Differences in clinical presentation and management between pre- and postsurgical diagnoses of urinary bladder paraganglioma: is there clinical relevance? A systematic review.

PURPOSE: Paraganglioma of the urinary bladder (UBPGL) is a rare neuroendocrine tumor diagnosed in many patients only after surgery. We, therefore, assessed clinical clues relevant to presurgical diagnosis and clinical consequences in patients with a missed presurgical diagnosis of UBPGL. MATERIALS AND METHODS: Case reports describing a UBPGL (published from 1-1-2001 and 31-12-2020) were identified in Pubmed. Two authors independently performed data extraction and assessed data quality according to the PRISMA guideline. Patients were divided into two groups: UBPGL diagnosis before and after surgery. RESULTS: We included 177 articles reporting 194 cases. In 90 (46.4%) patients, the UBPGL was diagnosed before and in 104 (53.6%) after surgery. In presurgically diagnosed UBPGL, hypertension and catecholamine-associated symptoms were 2- to 3-fold (p < 0.001) more frequent than in postsurgically diagnosed patients whereas hematuria was twofold (p = 0.003) more prevalent in those with postsurgical diagnosis. Hypertension was an independent factor for presurgical biochemical testing (OR 4.45, 95% CI 1.66-11.94) while hematuria (OR 0.23, 95% CI 0.09-0.60) was an independent factor for not performing presurgical biochemical testing. Most patients diagnosed after surgery were not pretreated with alpha-adrenoceptor blockade (95.2%), underwent more frequently transurethral resection instead of cystectomy (70.2% vs. 23.1%) and had more frequent peroperative complications and residual tumor mass. CONCLUSIONS: In nearly half of all patients with a UBPGL, the diagnosis was not established before surgery. Hypertension and hematuria contributed independently to a presurgical diagnosis. Postsurgical diagnosis, which was associated with suboptimal presurgical and surgical management, resulted in more peroperative complications and incomplete tumor resections.

Decision Regret and Quality of Life after Focal Therapy with Vascular-Targeted Photodynamic Therapy (TOOKAD®) for Localized Prostate Cancer.

PURPOSE: The aim of the study was to assess quality of life (QoL), decision involvement, and decisional regret after treatment with vascular-targeted photodynamic therapy (VTP) (TOOKAD®) for unilateral low-risk prostate cancer. METHODS: Validated questionnaires (EORTC QLQ-C30 and QLQ-PR25) capturing QoL post-treatment, involvement in decision-making (Control Preferences Scale) and decision regret (Decisional Regret Scale), were given to patients at the 12-month visit after undergoing VTP at our institution between May 2018 and February 2021. RESULTS: Out of 44 patients, 36 patients were included in this study and 31 (86.1%) responded to the questionnaires. Mean overall health score capturing QoL at 12 months was 79.3 (standard deviation: ±18.1). 70.9% of the patients (n = 22) had no decision regret, and 67.8% of men (n = 21) had an active role in decision-making. In control biopsy at 12 months post-treatment, 19.4% of patients (n = 7) presented with local recurrence and progression to higher Gleason score (GS) was found in 13.8% of patients (n = 5). Patients (n = 3) presenting with tumor recurrence or progression to higher GS in control biopsy showed a significantly higher level of decision regret (p < 0.009). CONCLUSION: Only 9.7% of men (n = 3) felt a strong emotion of regret at 12 months after VTP. Level of decision regret was significantly higher in patients with local recurrence or tumor progression detected in control biopsy. QoL was stable after VTP.

Is the Post-Radical Prostatectomy Gleason Score a Valid Predictor of Mortality after Neoadjuvant Hormonal Treatment?

