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BACKGROUND: One of the major challenges in prostate cancer (PCa) treatment is distinguishing insignificant PCa from those forms that need active treatment. We evaluated the impact of PSA isoforms on risk stratification in patients with low-risk PCa as well as in active surveillance (AS) candidates who underwent radical prostatectomy. METHODS: A total of 112 patients with biopsy confirmed Gleason score (GS) 6 PCa of four different international institutions were prospectively enrolled in the study. Blood withdrawal was performed the day before radical prostatectomy. In addition, patients were classified according to the EAU and NCCN criteria for AS candidates. PSA, free PSA (fPSA) and proPSA were measured using dual monoclonal antibody sandwich immunoassays. In addition, the Prostate Health Index (PHI=proPSA/fPSA × âˆšPSA) was calculated. Final histology of the radical prostatectomy specimens was correlated to PSA, its isoforms and PHI. RESULTS: Serum proPSA levels were significantly elevated in those patients with an upgrade in final histology (GS⩾7). In addition, higher proPSA levels were predictive for extraprostatic extension (⩾pT3a) as well as for positive surgical margins. Interestingly, PHI had an even higher predictive power when compared with proPSA alone concerning GS upgrading, extraprostatic extension and surgical margins in both the total and the AS patient group. CONCLUSION: We showed in a multicenter study that proPSA is a valuable biomarker to detect patients with aggressive PCa in a cohort of GS 6 patients, who would benefit from active tumor therapy. Combining proPSA with the standard markers PSA and fPSA using PHI further increases the predictive accuracy significantly. Moreover, our data support the use of PHI for monitoring PCa patients under AS.

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PURPOSE: Persistently elevated prostate-specific antigen (PSA) values following negative biopsies result in a diagnostic dilemma. In order to improve detection rates in patients with former negative biopsies and persistently elevated PSA values, magnetic resonance tomography (MRT), magnetic resonance spectroscopy (MRS), and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed prior to prostate rebiopsies. MATERIALS AND METHODS: Over a 14-month period, 67 patients (mean age of 66 years) with a history of 1-5 negative biopsies underwent endorectal magnetic resonance imaging (MRI) using T2-weighted MRT MRS and DW-MRI before an additional prostate biopsy was performed. Subsequently, 5 contrast-enhanced transrectal ultrasound-guided biopsies were performed according to a 10-core systematic scheme. Out of the 67 men, 25 patients had positive biopsies and opted for radical prostatectomy. Histological evaluation of cancer localization, PSA, diameters of primary tumors, numbers and diameters of satellite tumors, prostate volume, and staging pathology was performed. These findings were compared with MRI and MRS results. RESULTS: Serum PSA levels ranged from 3.1 to 19.5 g/ml (median level of 7.96 ng/ml). After the 25 patients underwent radical prostatectomy, analysis of 20 whole-mount sections of 25 radical retropubic prostatectomy (RPE) specimens presented results agreeing with the tumor location from MRI and MRS data. CONCLUSIONS: The aim of image-guided diagnostics should be to provide more critical information prior to biopsy. Furthermore, the acquisition of such data is important for better risk stratification in therapeutic decisions.

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OBJECTIVES: Endoscopic therapy for vesicoureteral reflux (VUR) using dextranomer/hyaluronic acid (Dx/HA) has become increasingly popular, but the subjective impact of this therapy and subsequent reflux resolution on health-related quality of life (HRQoL) remains unclear. The aim of this study was to address this issue. MATERIALS AND METHODS: One hundred children (65 girls, 35 boys; mean age 4.46 years) cured of primary VUR by endoscopic treatment were retrospectively reviewed. The Glasgow children's benefit inventory (GCBI) - a validated, reproducible, post-interventional questionnaire consisting of four subscales - supplemented by sociodemographic and disease-specific questions was employed. The HRQoL benefit was calculated on a scale ranging from -100 (complete failure) to +100 (complete success) and correlated with supplementary data. RESULTS: Total response rate was 88%. Mean total GCBI score was 28.4+/-20.3 representing a significant HRQoL amelioration. All GCBI subscores improved with the physical health subscale being most relevant. A gender-specific, significant difference in relative GCBI scores was discovered. Correlation with critical life events and time since operation proved the positive effect on HRQoL to be durable. CONCLUSIONS: Resolution of primary VUR secondary to Dx/HA treatment significantly improves HRQoL. HRQoL is positively affected in many areas and not only in those directly associated with VUR. These improvements are not temporary, suggesting that successful Dx/HA therapy may be superior to medical management in terms of children's quality of life.

