Isoform-independent promotion of contractility and proliferation, and suppression of survival by with no lysine/K kinases in prostate stromal cells.

With no lysine/K kinases (WNKs) promote vasocontraction and vascular smooth muscle cell proliferation. In the prostate, smooth muscle contraction and growth may be critical for the development and medical treatment of voiding symptoms in benign prostatic hyperplasia. Here, we examined the effects of isoform-specific WNK silencing and of the WNK inhibitor WNK463 on growth-related functions and contraction in prostate stromal cells, and in human prostate tissues. Impacts of WNK silencing by transfection of cultured stromal cells with isoform-specific siRNAs were qualitatively and quantitatively similar for each WNK isoform. Effects of silencing were largest on cell death (3-5 fold increase in annexin V-positive/7-AAD-positive cells), on proliferation rate, Ki-67 mRNA expression and actin organization (reduced around two-thirds). Contraction in matrix contraction assays and viability were reduced to a lower degree (approximately half), but again to a similar extent for each WNK isoform. Effects of silencing were quantitatively and qualitatively reproduced by 10 µM WNK463, while 1 µM still induced cell death and breakdown in actin organization, without affecting proliferation or viability. Using 500 nM and 10 µM, WNK463 partly inhibited neurogenic and U46619-induced contractions of human prostate tissues (around half), while inhibition of α1-adrenergic contractions (around half) was limited to 10 µM. All four WNK isoforms suppress cell death and promote proliferation in prostate stromal cells. WNK-driven contraction of stromal cells appears possible, even though to a limited extent. Outcomes of isoform-specific WNK silencing can be fully reproduced by WNK463, including inhibition of smooth muscle contraction in human prostate tissues, but require high concentrations.

Selective inhibition of neurogenic, but not agonist-induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle.

BACKGROUND: Phospholipases A2 (PLA2 ) may be involved in α1 -adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1 -adrenergic contractions of the prostate, is still unknown. While α1 -adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2 . Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1 -adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls. RESULTS: Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1 -adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM). CONCLUSIONS: Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1 -adrenergic agonists occur PLA2 -independent. Lacking sensitivity to montelukast excludes an involvement of PLA2 -derived leukotrienes in promotion of contractile neurotransmission.

Age and ECOG Performance Status as Predictors of Survival of Patients with Upper Urinary Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy.

INTRODUCTION: This study aimed to evaluate the impact of chronological and biological age on perioperative complications and survival after radical nephroureterectomy (RNU). Elderly patients with upper-tract urothelial carcinoma might be overtreated by RNU. METHODS: We retrospectively analyzed patients undergoing RNU. To evaluate the perioperative risk, patients were divided into four groups (<75; 75-79; 80-84; ≥85 years). The endpoints are perioperative complications and survival (overall survival [OS]). We calculated a risk score including chronological and biological age (Eastern cooperative oncology group performance status). Statistical analysis was performed by Kruskal-Wallis, Mann-Whitney U, χ2, log-rank, and Breslow tests. RESULTS: 194 patients were included in the study. Median follow-up was 25.5 months. Elderly cohorts ≥2 presented a higher number of days in intensive care unit following RNU (p < 0.001). Complication rates increased from cohort 1-4 with rates of 48.8%; 55.2%; 92.0%; 85.7% (p < 0.001). Median survival was 115, 55, 28, and 20 months for cohorts 1, 2, 3, and 4, respectively. The combined risk score revealed a significant 5-year OS benefit for patients with score 0 (82.3%) compared to score 1 (46.0%) and score 2 (15.0%; p < 0.001). DISCUSSION/CONCLUSION: We evaluated the impact of chronological and biological age on perioperative complications and survival after RNU. A combined risk score of chronological and biological age correlates with survival after RNU.

Inhibition of human prostate smooth muscle contraction by the inhibitors of protein kinase C, GF109203X, and Go6983.