PURPOSE: To evaluate the validity of the Gleason score after neoadjuvant hormonal treatment as predictor of disease-specific mortality after radical prostatectomy. PATIENTS AND METHODS: A total of 2,880 patients with a complete data set and a mean follow-up of 10.3 years were studied; 425 of them (15%) had a history of hormonal treatment prior to surgery. The cumulative incidence of deaths from prostate cancer was determined by univariate and multivariate competing risk analysis. Cox proportional hazard models for competing risks were used to study combined effects of the variables on prostate cancer-specific mortality. RESULTS: A higher portion of specimens with a history of neoadjuvant hormonal treatment were assigned Gleason scores of 8-10 (28 vs. 17%, p < 0.0001). The mortality curves in the Gleason score strata <8 vs. 8-10 were at large congruent in patients with and without neoadjuvant hormonal treatment. In patients with neoadjuvant hormonal treatment, a Gleason score of 8-10 was an independent predictor of prostate cancer-specific mortality; the hazard ratio was, however, somewhat lower than in patients without neoadjuvant hormonal treatment. CONCLUSION: This study suggests that the prognostic value of the post-radical prostatectomy Gleason score is not meaningfully jeopardized by heterogeneous neoadjuvant hormonal treatment in a routine clinical setting.

Risk stratification for locoregional recurrence after radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: To externally validate the Christodouleas risk model incorporating pathological tumor stage, lymph node (LN) count and soft tissue surgical margin (STSM) and stratifying patients who develop locoregional recurrence (LR) after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). In addition, we aimed to generate a new model including established clinicopathological features that were absent in the Christodouleas risk model. METHODS: Prospectively assessed multicenter data from 565 patients undergoing RC for UCB in 2011 qualified for final analysis. For the purpose of external validation, risk group stratification according to Christodouleas was performed. Competing-risk models were calculated to compare the cumulative incidences of LR after RC. RESULTS: After a median follow-up of 25 months (interquartile range 19-29), the LR-rate was 11.5 %. The Christodouleas model showed a predictive accuracy of 83.2 % in our cohort. In multivariable competing-risk analysis, tumor stage ≥pT3 (HR 4.32, p < 0.001), positive STSM (HR 2.93, p = 0.005), lymphovascular invasion (HR 3.41, p < 0.001), the number of removed LNs <10 (HR 2.62, p < 0.001) and the administration of adjuvant chemotherapy (HR 0.40, p = 0.008) independently predicted the LR-rate. The resulting risk groups revealed significant differences in LR-rates after 24 months with 4.8 % for low-risk patients, 14.7 % for intermediate-risk patients and 38.9 % for high-risk patients (p < 0.001 for all), with a predictive accuracy of 85.6 %, respectively. CONCLUSIONS: The Christodouleas risk model has been successfully externally validated in the present prospective series. However, this analysis finds that overall model performance may be improved by incorporating lymphovascular invasion. After external validation of the newly proposed risk model, it may be used to identify patients who benefit from an adjuvant therapy and suit for inclusion in clinical trials.

Mucosa of murine detrusor impairs ß2 -adrenoceptor-mediated relaxation.

AIMS: To investigate the role of the mucosa in (-)-isoprenaline-induced relaxation of mouse detrusor muscle and to characterize the ß-adrenoceptor subtypes involved. METHODS: Isolated intact and mucosa-denuded muscle strips from the urinary bladder of male C57BL6 mice were pre-contracted with KCl (40 mM) and were relaxed with increasing concentrations of the ß-adrenoceptor (ß-AR) agonist (-)-isoprenaline and forskolin in the presence and absence of the subtype-selective ß-AR blockers CGP20712A (ß1 -ARs), ICI118,551 (ß2 -ARs), and L748,337 (ß3 -ARs). RESULTS: Force development in response to KCl was larger in mucosa-denuded than in intact preparations and was almost completely relaxed with increasing concentrations of (-)-isoprenaline. Mucosa-denuded muscles were about 10-fold more sensitive to (-)-isoprenaline than intact muscles. CGP20712A did not affect the concentration-response curves (CRCs) to (-)-isoprenaline, ICI118,551 shifted the CRC further to the right in denuded than in intact strips so that the difference between them was abolished. Combined exposure to ß1 -AR and ß2 -AR blocker yielded the same result. L748,337 did not significantly affect the CRC to (-)-isoprenaline but caused additional blockade to ICI118,551 in the presence of intact mucosa. CONCLUSIONS: The mucosa of mouse detrusor strips impairs KCl-induced force development and reduces the sensitivity to ß-AR-induced relaxation. The relaxing response to (-)-isoprenaline as well as the mucosa effect thereupon are mainly mediated by ß2 -ARs. A minor involvement of ß3 -ARs becomes apparent particularly at high (-)-isoprenaline concentrations.