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PURPOSE: Vesicoureteral reflux is caused by a defective valve mechanism of the ureterovesical junction. Previous studies have revealed structural and metabolic changes in the intravesical ureter, impairing its contractile properties. Smooth musculature and nerves are replaced by collagen, while matrix degrading enzymes are over expressed. We investigated the presence of regulating cytokines and the extracellular matrix composition to elucidate further the pathophysiology of vesicoureteral reflux. MATERIALS AND METHODS: Ureteral endings were obtained from 28 children during antireflux surgery, and 14 age matched autopsy specimens served as controls. Routine histological sections were immunostained for insulin-like growth factor-1, nerve growth factor, transforming growth factor-beta1, tumor necrosis factor-alpha and vascular endothelial growth factor. Smooth muscle staining was supplemented by tenascin C, tetranectin and fibronectin detection. Staining patterns were investigated using computer assisted, high power field magnification analyses. RESULTS: Tumor necrosis factor-alpha and transforming growth factor-beta1 were significantly more abundant in vesicoureteral reflux samples, whereas insulin-like growth factor-1, nerve growth factor and vascular endothelial growth factor were more prevalent in healthy controls. Fibronectin was intensely expressed in refluxing ureters, while it was scarce in healthy children. Tenascin C was notable within the urothelium of both groups. Only vesicoureteral reflux samples displayed tenascin C in the musculature and connective tissue. Tetranectin staining was only detected in vesicoureteral reflux. CONCLUSIONS: Several cytokines are differentially expressed in primary refluxing ureters, indicating an ongoing tissue remodeling process in the ureterovesical junction region. Additionally, the smooth muscle coat is widely lacking, while extracellular matrix proteins typical for tissue shrinkage and reorganization are over expressed. These alterations are likely to contribute to the malfunctioning active ureteral valve mechanism in primary vesicoureteral reflux.

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During the 10(th) week of gestation human prostate development is about to start. Androgens are the crucial factors to stimulate the initial interactions between the epithelium and mesenchyme. One of the key events in androgen metabolism is the transformation of circulating testosterone to 5alpha-dihydrotestosterone (DHT) by tissue-linked 5alpha-reductase. Both, the formation of a male phenotype and the androgen-mediated growth of the prostate are mediated by DHT. To date the function of 5alpha-reductase 1 (5alphaR1) still remains unclear whereas 5alpha-reductase 2 (5alphaR2) is supposed to be the predominant isoenzyme in human accessory sex tissue. Only little data are available on the detection, distribution, and effects of both isoenzymes during fetal life and infancy. Recently, immunohistochemical investigations of serial sections from fetuses and infants using specific antibodies directed against 5alphaR1 and 5alphaR2 seem to shed light on that issue. Moreover, the detection of downstream products of androgen synthesis using RT-PCR analyses for 17-beta hydroxysteroid dehydrogenase Type 2 (17 betaHSD 2), 17 betaHSD Type 3 and 17 betaHSD Type 7 adds to discovering the molecular biological background. New studies confirm that both isoenzymes are present throughout fetal development. On the transcriptional level RT-PCR for 5alphaR1 and 5alphaR2 certifies these findings. 17 betaHSD 2, 3 and 7 representing the most relevant enzymatic downstream products of cellular androgen synthesis were revealed by RT-PCR as well. Current studies discovered the expression and distribution of both 5alpha-reductase isoenzymes as well as the potential contribution of 5alphaR1 during fetal human prostate development.