INTRODUCTION: Prostate smooth muscle contraction is promoted by receptor-induced activation of intracellular signaling pathways. The presumed involvement in etiology and medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) imparts a high clinical relevance to prostate smooth muscle contraction, which is contrasted by incomplete understanding at the molecular level. Involvement of protein kinase C (PKC) has been commonly assumed, but available studies were limited to nonhuman prostate smooth muscle or cell cultures. Here, we examined the effects of the PKC inhibitors Go6983 and GF109203x on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS), α1 -adrenergic agonists (noradrenaline, phenylephrine, methoxamine), thromboxane A2 analog U46619, endothelin-1, or calcium chloride in an organ bath. RESULTS: GF109203X (500 nM) and Go6983 (300 nM) reduced EFS-, noradrenaline-, phenylephrine-, methoxamine-, and U46619-induced contractions of human prostate tissues, with maximum inhibitions approaching up to 55%. Using concentrations of 3 µM, GF109203X and Go6983 inhibited EFS- and noradrenaline-induced contractions, with similar effect sizes as 500 and 300 nM, respectively. Endothelin-1-induced contractions were not inhibited by GF109203X, and to neglectable extent by Go6983. After depolarization in calcium-free solution, calcium chloride-induced concentration-dependent contractions, which were inhibited by GF109203X and Go6983. CONCLUSIONS: GF109203X and Go6983 inhibit neurogenic, α1 -adrenergic, and thromboxane A2 -induced smooth muscle contractions in the human prostate, suggesting a role of PKC for human prostate smooth muscle contraction. The inhibition may by be imparted by inhibition of calcium sensitivity.

Inhibition of Full Smooth Muscle Contraction in Isolated Human Detrusor Tissues by Mirabegron Is Limited to Off-Target Inhibition of Neurogenic Contractions.

Mirabegron is used for treatment of storage symptoms in overactive bladder (OAB) caused by spontaneous bladder smooth muscle contractions. However, owing to limitations in available studies using human tissues, central questions are still unresolved, including mechanisms underlying improvements by mirabegron and its anticontractile effects in the detrusor. Here, we assessed concentration-dependent mirabegron effects on contractions of human detrusor tissues in frequency-response curves and concentration-response curves for different cholinergic and noncholinergic agonists. Detrusor tissues were sampled from patients undergoing radical cystectomy. Contractions were induced by electric field stimulation (EFS) and by cumulative concentrations of cholinergic agonists, endothelin-1, and the thromboxane A2 analog U46619. EFS-induced contractions were inhibited using 10 µM mirabegron, but not using 1 µM. Inhibition by 10 µM mirabegron was resistant to the ß 3-adrenergic antagonist L-748,337. Concentration-dependent contractions by carbachol were not inhibited by 1 µM or 10 µM mirabegron. Concentration-response curves for methacholine were slightly right-shifted by 10 µM, but not 1 µM mirabegron. Concentration-dependent contractions by endothelin-1 or U46619 were not changed by mirabegron. In contrast, the muscarinic antagonist tolterodine right-shifted concentration-response curves for carbachol and methacholine and inhibited EFS-induced contractions. In conclusion, inhibition of neurogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known binding constant (Ki values) for ß 3-adrenoceptors. Full contractions by cholinergic agonists, endothelin-1, and U46619 are not affected by therapeutic concentrations of mirabegron. Improvements of storage symptoms are most likely not imparted by inhibition of ß 3-adrenoceptors in the bladder wall itself. SIGNIFICANCE STATEMENT: Mirabegron is used for overactive bladder (OAB) treatment, but the underlying mechanisms are unclear, and preclinical and clinical findings are controversial due to limitations in available studies. Our findings suggest that inhibition of detrusor contractions by mirabegron is limited to neurogenic contractions, which requires unphysiologic concentrations and does not involve ß 3-adrenoceptors. Mechanisms accounting for improvements of OAB by mirabegron are located outside the urinary bladder.

Accuracy and prognostic value of radiological lymph node features in variant histologies of bladder cancer.

