Expression of neutral endopeptidase, endothelin-1, and nuclear factor kappa B in prostate cancer: interrelations and associations with prostate-specific antigen recurrence after radical prostatectomy.

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

OBJECTIVES: Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. METHODS: Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. RESULTS: Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. CONCLUSIONS: These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome.

Lack of prognostic significance of p16 and p27 after radical prostatectomy in hormone-naïve prostate cancer.

BACKGROUND: Loss of normal cell cycle control is an early event in the evolution of cancer. The expression of cyclin-dependent kinase (CDK) inhibitors p16 and p27 has been previously associated with progression of prostate cancer (PC). 70 patients diagnosed with early stage PCwere treated with radical prostatectomy (RP) at our institution and their tumor specimens were immunohistochemically evaluated for expression of p16 and p27. Available clinical data of time to PSA recurrence were correlated with the examined parameters and combined with pre-operative PSA level, Gleason score and pathological TNM (pT) stage assessment. RESULTS: Nuclear overexpression of p16 was not associated with time to biochemical failure (BF) (p = 0.572). Same was the case for nuclear p27 overexpression (p = 1.000). Also, no significant correlations were found between either p16 or p27, and pre-operative PSA level, pT stage and Gleason grade. pT stage emerged as the only independent prognostic factor for biochemical recurrence (p = 0.01). CONCLUSIONS: These data question previously reported data supporting the prognostic relevance of both p16 and p27 proteins in early PC.

CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy.

INTRODUCTION: The cell surface endopeptidase CD10 (neutral endopeptidase) and nuclear factor-κB (NF-κB) have been independently associated with prostate cancer (PC) progression. We investigated the correlations between these two factors and their prognostic relevance in terms of biochemical (prostate-specific antigen, PSA) relapse after radical prostatectomy (RP) for localized PC. PATIENTS AND METHODS: The immunohistochemical expression of CD10 and NF-κB in samples from 70 patients who underwent RP for localized PC was correlated with the preoperative PSA level, Gleason score, pathological stage and time to PSA failure. RESULTS: CD10 expression was inversely associated with NF-κB expression (p < 0.001), stage (p = 0.03) and grade (p = 0.003), whereas NF-κB was directly related with stage (p = 0.006) and grade (p = 0.002). The median time to PSA failure was 56 months. CD10 and NF-κB were directly (p < 0.001) and inversely (p < 0.001) correlated with biochemical recurrence-free survival, respectively. CD10 expression (p = 0.022) and stage (p = 0.018) were independently associated with time to biochemical recurrence. CONCLUSION: Low CD10 expression is an adverse prognostic factor for biochemical relapse after RP in localized PC, which is also associated with high NF-κB expression. Decreased CD10 expression which would lead to increased neuropeptide signaling and NF-κB activity may be present in a subset of early PCs.

p53 and cyclooxygenase-2 expression are directly associated with cyclin D1 expression in radical prostatectomy specimens of patients with hormone-naïve prostate cancer.

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.

Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men.

BACKGROUND: Catechol-estrogen metabolites can induce carcinogenesis by acting as endogenous tumor initiators. Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme, is a main metabolic pathway of estrogen detoxification in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphisms and prostate cancer risk. PATIENTS AND METHODS: 129 patients with prostate cancer and 260 healthy controls were included in our study. A(TA)TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. RESULTS: No significant differences were observed between the cancer group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes (P>0.05). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype (TA(7)/TA(7) vs TA(6)/TA(7)+TA(6)/TA(6)) (P=0.18). In addition, no association was revealed between UGT1A1 genotype distribution and Gleason score (P=0.55). CONCLUSION: Our data suggest that the TA repeat polymorphism of UGT1A1 gene does not seem to alter prostate cancer risk susceptibility in Caucasian men.

Fascin determination in urothelial carcinomas of the urinary bladder: a marker of invasiveness.