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PURPOSE: Human prostate development starts in the tenth week of gestation. Initial interactions between the epithelium and mesenchyma are stimulated by androgens. The transformation of circulating testosterone to 5alpha-dihydrotestosterone by tissue linked 5alpha-reductase is a key event in androgen metabolism. The 5alpha-dihydrotestosterone mediates androgen effects in the urogenital sinus and external genitalia, leading to the formation of a male phenotype and androgen mediated prostate growth. Supposedly 5alpha-reductase 2 is the predominant isoenzyme in human accessory sex tissue, whereas the function of 5alpha-reductase 1 remains unclear. We focused on the detection, distribution and effects of the 2 isoenzymes during gestation and infancy. MATERIALS AND METHODS: Serial sections from fetuses and infants were immunostained using antibodies directed against 5alpha-reductase 1 and 2. Additionally, to detect the downstream products of androgen synthesis reverse transcriptase-polymerase chain reaction analyses were done for 17 beta-hydroxysteroid dehydrogenase types 2, 3 and 7. RESULTS: Immunohistochemistry revealed positive staining for each isoenzyme throughout fetal development. Moreover, reverse transcriptase-polymerase chain reaction for 5alpha-reductase 1 and 2 confirmed these findings on the transcription level. Additionally, the most relevant enzymatic downstream products of cellular androgen synthesis (17 beta-hydroxysteroid dehydrogenase 2, 3 and 7) were also detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS: To our knowledge this is the first study revealing the expression and distribution of each 5alpha-reductase isoenzyme as well as the potential contribution of 5alpha-reductase 1 during fetal human prostate development.

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PURPOSE: To enhance our understanding of sonographically visible alterations in bladder wall thickness, we delineated phenotypic changes occurring in developing smooth muscle cells of the fetal and postnatal bladder with respect to gender specific differences. MATERIALS AND METHODS: Bladders of 30 male and 18 female fetuses and 4 stillborn infants were immunostained with an alpha-smooth muscle actin antibody. Morphological and morphometric assessment was performed with the assistance of an image analysis system. RESULTS: Alpha-smooth muscle actin expression in fetal bladder wall was detectable at 9 weeks of gestation. Bladder wall thickness and mean profile area of smooth muscle bundles increased significantly with advancing gestation, mediated by linear growth patterns. Fetal bladder wall development occurred uniformly, unrelated to gender. CONCLUSIONS: Although the lower urinary tract emerges in a gender specific way, our results suggest that in normal fetal growth detrusor muscle formation proceeds independent of genital sex.

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PURPOSE: Previous studies have revealed structural and metabolic changes in the distal most ureter, impairing its contractile properties, and, thus, having a role in the pathogenesis of vesicoureteral reflux. Musculature and nerves are replaced by interstitial collagen, while matrix degrading enzymes are over expressed. We investigated the microvessel architecture of the ureterovesical junction to elucidate further the pathophysiology of vesicoureteral reflux. MATERIALS AND METHODS: Ureteral endings were obtained from 28 children during antireflux surgery. Ureteral tissue from 14 age matched autopsy specimens served as control. Routine histological paraffin embedded sections were immunostained, detecting CD31 as an endothelial marker as well as vascular endothelial growth factor. Microvessel density and vascular endothelial growth factor expression were investigated based on computer assisted high power field magnification analyses. The t test and the Spearman rho test were applied for statistical evaluation. RESULTS: Overall, microvessel density was significantly reduced in cases of vesicoureteral reflux. While reflux grade and age were not correlated with microvessel density, it was particularly decreased in regions lacking smooth musculature. Vascular endothelial growth factor was observed in smooth muscle, endothelial and connective tissue cells. Additionally, cellular vascular endothelial growth factor expression was markedly abridged in cases of vesicoureteral reflux compared to healthy controls. CONCLUSIONS: Overall microperfusion is supposed to be impaired, leading to tissue ischemia due to reduction of vascular endothelial growth factor expression and subsequent microvessel density. Diminished ureteral perfusion is likely to induce and support smooth muscle dysfunction as well as subsequent extracellular matrix remodeling, including increased collagen deposition. These ongoing functional and structural alterations may further deteriorate the active valve mechanism of the ureterovesical junction, causing vesicoureteral reflux.