Pharmacological Modulation of Mucosa-Related Impairment of ß-Adrenoceptor-Mediated Relaxation in Human Detrusor.

OBJECTIVES: The mucosa of human detrusor strips impairs catecholamine-induced relaxation. In order to elucidate which signal transduction pathways are involved in this cross talk between the mucosa and detrusor, we have studied the effects of several pharmacological agonists and antagonists on noradrenaline-mediated relaxation in intact and mucosa-denuded detrusor strips. PATIENTS AND METHODS: Strips of detrusor tissue were obtained from patients who had undergone cystectomy for bladder cancer and were set up for force measurement. KCl- or carbachol-precontracted strips were relaxed with increasing concentrations of noradrenaline in the absence and in the presence of nitric oxide synthase inhibitor, L-NAME; P2X-receptor antagonist, PPADS; ETA-receptor antagonist, BQ-123; ETB-receptor antagonist, BQ-788; cyclooxygenase inhibitor, diclofenac; AT1-receptor antagonist, candesartan; and NK1-receptor antagonist, L-703,606. RESULTS: In intact strips, KCl-stimulated force was enhanced by all blockers; carbachol-stimulated force increased with L-703,606. In denuded strips, only L-NAME augmented the KCl-stimulated contraction. Noradrenaline relaxed the precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. L-NAME, PPADS and BQ-123/BQ-788 had little effect on noradrenaline-induced relaxation, whereas diclofenac, candesartan and L-703,606 sensitized intact carbachol-stimulated detrusor strips to noradrenaline-induced relaxation. CONCLUSION: Inhibition of the noradrenaline-induced relaxation of precontracted human detrusor strips by the mucosa is attenuated by diclofenac, candesartan and L-703,606 suggesting the involvement of prostanoids, angiotensin and neurokinin pathways. Further experiments are required to unravel the exact mechanisms.

ß-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor.

AIMS: To study the ß-adrenoceptor subtypes involved in the relaxation responses to (-)-isoprenaline in carbachol-pre-contracted (CCh) mouse detrusor muscle with intact and denuded mucosa. METHODS: Isolated muscle strips from the urinary bladder of male C57BL6 mice or ß2-adrenoceptor knockout mice were pre-contracted with CCh, 1 µM and relaxed with increasing concentrations of the ß-adrenoceptor (ß-AR) agonist (-)-isoprenaline and forskolin. For estimating the ß-AR subtypes involved, subtype-selective receptor blockers were used, that is, CGP 20712A (ß1-ARs), ICI 118,551 (ß2-ARs), and L748,337 (ß3-ARs). RESULTS: Unlike in KCl-pre-contracted muscle, the mucosa did not affect the sensitivity of the relaxation response to (-)-isoprenaline in CCh-pre-contracted murine detrusor strips. Increasing concentrations of (-)-isoprenaline produced a biphasic concentration-relaxation response without any difference both during the presence and absence of mucosa. The relaxation fraction produced by low (-)-isoprenaline concentrations was mediated by ß2-AR as evidenced by a shift of the concentration-response curve to higher concentrations with ICI 118,551, but not with CGP 20712A and L748,337, and by the absence of this fraction in ß2-AR-KO mice. The relaxation response with low sensitivity to (-)-isoprenaline was not affected by any of the ß-AR subtype-selective blockers and was the only response detected in detrusor strips from ß2-AR-KO mice. CONCLUSIONS: In CCh-pre-contracted mouse detrusor, ß2-ARs are responsible for the relaxation component with high sensitivity to (-)-isoprenaline as indicated by the conversion of a biphasic into a monophasic CRC with ICI 118,551 or by its absence in ß2-AR KO mice. The mucosa does not impair relaxation under these conditions.

Mucosa of human detrusor impairs contraction and ß-adrenoceptor-mediated relaxation.