PURPOSE: To provide first evidence of lymph node (LN) staging using CT scan and its prognostic value in variant histologies of bladder cancer. This knowledge may optimize patient management with variant histologies based on CT morphological findings. METHODS: Preoperative CT scans of patients with variant histologies who underwent RC between 2004 and 2019 were reanalyzed by two independent radiologists in a blinded review process. Specificity, sensitivity, and accuracy for LN staging as well as LN characteristics were evaluated. Correlation with survival was investigated by Kaplan-Meier method, log-rank test and multivariate analysis. RESULTS: 1361 patients with primary tumor of the bladder underwent RC, of which 163 (12%) patients revealed variant histologies. 65 (47.8%) patients have shown an urothelial variant (UV) and 71 (52.2%) a non-urothelial variant (NUV). LN metastases were found in 18 (27.7%) patients with UV and 21 (29.6%) patients with NUV. The accuracy to detect LN metastasis for all variant histologies was 62% with a sensitivity of 46% and a specificity of 70%. Subgroups of UV and NUV revealed an accuracy of 67% and 57%. An increased number of regional LN (HR 2.8; 1.34-6.18) and the loss of fatty hilum (HR 0.36, 0.17-0.76) were prognostic parameters. In multivariate analysis, a fatty hilum (HR 0.313, 0.104-0.945) and the presence of lymph node metastases (HR 2.866, 1.140-7.207) were prognostic. CONCLUSION: This first study on CT morphological behavior of variant histologies revealed an accuracy of UV and NUV comparable to UC with low specificity for all variant histologies. CT scan prior RC should be interpreted in regard to histological subtypes.

Improving Drinking and Micturition Habits in Preschool Children: An Educational Project.

INTRODUCTION: Children worldwide often do not drink enough. However, sufficient fluids are essential for physical and cognitive health. A regular and adequate supply of fluids also supports bladder maturation in the context of acquiring urinary continence. We investigated whether training preschool children and their caretakers improves drinking and micturition habits. METHODS: This field study in a pre-post design was conducted in 6 kindergartens in the district of Garmisch-Partenkirchen from October 2018 to February 2019. An intervention group (IG) received a 3-day training on drinking and micturition habits and was compared to a control group (CG) without any training. Caretakers (IG + CG) were instructed about drinking and voiding management, too. Behavioral changes were identified by questionnaires. To analyze the long-term effect, group interviews were performed with the IG 3 months after training. The training was evaluated on different levels. RESULTS: After training, the estimated total daily fluid intake in the IG (1,160 mL) significantly exceeded that of CG (830 mL) (p = 0.015). In the IG, fluid intake until 12:00 a.m. increased (p = 0.001), children took more time for voiding (p = 0.029), and urgency decreased (p = 0.008). Children (IG + CG) used leg support to enable pelvic floor relaxation more often both at home (p = 0.026) and in kindergarten (p = 0.047). Nocturnal enuresis was reduced by approximately 46% in the IG (p = 0.485). Group interviews in the IG showed a considerable learning effect. CONCLUSION: The present study could demonstrate an increased intake of fluids and significant changes in micturition behavior in the IG. So far, this is the first educational project in Germany addressing drinking and voiding management. Our results suggest that a training of preschool children and their caretakers is feasible and effective. Further nationwide research will be needed to confirm our results and assess the need for prevention in these areas.

The Impact of Fluorescence in situ Hybridization on the Staging of Upper Tract Urothelial Carcinoma.

OBJECTIVES: The aim of the study was to evaluate the impact of fluorescence in situ hybridization (FISH) diagnostics on the T stage in final histology specimen of patients undergoing radical nephroureterectomy (RNU) due to upper tract urothelial carcinoma (UTUC) at a large tertiary care center. METHODS: We retrospectively analyzed patients who underwent RNU at our center between 2008 and 2020. Inclusion criteria were RNU due to UTUC. Urine cytologies were used for FISH analysis to detect chromosomal abnormalities. Pre-FISH group was defined as patients without access to routine preoperative urinary FISH testing (2008-2014), and FISH group was defined as patients with access to routine FISH testing. Primary outcome was T stage in final histology. Statistical analysis was performed by χ2 test and Mann-Whitney U test. RESULTS: Out of 212 patients who underwent RNU at our center between 2008 and 2020, 155 patients were included into the final analysis. The median age was 71 (range 33-90) years, and 108 (69.7%) patients were male and 47 (30.3%) female. Age and gender were not differently distributed in both groups (age: p = 0.925; gender: p = 0.682). Organ-confined disease was found in 37/72 patients in the pre-FISH cohort and in 48/83 patients in the FISH cohort (p = 0.422). Within organ-confined disease, 18/37 patients revealed a T stage smaller than T1 in the pre-FISH cohort and 35/48 patients in the FISH cohort (p = 0.022). CONCLUSIONS: Preoperative FISH diagnostics add important information to preoperative diagnostic workup of patients with UTUC. Within organ-confined disease, a significant shift toward T stages lower than T1 is observed. Further research is required to determine the impact of this shift on survival in UTUC.

