De-obstruction of bladder outlet in humans reverses organ remodelling by normalizing the expression of key transcription factors.

BACKGROUND: Benign prostatic hyperplasia in elderly males often causes bladder outlet obstruction termed benign prostatic obstruction (BPO). BPO induces lower urinary tract symptoms and quantifiable urodynamic alterations in bladder function. When conservative medical treatments are exhausted, surgical interventions like transurethral resection of the prostate (TURP) are employed for bladder outlet de-obstruction. Elucidating the molecular changes in the human bladder resulting from BPO and their reversal post-de-obstruction is pivotal for defining the "point of no return", when the organ deterioration becomes irreversible. In this study we carried out a comprehensive molecular and urodynamic characterization of the bladders in men with BPO before TURP and 3 months after the relief of obstruction. METHODS: We report integrated transcriptome and proteome analysis of bladder samples from male patients with BPO before and 3 months after de-obstruction surgery (TURP). mRNA and protein profiles were correlated with urodynamic findings, specifically voiding detrusor pressure (PdetQmax) before TURP. We delineated the molecular classifiers of each group, pointing at the different pre-TURP bladder status. RESULTS: Age-matched patients with BPO without DO were divided into two groups based on the PdetQmax values recorded by UDI before de-obstruction: high and medium pressure (HP and MP) groups. Three months after de-obstruction surgery, the voiding parameters PdetQmax, Qmax and RV were significantly improved in both groups, without notable inter-group differences in the values after TURP. Patients with high PdetQmax showed less advanced remodeling and inflammatory changes than those with lower values. We detected significant dysregulation of gene expression, which was at least partially reversed by de-obstruction in both patients' groups. Transcription factor SOX21 and its target thrombospondin 4 (THBS4) demonstrated normalization post-TURP. CONCLUSIONS: Our findings reveal substantial yet incomplete reversal of cell signalling pathways three months after TURP, consistent with improved urodynamic parameters. We propose a set of biomarker genes, indicative of BPO, and possibly contributing to the bladder changes. This study unveils the stages of progressive obstruction-induced bladder decompensation and offers insights into selecting an optimal intervention point to mitigate loss of contractility.

Machine Learning-Based Classification of Transcriptome Signatures of Non-Ulcerative Bladder Pain Syndrome.

Lower urinary tract dysfunction (LUTD) presents a global health challenge with symptoms impacting a substantial percentage of the population. The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non-ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)-based approach for the identification of mRNA signatures specific to non-ulcerative BPS. Using next-generation sequencing (NGS) transcriptome data from bladder biopsies of patients with BPS, benign prostatic obstruction with DO, and controls, our statistical approach successfully identified 13 candidate genes capable of discerning BPS from control and DO patients. This set was validated using Quantitative Polymerase Chain Reaction (QPCR) in a larger patient cohort. To confirm our findings, we applied both supervised and unsupervised ML approaches to the QPCR dataset. A three-mRNA signature TPPP3, FAT1, and NCALD, emerged as a robust classifier for non-ulcerative BPS. The ML-based framework used to define BPS classifiers establishes a solid foundation for comprehending the gene expression changes in the bladder during BPS and serves as a valuable resource and methodology for advancing signature identification in other fields. The proposed ML pipeline demonstrates its efficacy in handling challenges associated with limited sample sizes, offering a promising avenue for applications in similar domains.

Molecular Characterization of Non-Neurogenic and Neurogenic Lower Urinary Tract Dysfunction (LUTD) in SCI-Induced and Partial Bladder Outlet Obstruction Mouse Models.

We examined bladder function following spinal cord injury (SCI) by repeated urodynamic investigation (UDI), including external urethral sphincter (EUS) electromyography (EMG) in awake restrained mice and correlated micturition parameters to gene expression and morphological changes in the bladder. A partial bladder outlet obstruction (pBOO) model was used for comparison to elucidate both the common and specific features of obstructive and neurogenic lower urinary tract dysfunction (LUTD). Thirty female C57Bl/6J mice in each group received an implanted bladder catheter with additional electrodes placed next to the EUS in the SCI group. UDI assessments were performed weekly for 7 weeks (pBOO group) or 8 weeks (SCI group), after which bladders were harvested for histological and transcriptome analysis. SCI mice developed detrusor sphincter dyssynergia (DSD) one week after injury with high-pressure oscillations and a significantly increased maximal bladder pressure Pmax and were unable to void spontaneously during the whole observation period. They showed an increased bladder-to-bodyweight ratio, bladder fibrosis, and transcriptome changes indicative of extracellular matrix remodeling and alterations of neuronal signaling and muscle contraction. In contrast, pBOO led to a significantly increased Pmax after one week, which normalized at later time points. Increased bladder-to-bodyweight ratio and pronounced gene expression changes involving immune and inflammatory pathways were observed 7 weeks after pBOO. Comparative transcriptome analysis of SCI and pBOO bladders revealed the activation of Wnt and TGF-beta signaling in both the neurogenic and obstructive LUTD and highlighted FGF2 as a major upregulated transcription factor during organ remodeling. We conclude that SCI-induced DSD in mice leads to profound changes in neuronal signaling and muscle contractility, leading to bladder fibrosis. In a similar time frame, significant bladder remodeling following pBOO allowed for functional compensation, preserving normal micturition parameters.