OBJECTIVES: To elucidate the impact of the mucosa on detrusor muscle function by investigating force of contraction under various stimulatory conditions and during subsequent relaxation using catecholamines. PATIENTS AND METHODS: Detrusor tissue was obtained from patients who had undergone cystectomy for bladder cancer and strips of intact or mucosa-denuded muscle were set up for force measurement. Preparations were precontracted with KCl, carbachol or electric-field stimulation (EFS). Precontracted strips were relaxed using increasing concentrations of catecholamines in the absence and presence of the subtype-selective ß-adrenoceptor (AR) blockers CGP 20712A (ß1-ARs), ICI 118,551 (ß2-ARs), and L-748,337 (ß3-ARs). RESULTS: Force development in response to KCl (40 mM), carbachol (1 µM) or EFS was larger in the absence of mucosa than in intact muscle strips. The force of contraction of mucosa-denuded strips with detached urothelium incubated in the same chamber was as low as in intact strips. Noradrenaline relaxed precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. CGP 20712A did not affect noradrenaline-induced relaxation of denuded and intact strips, and ICI 118,551 did not influence noradrenaline-induced relaxation in denuded strips, but abolished the difference between denuded and intact strips. The antagonism of the relaxant effects of noradrenaline by L-748,337 was slightly smaller in intact than denuded strips. CONCLUSIONS: The mucosa of human detrusor strips impairs force development when stimulated with KCl, carbachol or EFS. The mucosa also blunts the relaxing effects of catecholamines. The latter effect does not involve the activation of ß1-ARs but only of ß2-ARs, whereas ß3-ARs mediate the relaxation of human detrusor.

Vascular-targeted Photodynamic Therapy in Unilateral Low-risk Prostate Cancer in Germany: 2-yr Single-centre Experience in a Real-world Setting Compared with Radical Prostatectomy.

BACKGROUND: Vascular-targeted photodynamic therapy (VTP) is an approved treatment option for unilateral low-risk prostate cancer (PCa). OBJECTIVE: Herein, we report our initial experience of patients treated by VTP. We compared short-term functional and oncological outcomes with those of a consecutive cohort of patients undergoing radical prostatectomy (RP) for unilateral low-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: Patients with unilateral low-risk PCa undergoing VTP (n = 41) and RP (n = 49) were evaluated in a real-world setting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Oncological outcome after VTP was measured by magnetic resonance imaging-based rebiopsy at 12 and 24 mo. Functional outcome after 1 yr was investigated by International Index of Erectile Function 5 and International Prostate Symptom Score questionnaires. Continence was evaluated by pad use. RESULTS AND LIMITATIONS: In 12- and 24-mo control biopsy (n = 22) after VTP, 45% of VTP patients showed no evidence of PCa. Both low- and intermediate-risk PCa were detected in 27% of patients. None of the RP patients had a PCa recurrence. Of VTP and RP patients, 71% and 30%, respectively, preserved erectile function. Of VTP patients, 88% had no bladder outlet obstruction. Of RP patients, 96% and 4% used zero to one and two or more pads per day, respectively. Data acquisition was performed outside of a clinical trial. The short-term follow-up and the small number of rebiopsied patients have to be considered. CONCLUSIONS: VTP is a promising treatment option in unilateral low-risk PCa presenting a lower complication profile than RP in a real-world setting. However, recurrence and progression after VTP are common in this low-risk PCa cohort, and have to be discussed critically with patients who wish VTP instead of active surveillance. Therefore, a rigorous surveillance strategy with multiparametric magnetic resonance imaging and control biopsy is required. PATIENT SUMMARY: Vascular-targeted photodynamic therapy (VTP) is a promising therapy option in patients with unilateral low-risk prostate cancer. However, tumour recurrence has to be taken into account. Noninferiority of VTP to standard curative treatment options still has to be confirmed.

Risk factors for incidental prostate cancer-who should not undergo vaporization of the prostate for benign prostate hyperplasia?