A NAV2729-sensitive mechanism promotes adrenergic smooth muscle contraction and growth of stromal cells in the human prostate.

Voiding symptoms in benign prostatic hyperplasia (BPH) are driven by prostate smooth muscle contraction and prostate growth. Smooth muscle contraction in the prostate and other organs critically depends on activation of the small monomeric GTPase RhoA and probably Rac1. A role of another GTPase, ADP-ribosylation factor 6 (ARF6), for smooth muscle contraction has been recently suggested by indirect evidence but remains to be proven for any organ. Here, we report effects of NAV2729, an inhibitor with assumed specificity for ARF6, in human prostate tissues and cultured prostate stromal cells (WPMY-1). NAV2729 (5 µm) inhibited neurogenic and α1-adrenergic contractions of human prostate tissues. Contractions induced by endothelin-1, by the thromboxane A2 agonist U46619, or by high molar KCl were not inhibited. Correlation analyses suggested up-regulation of prostatic ARF6 expression with increasing degree of BPH, as ARF6 expression increased with the content of prostate-specific antigen (PSA) of prostate tissues. NAV2729 inhibited ARF6 activity but not other GTPases (ARF1, RhoA, Rac1) in prostate tissues and in WPMY-1 cells. Proliferation of WPMY-1 cells was inhibited concentration-dependently by NAV2726, as reflected by decreased viability, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, and expression of Ki-67. Silencing of ARF6 expression mimicked effects of NAV2729 on viability and in the EdU assay. Effects of NAV2729 on viability and proliferation were attenuated in cells with silenced ARF6 expression. Our findings suggest that a NAV2729-sensitive mechanism promotes adrenergic contraction and stromal cell growth in the human prostate, which is probably ARF6-mediated. Similar actions in other organs and urodynamic effects of NAV2729 appear possible.

Inhibition of neurogenic and thromboxane A2 -induced human prostate smooth muscle contraction by the integrin α2ß1 inhibitor BTT-3033 and the integrin-linked kinase inhibitor Cpd22.

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.

New strategies for inhibition of non-adrenergic prostate smooth muscle contraction by pharmacologic intervention.

BACKGROUND: Inhibition of prostate smooth muscle contraction by α1 -adrenoceptor antagonists (α1 -blockers) is a first-line medical treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Increased smooth muscle tone in the hyperplastic prostate may drive urethral obstruction, resulting in bladder outlet obstruction and voiding symptoms. However, efficacy of α1 -blockers is limited, as non-adrenergic mediators including endothelin-1 and thromboxane A2 (TXA2 ) increase prostate smooth muscle tension in parallel to α1 -adrenoceptors. This may maintain urethral obstruction despite therapy with α1 -blockers. Consequently, future treatment options with higher efficacy need to target α1 -adrenergic and non-adrenergic contractions simultaneouly. Recently, several compounds were reported to inhibit adrenergic or neurogenic prostate contractions, however, their effects on non-adrenergic contraction are unknown. Here, we examined effects of inhibitors for Rac-GTPase, Src family kinases (SFKs), and p21-activated kinases (PAKs) on non-adrenergic prostate contractions. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Viability of cultured stromal cells was assessed by CCK-8 assay. RESULTS: Inhibition of α1 -adrenergic contractions by Rac inhibitors EHT1864 (100 µM) and NSC23766 (100 µM), and SFK inhibitors AZM475721 (10 µM) and PP2 (10 µM) was confirmed by inhibition of methoxamine-induced contractions. No effects of the PAK inhibitors FRAX486 (30 µM) and IPA3 (300 µM) on α1 -adrenergic contraction were confirmed by absent effects on methoxamine-inuced contractions. EHT1864 caused inhibition of endothelin-1- and U46619-induced contractions. EHT1864 reduced the viability of stromal cells concentration- and time-dependently. EHT1864 attenuated KCl-induced contractions of prostate strips only slightly, so that toxic effects may not account alone for inhibition of agonist-induced contractions. NSC23766 inhibited U46619-induced contractions, but not endothelin-1-induced contractions. AZM475271 had no effects on endothelin-1- or U46619-induced contractions, while PP2 inhibited U46619- but not endothelin-1-induced contractions. FRAX486 caused inhibition of U46619-induced contractions. IPA3 inhibited U46619-, but not endothelin-1-induced contractions. CONCLUSIONS: Of all six inhibitors, EHT1864 seems to be most promising from a translational point of view, as it inhibited TXA2 - and endothelin-1-induced besides α1 -adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac-GTPase inhibitors. In vivo, urodynamic effects of EHT1864 and possibly of FRAX486 may exceed those of α1 -blockers.