CONTEXT: Invasion and the depth of invasion affect significantly the prognosis in urothelial carcinomas. The histopathologic evaluation of invasion may be problematic in some cases. Application of new immunohistochemical markers may facilitate the assessment of invasion. Fascin, one of these markers, is an actin-bundling protein involved in tumor cell migration. Fascin expression is increased in various carcinomas. Prior to this research, to our knowledge, only one study exists regarding fascin expression in urothelial carcinomas. OBJECTIVE: To characterize the expression of fascin in additional cases of urothelial carcinoma and to verify statistically a relationship between fascin overexpression and invasiveness in these tumors. DESIGN: We examined fascin immunoreactivity in 116 specimens of urothelial carcinomas obtained from 116 patients including 96 men and 20 women. Fifty-eight cases were ranked as low-grade carcinomas, pTa stage, and 58 cases were ranked as high-grade carcinomas--11 were ranked as stage pTa, 21 were ranked as pT1, and 26 were ranked as pT2 carcinomas. Fascin immunoreactivity was assessed semiquantitatively in tumor cells. In each case, we ascribed 3 immunoreactivity scores, one for extent, one for intensity, and a combined immunoreactivity score. RESULTS: The combined immunoreactivity score was significantly higher in invasive carcinomas. In addition, strong staining was observed exclusively in invasive carcinomas. None of the pTa tumors demonstrated intense staining, including those ranked at the higher grade. CONCLUSIONS: Our results point to an association between fascin immunostaining and urothelial carcinoma invasiveness and suggest that fascin overexpression may be a marker of aggressive urothelial carcinomas.

Bladder stone formation after a tension-free vaginal tape procedure: report on two cases.

We present 2 cases of large bladder stones formed on a tension-free vaginal tape (TVT) which was inadvertently passed through the bladder during the continence procedure. The stones together with the intravesical portion of the slings were removed using a suprapubic approach. High clinical suspicion of bladder complications is necessary when evaluating patients with urinary symptoms after a TVT operation.

The effectiveness of a scientific symposium to change urologists' attitude towards treatment of LUTS/BPH.

PURPOSE: The use of interactive voting systems in continuing education helps to evaluate the alteration in the audience's views after a presentation. This study was designed to evaluate whether urologists' attitude towards management of benign prostate hyperplasia can be changed, and to estimate objectively the achievement of educational goals by using an interactive voting system. METHODS: The audience attitude was repetitively estimated by responding to questions using wireless keypads. Educational goal achievement was calculated by adding the percentage of those changing their opinion from "wrong" to "right" and that of those insisting on their initial "right" opinion. RESULTS: Giving a "wrong" answer and the probability of opinion change were independent of age and board certification. Being initially on the "wrong" side resulted in a greater probability of opinion change. The educational goals were achieved in 20.8-86.2% of cases. CONCLUSION: Satellite symposia are helpful learning environments. The use of an interactive voting system may help to evaluate objectively the achievement of educational goals.

Urodynamics prior to renal transplantation--its impact on treatment decision and final results.

OBJECTIVE: To evaluate the role of urodynamics prior to renal transplantation in a selected group of patients. MATERIAL AND METHODS: This retrospective study included 44 consecutive patients (20 males, 24 females; age range 7-57 years; mean age 27.14 +/- 15.17 years) referred for urodynamic evaluation due to known or suspected lower urinary tract dysfunction. End-stage renal disease was due to obstructive uropathy in nine patients, reflux nephropathy in 13, neuropathic bladder in nine and various parenchymal diseases in four; in nine patients the origin of renal failure remained obscure despite detailed investigations. All the patients were subjected to detailed video-urodynamics. RESULTS: In 30 patients (68.2%) a urodynamic abnormality was found which precluded kidney transplantation into their native bladders without major reconstruction, a minor corrective procedure and/or pharmacotherapy prior to transplantation. More specifically, seven patients were found to have infravesical obstruction, one had a small fibrotic bladder, seven had small capacity bladders due to long-term non-use, four were found on cystometry to have an idiopathic overactive detrusor and 11 exhibited evidence of neurogenic lower urinary tract dysfunction. Fourteen affected patients (32%) were subjected to treatment prior to kidney transplantation: three underwent bladder neck incision, seven recycling of their small bladders, one substitution and three augmentation cystoplasty. Kidney transplantation followed reconstruction 3-18 months later (mean 5 +/- 6.2 months). The follow-up ranged from 12 to 107 months (mean 25 +/- 21 months). CONCLUSION: Urodynamics prior to kidney transplantation in this selected group of patients established a definitive diagnosis of the type of lower urinary tract dysfunction, offered the opportunity for reconstructive surgery and enabled kidney transplantation.