BACKGROUND: Vaporization of the prostate (e.g., using laser devices) for treatment of benign prostatic hyperplasia does not allow for subsequent histological examination. Therefore, patients should be counseled about the risk of missing an incidental prostate cancer (incPCa). In this study the risk of an incPCa was determined based on all preoperative parameters. METHODS: Thousand three hundred and fifty seven (04/2004-09/2008) patients underwent transurethral resection of the prostate (TURP) in our department. Cases with less than 10 g removed tissue, PSA >20 ng/ml or with known PCa were excluded. Data of the remaining 1,000 consecutive patients were collected retrospectively and statistically analyzed using SAS. RESULTS: Mean age was 69.4 (36-96) years, mean PSA 4.41 (0.08-19.5) ng/ml, mean weight of removed tissue 30.9 (10-110) g. An incPCa was detected in 111 cases. Thirty-four out of these were considered to be clinically relevant (relPCa; stage T1b and/or Gleason sum ≥7). In univariate analysis age, volume of the prostate and body mass index correlated with incPCa while age, volume of the prostate and PSA correlated with relPCa. Predictive parameters for a multivariate logistic regression model are age and body mass index for incPCa and age, prostate volume, and number of prior biopsies for relPCa. CONCLUSIONS: More than 1 in 10 patients undergoing TURP has an incPCa and 3.4% have a relPCa. Patients should be counseled carefully about the risk of missing especially relPCa when undergoing vaporization of the prostate. Our model significantly improves prediction of relPCa compared to PSA and digital examination alone.

The muscarinic receptor antagonist propiverine exhibits α(1)-adrenoceptor antagonism in human prostate and porcine trigonum.

PURPOSE: Combination therapy of male lower urinary tract symptoms with α(1)-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e., block of L-type Ca(2+) channels. Here, we have investigated whether propiverine and its metabolites can additionally antagonize α(1)-adrenoceptors. METHODS: Human prostate and porcine trigone muscle strips were used to explore inhibition of α(1)-adrenoceptor-mediated contractile responses. Chinese hamster ovary (CHO) cells expressing cloned human α(1)-adrenoceptors were used to determine direct interactions with the receptor in radioligand binding and intracellular Ca(2+) elevation assays. RESULTS: Propiverine concentration-dependently reversed contraction of human prostate pre-contracted with 10 µM phenylephrine (-log IC(50) [M] 4.43 ± 0.08). Similar inhibition was observed in porcine trigone (-log IC(50) 5.01 ± 0.05), and in additional experiments consisted mainly of reduced maximum phenylephrine responses. At concentrations ≥1 µM, the propiverine metabolite M-14 also relaxed phenylephrine pre-contracted trigone strips, whereas metabolites M-5 and M-6 were ineffective. In radioligand binding experiments, propiverine and M-14 exhibited similar affinity for the three α(1)-adrenoceptor subtypes with -log K (i) [M] values ranging from 4.72 to 4.94, whereas the M-5 and M-6 did not affect [(3)H]-prazosin binding. In CHO cells, propiverine inhibited α(1)-adrenoceptor-mediated Ca(2+) elevations with similar potency as radioligand binding, again mainly by reducing maximum responses. CONCLUSIONS: In contrast to other muscarinic receptor antagonists, propiverine exerts additional L-type Ca(2+)-channel blocking and α(1)-adrenoceptor antagonist effects. It remains to be determined clinically, how these additional properties contribute to the clinical effects of propiverine, particularly in male voiding dysfunction.

Contractile responses in intact and mucosa-denuded human ureter-a comparison with urinary bladder detrusor preparations.