Inhibition of smooth muscle contraction and ARF6 activity by the inhibitor for cytohesin GEFs, secinH3, in the human prostate.

Prostate smooth muscle contraction is critical for etiology and treatment of male lower urinary tract symptoms (LUTS) and is promoted by small monomeric GTPases (RhoA and Rac). GTPases may be activated by guanosine nucleotide exchange factors (GEFs). GEFs of the cytohesin family may indirectly activate Rac, or ADP ribosylation factor (ARF) GTPases directly. Here we investigated the expression of cytohesin family GEFs and effects of the cytohesin inhibitor Sec7 inhibitor H3 (secinH3) on smooth muscle contraction and GTPase activities in human prostate tissues. Of all four cytohesin isoforms, cytohesin-1 and -2 showed the highest expression in real-time PCR. Western blot and fluorescence staining suggested that cytohesin-2 may be the predominant isoform in prostate smooth muscle cells. Contractions induced by norepinephrine, the α1-adrenoceptor agonist phenylephrine, the thromboxane A2 analog U-46619 , and endothelin-1 and -3, as well as neurogenic contractions induced by electric field stimulation (EFS), were reduced by secinH3 (30 µM). Inhibition of EFS-induced contractions appeared to have efficacy similar to that of inhibition by the α1-adrenoceptor antagonist tamsulosin (300 nM). Combined application of secinH3 plus tamsulosin caused larger inhibition of EFS-induced contractions than tamsulosin alone. Pull-down assays demonstrated inhibition of the small monomeric GTPase ARF6 by secinH3, but no inhibition of RhoA or Rac1. In conclusion, we suggest that a cytohesin-ARF6 pathway takes part in smooth muscle contraction. This may open attractive new possibilities in medical treatment of male LUTS.

Transrectal ultrasound guided prostate biopsy in the era of increasing fluoroquinolone resistance: prophylaxis with single-dose ertapenem.

PURPOSE: The aim of the study was to compare single-dose ertapenem (ERT) with the 3-day regime of ciprofloxacin (CIP) for prophylaxis of possible infections following transrectal prostate biopsy. METHODS: Data from a consecutive group of 542 patients from January 2012 to January 2017 were retrospectively analysed. As preinterventional prophylaxis patient group A (179) received 500 mg CIP twice a day for three days, beginning on the day before the biopsy (until June 2013); group B (363) received a single dose of ERT 60 min prior to intervention. The first follow-up examination for all patients was between post-intervention days 2 and 3. The second follow-up examination was between day 15 and 30 following biopsy. Urine was cultured in all cases and any adverse drug reactions (ADRs) related to the antibiotic treatment were noted. We also recorded all clinically relevant morbidities requiring intervention (ischuria, macrohaematuria, symptomatic urinary tract infections and urosepsis), as well as those not requiring active intervention (macrohaematuria, decreased urinary stream, pain, haemospermia). The main study criterion was the symptomatic urinary tract infection rate and ADRs. RESULTS: All 542 biopsied patients could be included in the study and the drop-out rate was zero. There were no significant differences between groups A and B with regards to complications not requiring intervention. There was, however, a significant reduction from 14.5% (group A) to 0.8% (group B) in infectious complications. This showed a significant correlation in favour of ERT (p < 0.001). Furthermore, in the ERT group there was also a distinct and significant reduction (p > 0.001) in the number of patients with bacteriuria (>10e4 cfu per ml urine) without fever (0.5%) compared to the CIP group (12.3%). CONCLUSION: A single-dose of 1 g of intravenous ERT applied 1 h before a scheduled transrectal prostate biopsy is a safe option and provides effective protection against infection-related complications arising from surgery.