Perioperative continuation of aspirin, oral anticoagulants or bridging with therapeutic low-molecular-weight heparin does not increase intraoperative blood loss and blood transfusion rate in cystectomy patients: an observational cohort study.

OBJECTIVE: To assess if uninterrupted anticoagulant agents' administration affects blood loss and blood transfusion during open radical cystectomy (RC) and urinary diversion. PATIENTS AND METHODS: We conducted an observational single-centre cohort study of a consecutive series of 1430 RC patients, between 2000 and 2020. Blood loss was depicted according to body weight and duration of surgery (mL/kg/h), and blood transfusion. The group 'with anticoagulant agents' was considered if surgery was performed with uninterrupted low-dose aspirin (ASS), oral anticoagulants (OAC) with an international normalised ratio (INR) goal of 2-2.5 or bridging with therapeutic low-molecular-weight heparin (LMWH). Outcomes were intraoperative blood loss, blood transfusion rate (separately analysed if administered within 24 h perioperatively or >24 h after surgery) and the 90-day major adverse cardiac events (MACE) rate. We used propensity score (PS)-matching analysis to adjust for imbalances between groups with or without anticoagulant agents. RESULTS: The PS-matched median (interquartile range [IQR]) blood loss was 2.10 (1.50-2.94) mL/kg/h in patients with anticoagulant agents vs 2.11 (1.47-2.94) mL/kg/h without anticoagulant agents (Padj > 0.99). The PS-matched blood transfusion rates were 26.2% vs 35.1% (Padj = 0.875) within 24 h perioperatively and 57.0% vs 55.0% (Padj = 0.680) if administered >24 h postoperatively. A sub-analysis of the three different anticoagulant agents could not detect any significance between ASS, OAC, or LMWH. The PS-matched incidence of MACE was 9.1% in the group with anticoagulant agents and 8.1% in those without anticoagulant agents (Padj > 0.99). Limitations include selection bias and retrospective analysis from prospectively assessed data. CONCLUSIONS: Perioperative continuation of ASS, uninterrupted OAC with low INR goal or bridging with LMWH had no impact on blood loss and transfusion rate in RC patients. Therefore, there might be no compulsory need for discontinuation of anticoagulant agents.

Impact of early postoperative creatinine increase on mid-term renal function after cystectomy.

OBJECTIVES: To determine whether early acute kidney injury affects mid-term renal function, to identify risk factors for impaired mid-term renal function, and to highlight the evolution of plasma creatinine and estimated glomerular filtration rate in the first 12 months after cystectomy and urinary diversion. METHODS: We conducted a single-center retrospective observational cohort study from 2000 to 2019. We included 900 consecutive patients undergoing cystectomy and urinary diversion. Patients with incomplete data and preoperative hemodialysis were excluded. Early acute kidney injury was defined as an increase in plasma creatinine of >50% or >26.5 µmol/L within 24 h after surgery. Multiple linear regression analysis was performed to model the association between risk factors and change in plasma creatinine and estimated glomerular filtration rate at 12 months. RESULTS: Early acute kidney injury was diagnosed in 183/900 patients (20.3%) and was associated with significant mid-term plasma creatinine increase compared to preoperative value (+10.0 µmol/L [95% confidence interval -1.5, 25.0] vs +4.0 µmol/L [-7.0, 13.0]; P < 0.001). Similarly, a significant estimated glomerular filtration rate change was found (-11.2 mL/min [95% confidence interval -19.8, 0.6] vs -4.9 mL/min [-15.6, 5.3]; P < 0.001). In the linear regression model, early acute kidney injury increased creatinine at 12 months by 9.8% (estimated glomerular filtration rate: decrease by 6.2 mL/min), male sex by 12.0%. Limitations include retrospective analysis from prospectively assessed data. CONCLUSIONS: Early acute kidney injury resulted in elevated plasma creatinine and decreased estimated glomerular filtration rate values 12 months postoperatively, albeit the clinical relevance remains questionable.