Human proximal and distal ureter tissues were studied to clarify whether the presence of mucosa affects contractile responses. In histological studies, human ureter was compared with urinary bladder (detrusor). Contractions in response to high KCl solution, phenylephrine, and carbachol were measured in intact and mucosa-denuded strips of human ureter. Tissue sections of human bladder and ureter were used for histological staining. Thirty-four percent of the ureter strips contracted spontaneously with highly variable patterns, and this was affected neither by mucosa nor by proximal or distal tissue origin. Upon stimulation with 40 mM KCl, ureter strips exhibited strong phasic and weak tonic contractions. In intact strips, normalized tonic force was lower than in denuded strips, but no consistent effect of mucosa was observed with phasic contractions. Absolute force values of phasic contractions were weaker in proximal than distal ureter strips, but similar when normalized to tissue wet weight. Stimulation with 80 mM KCl enhanced tonic contraction fourfold; phasic contractions occurred rarely. Phenylephrine produced no statistically significant stronger tonic contraction in distal compared with proximal ureter strips; nevertheless, in some strips, pre-existing spontaneous contractions increased. Carbachol did not influence ureter contractions. In the bladder, a suburothelial cell layer stained positive with α-smooth muscle actin (α-SMA)-specific antibodies could be further differentiated with vimentin- and desmin-specific antibodies. α-SMA positive cells were absent in suburothelial ureter tissue. Like in detrusor, the mucosa inhibits KCl-stimulated tonic ureter contractions. The mucosa of detrusor and ureter tissue exhibits distinct staining patterns for α-SMA, vimentin, and desmin. This suggests a different distribution of smooth muscle cells, fibroblasts, and myofibroblasts, which could be a target for pharmacological therapy of pathologic contractile processes.

Level of education and mortality after radical prostatectomy.

Estimating the risk of competing mortality is of importance in men with early prostate cancer to choose the most appropriate way of management and to avoid over- or under-treatment. In this study, we investigated the impact of the level of education in this context. The study sample consisted of 2630 patients with complete data on level of education (college, university degree, master craftsmen, comparable profession, or others), histopathological tumor stage (organ confined or extracapsular), lymph node status (negative or positive), and prostatectomy specimen Gleason score (<7, 7, or 8-10) who underwent radical prostatectomy between 1992 and 2007. Overall, prostate cancer-specific, competing, and second cancer-related mortalities were study endpoints. Cox proportional hazard models for competing risks were used to study combined effects of the variables on these endpoints. A higher level of education was independently associated with decreased overall mortality after radical prostatectomy (hazard ratio [HR]: 0.75, 95% confidence interval [95% CI]: 0.62-0.91, P = 0.0037). The mortality difference was attributable to decreased second cancer mortality (HR: 0.59, 95% CI: 0.40-0.85, P = 0.0052) and noncancer mortality (HR: 0.73, 95% CI: 0.55-0.98, P = 0.0345) but not to differences in prostate cancer-specific mortality (HR: 1.16, 95% CI: 0.79-1.69, P = 0.4536 in the full model). In conclusion, the level of education might serve as an independent prognostic parameter supplementary to age, comorbidity, and smoking status to estimate the risk of competing mortality and to choose optimal treatment for men with early prostate cancer who are candidates for radical prostatectomy.

ß-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in ß2-Adrenoceptor Knockout Mice.

BACKGROUND AND OBJECTIVE: In order to characterize the ß-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and ß2-AR knockout (ß2-AR KO) mice. MATERIALS AND METHODS: Urinary bladders were isolated from male WT and ß2-AR KO mice. ß-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-)-isoprenaline or ß3-AR agonist CL 316,243 in the presence and absence of the subtype-selective ß-AR blockers CGP 20712A (ß1-ARs), ICI 118,551 (ß2-ARs), and L748,337 (ß3-ARs). RESULTS: Quantitative real-time PCR confirmed lack of ß2-AR expression in bladder tissue from ß2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in ß2-AR KO than in WT. (-)-Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in ß2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 µM). The -logEC50 values for (-)-isoprenaline in WT and ß2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of ß2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and ß2-AR KO mice with a potency corresponding to the drug's affinity for ß3-AR. L743,337 shifted the CRCs to the right. CONCLUSION: Our findings in ß2-AR KO mice suggest that there is a large receptor reserve for ß2-AR in WT mice so that this ß-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, ß3-AR can also mediate murine detrusor relaxation.

Characterization of different carbon nanotubes for the development of a mucoadhesive drug delivery system for intravesical treatment of bladder cancer.