Local epidemiology and resistance profiles in acute uncomplicated cystitis (AUC) in women: a prospective cohort study in an urban urological ambulatory setting.

BACKGROUND: Acute uncomplicated cystitis (AUC) is a common ailment in the urological setting. Guidelines for urinary tract infections are based on large-scale multi-centre, epidemiological and international studies. The objective of this observational study was to establish whether the results of a multi-centre study on the resistance profile of Escherichia coli (E. coli) in patients with AUC could be directly applied to an urological practice in a major European city or whether there are divergences in the resistance profile. METHODS: An observational study was applied prospectively to 502 patients with AUC between January 2015 and January 2017). Personal data were anonymised. Exclusion criteria were the patient's age (<18) and treatment with an antibiotic in the week preceding examination. RESULTS: The average age was 32 (range 18-56). The most commonly detected bacteria was E. coli with 86%, followed by Enterococcus faecalis with 10% and Klebsiella pneumoniae with 4%. Resistance tests showed E. coli to be highly sensitive to fosfomycin (99.2%), nitrofurantoin (98.1%) and cefpodoxime (92.9%). E. coli exhibited resistance to ciprofloxacin (CIP) in 15.1%, to trimethoprim/sulfamethoxazole (TRS) in 25.2% and to amoxicillin/clavulanic acid (AMC) in 34% of cases. CONCLUSION: The comparison between data from this study and data from a multi-centre European (ECO-SENSI, ECO-SENSII and the 2014 update) showed relatively good sensitivity rates for fosfomycin and nitrofurantoin but significant differences in respect of resistance levels to TRS, CIP and AMC. AUC should therefore only be treated with TRS, CIP and AMC after a susceptibility test has been carried out.

Costs of conservative management of early-stage prostate cancer compared to radical prostatectomy-a claims data analysis.

BACKGROUND: Due to widespread PSA testing incidence rates of localized prostate cancer increase but curative treatment is often not required. Overtreatment imposes a substantial economic burden on health care systems. We compared the direct medical costs of conservative management and radical therapy for the management of early-stage prostate cancer in routine care. METHODS: An observational study design is chosen based on claims data of a German statutory health insurance fund for the years 2008-2011. Three hundred fifty-three age-matched men diagnosed with prostate cancer and treated with conservative management and radical prostatectomy, are included. Individuals with diagnoses of metastases or treatment of advanced prostate cancer are excluded. In an excess cost approach direct medical costs are considered from an insured community perspective for in- and outpatient care, pharmaceuticals, physiotherapy, and assistive technologies. Generalized linear models adjust for comorbidity by Charlson comorbidity score and recycled predictions method calculates per capita costs per treatment strategy. RESULTS: After follow-up of 2.5 years per capita costs of conservative management are €6611 lower than costs of prostatectomy ([-9734;-3547], p < 0.0001). Complications increase costs of assistive technologies by 30% (p = 0.0182), but do not influence any other costs. Results are robust to cost outliers and incidence of prostate cancer diagnosis. The short time horizon does not allow assessing long-term consequences of conservative management. CONCLUSIONS: At a time horizon of 2.5 years, conservative management is preferable to radical prostatectomy in terms of costs. Claims data analysis is limited in the selection of comparable treatment groups, as clinical information is scarce and bias due to non-randomization can only be partly mitigated by matching and confounder adjustment.

Do we need the nerve sparing radical prostatectomy techniques (intrafascial vs. interfascial) in men with erectile dysfunction? Results of a single-centre study.