Seminal Vesical Sparing Cystectomy for Bladder Cancer is Feasible with Good Functional Results without Impairing Oncological Outcomes: A Longitudinal Long-Term Propensity-Matched Single Center Study.

PURPOSE: Seminal vesicle-sparing radical cystectomy has been reported to improve short-term functional results without compromising oncological outcomes. However, there is still a lack of data on long-term outcomes after seminal vesicle-sparing radical cystectomy. The aim of this study was to compare oncological and functional outcomes in patients after seminal vesicle-sparing vs nonseminal vesicle-sparing radical cystectomy. MATERIALS AND METHODS: Oncological and functional outcomes of 470 consecutive patients after radical cystectomy and orthotopic ileal reservoir from 2000 to 2017 were evaluated. They were stratified into 6 groups according to nerve-sparing and seminal vesicle-sparing status as attempted during surgery: no sparing at all (55), unilateral nerve sparing (159), bilateral nerve sparing (132), unilateral seminal vesicle-sparing and unilateral nerve sparing (30), unilateral seminal vesicle sparing and bilateral nerve sparing (45), and bilateral seminal vesicle sparing (49) and used propensity modeling to adjust for preoperative differences. RESULTS: Median followup among the entire cohort was 64 months. Among the 6 groups, our analysis showed no difference in local recurrence-free survival (p=0.173). However, progression-free, cancer-specific and overall survival were more favorable in patients with seminal vesicle-sparing radical cystectomy (p <0.001, p=0.006 and p <0.001, respectively). Proportions of patients with erectile function recovery were higher in the seminal vesicle-sparing groups at all time points in all analyses, respectively, with pronounced earlier recovery in patients with bilateral seminal vesicle sparing. Importantly, patients with seminal vesicle sparing were significantly less in need of erectile aids to achieve erection and intercourse. Over the whole period, daytime urinary-continence was significantly better in the seminal vesicle sparing groups (OR 2.64 to 5.21). CONCLUSIONS: In a highly selected group of patients, seminal vesicle sparing radical cystectomy is oncologically safe and results in excellent functional outcomes that are reached at an earlier time point after surgery and remain superior over a longer period of time.

Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis.

BACKGROUND: Interstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the classic Hunner's ulcerative type and the more prevalent non-ulcerative disease. Our aim was to unravel the biological processes and dysregulated cell signaling pathways leading to the bladder remodeling in non-ulcerative bladder pain syndrome (BPS) by studying the gene expression changes in the patients' biopsies. METHODS: We performed paired microRNA (miRNA) and mRNA expression profiling in the bladder biopsies of BPS patients with non-Hunner interstitial cystitis phenotype, using comprehensive Next-generation sequencing (NGS) and studied the activated pathways and altered biological processes based on the global gene expression changes. Paired mRNA-miRNA transcriptome analysis delineated the regulatory role of the dysregulated miRNAs by identifying their targets in the disease-induced pathways. RESULTS: EIF2 Signaling and Regulation of eIF4 and p70S6K Signaling, activated in response to cellular stress, were among the most significantly regulated processes during BPS. Leukotriene Biosynthesis nociceptive pathway, important in inflammatory diseases and neuropathic pain, was also significantly activated. The biological processes identified using Gene Ontology over-representation analysis were clustered into six main functional groups: cell cycle regulation, chemotaxis of immune cells, muscle development, muscle contraction, remodeling of extracellular matrix and peripheral nervous system organization and development. Compared to the Hunner's ulcerative type IC, activation of the immune pathways was modest in non-ulcerative BPS, limited to neutrophil chemotaxis and IFN-γ-mediated signaling. We identified 62 miRNAs, regulated and abundant in BPS and show that they target the mRNAs implicated in eIF2 signalling pathway. CONCLUSIONS: The bladders of non-ulcerative BPS patients recruited in this study had alterations consistent with a strong cell proliferative response and an up-regulation of smooth muscle contractility, while the contribution of inflammatory processes was modest. Pathway analysis of the integrated mRNA-miRNA NGS dataset pinpointed important regulatory miRNAs whose dysregulation might contribute to the pathogenesis. Observed molecular changes in the peripheral nervous system organization and development indicate the potential role of local bladder innervation in the pain perceived in this type of BPS.