In order to increase the effectiveness of therapeutics for bladder carcinoma (BCa) treatment, alternative strategies for intravesical applications are needed. The use of carbon nanotubes (CNTs) as basis for a multifunctional drug transporter is a promising possibility to combine traditional chemotherapeutics with innovative therapeutic agents such as antisense oligodeoxynucleotides or small interfering RNA. In the current study four CNT types varying in length and diameter (CNT-1, CNT-2, CNT-3, CNT-4) were synthesized and then characterized with different spectroscopic techniques. Compared to the pristine CNT-1 and CNT-3, the shortened CNT-2 and CNT-4 exhibited more defects and lower aspect ratios. To analyze their mucoadhesive properties, CNTs were exposed to mouse bladders ex vivo by using Franz diffusion cells. All four tested CNT types were able to adhere to the urothelium with a mean covering area of 5-10%. In vitro studies on UM-UC-3 and EJ28 BCa cells were conducted to evaluate the toxic potential of these CNTs. Viability and cytotoxicity assays revealed that the shortened CNT-2 and CNT-4 induced stronger inhibitory effects on BCa cells than CNT-1 and CNT-3. In conclusion, CNT-1 and CNT-3 showed the most promising properties for further optimization of a multifunctional drug transporter.

Lee mortality index as comorbidity measure in patients undergoing radical cystectomy.

To investigate the recently described Lee mortality index as predictor of mortality after radical cystectomy. A total of 735 patients who underwent radical cystectomy for bladder cancer between 1993 and 2010 were studied. Median patient age was 67 years and the median follow-up was 7.8 years (censored patients). The Lee mortality index was assigned based on data derived from patient history, preoperative cardiopulmonary risk assessment and discharge records. The age-adjusted Charlson score and preoperative cardiopulmonary risk assessment classifications were used for comparison. Competing risk analysis and Cox proportional hazard models for competing risks were used for the statistical analysis. The Lee mortality index predicted competing mortality in a dose-response relationship with somewhat lower 10-year mortality rates than predicted (p = 0.0120). Beside the age-adjusted Charlson score, the Lee mortality index was an independent predictor of overall mortality (hazard ratio per unit increase 1.06, p = 0.0415) and replaced the age-adjusted Charlson score as predictor of competing mortality (hazard ratio (HR) per unit increase 1.27, p < 0.0001). The American Society of Anesthesiologists (ASA) physical status classification was also an independent predictor of overall (HR for ASA 3-4 versus 1-2: 1.53, p = 0.0002) and competing mortality (HR for ASA 3-4 versus 1-2: 1.62, p = 0.0044). The Lee mortality index is a promising and easily applicable tool to predict competing mortality after radical cystectomy. It is at least equal to the age-adjusted Charlson score and may be supplemented by information provided by the ASA classification.

Anticholinergic effects of cis- and trans-isomers of two metabolites of propiverine.

The muscarinic receptor antagonist propiverine used for therapy of overactive bladder undergoes first pass metabolism, leading to several active metabolites, which affect muscarinic receptors and L-type Ca(2+) channels with different potencies. M-5, the major metabolite in blood, and M-6 can be synthesized as cis- and trans-isomers. We systematically investigated the pharmacodynamic profiles of the isomers on detrusor contractile function. In murine and porcine detrusor, the effects of the derivatives were examined on contractions induced by electric field stimulation (EFS), cumulatively increasing concentrations of carbachol or high KCl concentration. EFS contractions were concentration-dependently reduced by the M-5 and M-6 isomers although to a different extent. M-5(cis) was slightly more potent than M-5(trans), but the differences did not reach statistical significance. M-6(cis) was significantly more potent than M-6(trans). Responses to carbachol were antagonized by all compounds due to rightward shifts of the concentration-response curves, but only M-5(trans) also significantly reduced the maximum response. pK (B) values obtained with Schild plot analysis indicated slightly higher potency for M-6(cis) than M-6(trans). Ca(2+) influx-dependent contractions elicited by K(+) depolarization were less impaired by low concentrations of the M-6 isomers, but strongly suppressed by 100 microM of the M-5 isomers, suggesting an additional effect of the two M-5 isomers on Ca(2+) influx. All investigated isomers of M-5 and M-6 are biologically active in reducing detrusor contraction in animal tissue. While M-5( cis,) M-6(cis), and M-6(trans) possess surmountable or partially surmountable antagonistic properties at muscarinic receptors, M-5(trans) is a strong non-competitive antagonist. However, at higher concentration ranges, all four compounds seem to have additional effects on Ca(2+) influx.