OBJECTIVES: To report effect of different nerve sparing techniques (NS) during radical prostatectomy (RP) (intrafascial-RP vs. interfascial-RP) on post-RP incontinence outcomes (UI) in impotent/erectile dysfunction (ED) men. PATIENTS AND METHODS: A total of 420 impotent/ED patients (International Index of Erectile Function-score <15) with organ-confined prostate cancer were treated with bilateral-NS [intrafascial-RP (239) or interfascial-RP (181)] in our institution. Intrafascial-RP was indicated for biopsy Gleason score ≤6 and PSA ≤10 ng/ml while interfascial-RP for Gleason score ≤7 and higher serum PSA. Seventy-seven patients with bilateral non-NS-RP were taken for comparison. No patient received pre-/postoperative radiation/hormonal therapy or had prostatic enlargement surgery. UI was assessed 3, 12 and 36 months postoperatively by third party. Continence was defined as no pads/day, safety 1 pad/day as separate group, 1-2 pads/day as "mild-incontinence" and >2 pads/day as "incontinence". RESULTS: All groups had comparable perioperative criteria without significant preoperative morbidities. International Prostate Symptom Score showed severe symptoms in 5 % of patients without correlation to UI. UI-recovery increased until 36 months. Full continence was reported from 56 versus 62 and 53 % patients after intrafascial-RP versus interfascial-RP and wide excision at 3 months, respectively (p = 0.521). Corresponding figures at 12 months were 70 versus 61 versus 51 % (p = 0.114) and at 36 months 85 versus 75 versus 65 % (p = 0.135), respectively. After 12 and 36 months, there was tendency to better UI-results in advantage of NS-technique; best results were achieved in intrafascial-RP group. UI-recovery was age-dependant. Advantage was found in NS-group compared with non-NS-group in older patients (>70 years, p = 0.052). CONCLUSIONS: Impotent/ED patients have higher chances of recovering full continence after NS-RP. NS should be planned independently of preoperative potencystatus whenever technically and oncologically feasible. Age and lower urinary symptoms are not restrictions. Current data should be considered in preoperative patient counselling.

Long-term results after acute therapy of obstructive pyelonephritis.

INTRODUCTION: To evaluate therapeutic results till 5 years after therapy of obstructive pyelonephritis (OPN) emphasizing regular follow-up. MATERIAL AND METHODS: During 5 years, 57 patients with OPN were treated. The patients' charts were reviewed retrospectively for clinical data. These were completed by a questionnaire. RESULTS: In the group of 57 patients (average age 56 years), about two third were women. Urolithiasis (65%) and tumors (21%) were the main causes of obstruction; fever (91%) and loin pain (86%) the main symptoms. Three fourth of the patients showed renal insufficiency and nearly 50% anemia. E. coli and Proteus spp. were the dominating organisms. Sonography detected obstruction in 93% cases. In one third of cases, CT scan was added; 81% percutaneous nephrostomy and 19% ureteral stenting were the initial methods of urinary drainage. During therapy, 23% nephrectomies (19% complete, 4% partial) were performed. Long-term follow-up showed 11% recurrent OPN and 33% recurrent UTI. CONCLUSIONS: After diagnosis of OPN, primary nephrostomy or ureteral stenting and antibiotic therapy are the first measures. If recurrent urinary tract infections or OPN occur, long-term follow-up and low-dose antibiotic prophylaxis may be discussed.

Inhibition of smooth muscle force generation by focal adhesion kinase inhibitors in the hyperplastic human prostate.

Smooth muscle contraction may be critical for lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia and requires stable anchorage of the cytoskeleton to the cell membrane. These connections are regulated by focal adhesion kinase (FAK). Here, we addressed the involvement of FAK in the regulation of smooth muscle contraction in hyperplastic human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Expression of FAK and focal adhesion proteins was assessed by Western blot analysis and immunohistochemical stainings. Effects of the FAK inhibitors PF-573228 and Y-11 on contraction of prostate strips were examined in the organ bath. Expression of FAK and focal adhesion proteins (integrin-5α, paxilin, and c-Src) was detected by Western blot analysis in prostate samples. By double immunofluorescence staining with calponin and pan-cytokeratin, expression of FAK was observed in stromal and epithelial cells. Immunoreactivity for FAK colocalized with integrin-5α, paxilin, talin, and c-Src. Stimulation of prostate tissues with the α1-adrenergic agonist phenylephrine increased the phosphorylation state of FAK at Tyr³97 and Tyr9²5 with different kinetics, which was blocked by the α1-adrenoceptor antagonist tamsulosin. Norepinephrine and phenylephrine induced concentration-dependent contractions of prostate strips. Both FAK inhibitors PF-573228 and Y-11 significantly inhibited norepinephrine- and phenylephrine-induced contractions. Finally, PF-573228 and Y-11 inhibited contractions induced by electric field stimulation, which was significant at the highest frequency. In conclusion, α1-adrenergic smooth muscle contraction or its regulation involves FAK in the human prostate. Consequently, FAK may be involved in the pathophysiology of LUTS and in current or future LUTS therapies.