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PURPOSE: Despite high success rates for primary hypospadias repair, some cases require multiple procedures for ultimate reconstruction. We report our experience with single stage dorsal inlay urethroplasty using skin grafts for complex reoperations. MATERIALS AND METHODS: A total of 31 patients (mean age 13.8 years) with failed previous hypospadias surgery were included in the study. Indications included fistulas, strictures, diverticula and repair breakdown. The urethral plate had been removed or was severely scarred in all patients. A free penile or groin skin graft was sutured and quilted to the corpora cavernosa, guaranteeing sufficient blood supply. The neourethra was tubularized and covered with a tunica vaginalis or dartos flap, followed by glanuloplasty. Outcome analysis included urethrograms, urethral ultrasound and flow measurements. RESULTS: Foreskin was used in 15 cases, penile skin in 12 and inguinal skin in 4. Average graft length was 3.92 cm. A total of 20 patients required glanuloplasty with a skin graft extended to the tip of the glans. After a mean followup of 30.71 months 5 patients underwent redo surgery, for a complication rate of 16.1%. Urethral stricture of the proximal anastomosis was the most frequent finding. CONCLUSIONS: This single stage approach using dorsal skin grafts is a reliable method to create a substitute urethral plate for tubularization. Complication rates are equivalent to those of staged procedures. Foreskin should be used as a graft donor site to optimize the outcome if available. This approach represents a safe option for reoperations even if the urethral plate or midline penile skin is grossly scarred.

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OBJECTIVE: There is a consensus that transvesical reimplantation is more appropriate in cases of bilateral vesicoureteral reflex (VUR). In contrast to that it is not yet clear which approach should be used in unilateral VUR. This prospective, randomized trial compared the benefits and drawbacks of the intravesical and extravesical techniques in terms of operative comorbidity. METHODS: Forty-four children (29 girls, 15 boys, mean age, 67.23 mo) with unilateral VUR were assigned to two groups: 22 patients underwent Lich-Gregoir reimplantation and 22 underwent the intravesical Politano-Leadbetter technique. Follow-up evaluation included renal ultrasonography and voiding cystourethrography (VCUG) 6 mo postoperatively. The groups were compared for operative time, duration of hematuria, upper tract dilation, discomfort and pain, analgesic requirements, voiding dysfunction, and reflux persistency. RESULTS: No child had persistent VUR. Contralateral degrees II VUR was noted in five patients without significant difference regarding the treatment (p = 0.345). It was transient in all cases. Operative time was shorter using the extravesical technique (66.73 min versus 79.28 min; p < 0.0001). Gross hematuria occurred only after intravesical reimplantation lasting 4.19 d (p < 0.00001). The objective pain score was worse after intravesical surgery (p = 0.002). Analgesic requirements were higher after the Politano reimplantation (p = 0.039). CONCLUSIONS: Both unilateral extravesical and intravesical reimplantation definitively correct VUR. The mean operative time was significantly shorter using the Lich-Gregoir technique, which underlines its simplicity; additionally, gross hematuria can be avoided. Postoperative pain and bladder spasms were reduced using the extravesical approach. Consequently, it represents an effective surgical technique to correct reflux while operative morbidity is low. Therefore it is the method of choice in cases of unilateral VUR requiring correction.

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