the receiver-operating characteristics curves (P<0.02), the net reclassification improvement (P<0.001) and integrated discrimination improvement (P<0.001) measures. These results suggest that functional polymorphisms in adipokine pathways may act individually and cumulatively to affect risk and severity of prostate cancer, supporting the influence of adipokine pathways in the pathogenesis of prostate cancer. Use of such adipokine multilocus genetic risk score can enhance the predictive value of PSA and age in estimating absolute risk, which supports further evaluation of its clinical significance.

Can serum angiogenin be used to improve the diagnostic performance in prostate cancer screening

Several biomarkers have been studied to avoid unnecessary biopsies resulting from suboptimal performance of prostate-specific antigen (PSA) testing. We aimed to assess the use of serum angiogenin as a prostate cancer diagnostic tool among candidates for biopsy. We selected 252 patients referred for ultrasound-guided transrectal prostate biopsy on the basis of an abnormal digital rectal examination and/or elevated total PSA. Serum angiogenin was quantitatively analyzed by solid-phase enzyme-linked immunosorbent assay. Results of the prostatic pathology assessment (cancer vs. noncancer) were defined by biopsy. The median serum angiogenin levels were significantly higher in patients with prostate cancer (median: 487 500 vs. 414 800 pg/ml, P=0.008). Among patients with baseline tPSA of 4.0 ng/ml or less, 37.5% had serum angiogenin less than 389 000 pg/ml (sensitivity: 88.9%; specificity: 45.2%), and the probability of having prostate cancer varied from 22.5% before testing to 6.7% among those with low angiogenin levels. When further restricting the analyses to a group of patients with even lower probability of having cancer, on the basis of tPSA and f/t PSA values, the evaluation of serum angiogenin did not contribute toward a meaningful variation in the post-test probability of cancer. In conclusion, serum angiogenin levels may be useful to distinguish between cancer and noncancer patients among the candidates for prostatic biopsy in regular clinical practice. Further investigation is needed among patients with low PSA levels and to understand the relation between this biomarker and the long-term survival of prostate cancer patients.

Controversies in using urine samples for prostate cancer detection: PSA and PCA3 expression analysis

PURPOSE Prostate cancer (PCa) is one of the most commonly diagnosed malignancies in the world. Although PSA utilization as a serum marker has improved prostate cancer detection it still presents some limitations, mainly regarding its specificity. The expression of this marker, along with the detection of PCA3 mRNA in urine samples, has been suggested as a new approach for PCa detection. The goal of this work was to evaluate the efficacy of the urinary detection of PCA3 mRNA and PSA mRNA without performing the somewhat embarrassing prostate massage. It was also intended to optimize and implement a methodological protocol for this kind of sampling. MATERIALS AND METHODS Urine samples from 57 patients with suspected prostate disease were collected, without undergoing prostate massage. Increased serum PSA levels were confirmed by medical records review. RNA was extracted by different methods and a preamplification step was included in order to improve gene detection by Real-Time PCR. RESULTS An increase in RNA concentration with the use of TriPure Isolation Reagent. Despite this optimization, only 15.8% of the cases showed expression of PSA mRNA and only 3.8% of prostate cancer patients presented detectable levels of PCA3 mRNA. The use of a preamplification step revealed no improvement in the results obtained. CONCLUSION This work confirms that prostate massage is important before urine collection for gene expression analysis. Since PSA and PCA3 are prostate specific, it is necessary to promote the passage of cells from prostate to urinary tract, in order to detect these genetic markers in urine samples.

Molecular Study of the PCA3 Gene: Genotypic Analysis of PCA3 Polymorphism -845G>A and Metastatic Prostate Cancer

AIMS The prostate cancer gene 3 (PCA3) is a prostate-specific, non-protein-coding RNA. It is overexpressed in prostate cancer compared with the normal prostate and has a negative expression in other tissues. This case-control study sought to analyze the frequency of the polymorphism PCA3 -845 G>A in participants without prostate cancer and patients with metastatic prostate cancer. RESULTS Carriers of GA and AA genotype had a higher risk for metastatic prostate cancer (odds ratio [OR] for genotype GA, 1.79 [95% confidence interval (CI), 1.14-2.29]; p=0.007; OR for genotype AA, 2.38 [95% CI, 1.22-4.65]; p=0.006). Furthermore, the recessive model showed that A allele carriers have an increased risk for developing metastatic prostate cancer (OR, 1.91 [95% CI, 1.26-2.90]; p=0.001). CONCLUSIONS These results suggest a link between PCA3 and metastatic prostate cancer. The evaluation of individual genetic profiles, according to the PCA3 -845 G>A polymorphism, may elucidate the function of this gene and the mechanisms involved in its regulation and role in prostate cancer.