Do young patients with renal cell carcinoma feature a distinct outcome after surgery? A comparative analysis of patient age based on the multinational CORONA database.

PURPOSE: We analyzed the distinct clinicopathological features and prognosis of patients with renal cell carcinoma age 40 years or less compared to a reference group of patients 60 to 70 years old. MATERIALS AND METHODS: Overall 2,572 patients retrieved from a multicenter international database comprised of 6,234 patients with surgically treated renal cell carcinoma were included in this retrospective study. Clinical and histopathological features of 297 patients 40 years old or younger (4.8%) were compared to those of 2,275 patients (36.5%) 60 to 70 years old, who served as the reference group. Median followup was 59 months. The impact of young age and further parameters on disease specific mortality and all cause mortality was evaluated by multivariate Cox proportional hazards regression analyses. RESULTS: Young patients more frequently underwent nephron sparing surgery (27% vs 20%, p = 0.008) and regional lymph node dissection compared to older patients (38% vs 32%, p = 0.025). Organ confined tumor stage (81% vs 70%, p <0.001), smaller tumor diameter (4.5 vs 4.7 cm, p = 0.014) and chromophobe subtype (10% vs 4%, p <0.001) were significantly more frequent in young patients. On multivariate analysis older patients had a higher disease specific (HR 2.21, p <0.001) and all cause mortality (HR 3.05, p <0.001). The c indices for the Cox models were 0.87 and 0.78, respectively. However, integration of the variable age group did not significantly increase the predictive accuracy of the disease specific and all cause mortality models. CONCLUSIONS: Young patients with renal cell carcinoma (40 years old or younger) have significantly different frequencies of clinical and histopathological features, and a significantly lower all cause and disease specific mortality compared to patients 60 to 70 years old.

Outcomes of a bladder preservation technique in female patients undergoing pelvic exenteration surgery for advanced gynaecological tumours.

INTRODUCTION AND HYPOTHESIS: The purpose of the study was to report the feasibility of the bladder preservation technique (BPT) during pelvic exenteration for primary advanced gynaecological pelvic tumours (PRSGT) as an alternative for continent urinary diversion. METHODS: Sixteen consecutive female patients underwent BPT during PRSGT. Median age was 50.8 years (range 37-65). Tumours included cervical (5 patients), corpus/vaginal (9), and ovarian (2) carcinomas. In resectable tumours, the excision of the distal ureters and the posterior bladder wall with an inverted "V" incision into the trigone down to the vaginal wall was performed with bladder blood and nerve supply preservation. The remaining mobilized leaflets were fixed to the psoas muscle/sacral promontory. Average follow-up was 34 months (range 24-108). Follow-up parameters included postoperative continence grade (full [no pads], stress incontinence grade I [1-2 pads], and grade II [>2 pads]), urinary tract infections, micturation problems/residual urine, ureteric reflux as well as patients' global satisfaction (PGS). RESULTS: All surgeries were done successfully. One patient developed a vesicovaginal fistula 4 weeks postoperatively and was managed conservatively. Fifteen patients (94 %) were able to empty their bladders postoperatively. Prolonged full continence was reported from 8 patients (50 %), incontinence grade I in 3 (18.8 %), and grade II in 5 (31.3 %). Two patients (incontinence grade II) developed cystoceles necessitating transvaginal bladder neck suspension with a fascia lata sling and were continent postoperatively. Another patient (6 %) underwent re-excision of a recurrent pelvic tumour necessitating intermittent self-catheterization. Postoperative hydronephrosis (grade I-II) was observed in 4 patients (25 %) and vesico-ureteral reflux (grade IV) in 4 (25 %) without the need for intervention. PGS and willingness to recommend their procedure to others were favourable. CONCLUSIONS: In patients for whom complete bladder resection is not indicated for oncological reasons, BPT during PRSGT with ureteric reimplantation is feasible and safe and provides good functional results as well as patient global satisfaction. Lower tract surgeries could be safely carried out afterward. Long-term functional results support durable good PGS.