Intra-operative norepinephrine administration and cancer-related outcomes following radical cystectomy for bladder cancer: A cohort study.

BACKGROUND: The impact of anaesthetic techniques on recurrence of cancers is controversial. Elevated plasma catecholamine levels have been implicated in angiogenesis and metastasis in various cancers. OBJECTIVES: To assess the potential association between continuous intra-operative norepinephrine administration and tumour-related outcome in muscle-invasive bladder cancer patients undergoing radical cystectomy with urinary diversion. DESIGN: Retrospective observational cohort study. SETTING: Single tertiary centre, from 2000 to 2017. PATIENTS: We included a consecutive series of 1120 urothelial carcinoma patients undergoing radical cystectomy and urinary diversion, including 411/1120 patients (37%) who received a continuous intra-operative administration of more than 2 µg kg BW h norepinephrine. MAIN OUTCOME MEASURES: The primary outcome was time to tumour recurrence within 5 years after surgery, with death as competing outcome. We used inverse probability of treatment weighting to adjust for imbalances between treatment groups, one having received more than 2 µg kg BW h norepinephrine and the other having received less. We furthermore adjusted for intra-operative variables or years of surgery as sensitivity analyses. RESULTS: The continuous administration of more than 2 µg kg BW h norepinephrine slightly increased tumour recurrence (hazard ratio: 1.47, 95% CI 0.98 to 2.21; P = 0.061). After adjustment for intra-operative variables, and year of surgery hazard ratios were 1.82 (95% CI 1.13 to 2.91, P = 0.013) and 1.85 (95% CI 1.12 to 3.07, P = 0.017), respectively. Overall mortality (with or without tumour recurrence) was not affected by norepinephrine (hazard ratio: 0.84, 95% CI 0.65 to 1.08, P = 0.170). CONCLUSION: Continuous administration of more than 2 µg kg BW h norepinephrine was associated with a slightly increased hazard ratio for tumour recurrence if adjusted for intra-operative variables and year of surgery. This observation could reflect a low potential pro-oncogenic effect of norepinephrine during the intra-operative period. TRIAL REGISTRATION: Not applicable.

Tumor Necrosis Factor-α Initiates miRNA-mRNA Signaling Cascades in Obstruction-Induced Bladder Dysfunction.

Bladder outlet obstruction (BOO) and the ensuing clinical lower urinary tract dysfunction are common in elderly patients. BOO is accompanied by urodynamic changes in bladder function and leads to organ fibrosis and ultimately loss of contractility. Comprehensive transcriptome analysis of bladder samples from human patients with different urodynamically defined phenotypes of BOO revealed tumor necrosis factor (TNF)-α as the top upstream signaling pathway regulator. Herein, we validated next-generation sequencing and pathway analysis in cell-based models using bladder smooth muscle and urothelial cells exposed to TNF-α. miRNA profiling and transcriptome analysis of TNF-α-treated bladder smooth muscle cells revealed striking similarities with human BOO. Using a comparative approach, TNF-specific and TNF-independent pathways were delineated in human biopsy specimens. Concomitant down-regulation of smooth muscle cell-specific miRNAs and smooth muscle markers after TNF-α treatment was in accordance with the loss of contractility in humans in advanced obstruction-induced bladder remodeling. The expression levels of four abundant TNF-regulated miRNAs were modulated; the compensatory up-regulation of miR-199a-5p reduced NF-κB signaling. Essential hubs of TNF-α signaling pathways mitogen-activated protein kinase kinase kinase (apoptosis signal-regulating kinase 1) and inhibitor of nuclear factor κ B kinase subunit ß (IκB kinase ß) were targeted by miR-199a-5p. miR-199a-5p might be part of a negative feedback loop, reducing the impact of TNF, whereas its down-regulation in acontractile bladders from BOO patients advances the disease. The compensatory up-regulation of miR-199a-5p together with TNF-α inhibition may be therapeutically beneficial.

Positive Pre-cystectomy Biopsies of the Prostatic Urethra or Bladder Neck Do Not Necessarily Preclude Orthotopic Bladder Substitution.

PURPOSE: We investigated the influence of positive pre-cystectomy biopsies of the prostatic urethra in males and the bladder neck in females on urethral recurrence, cancer specific and overall survival, and functional outcomes after orthotopic bladder substitution. MATERIALS AND METHODS: We retrospectively analyzed the records of 803 consecutive patients, including 703 males and 100 females, who underwent orthotopic bladder substitution as well as pre-cystectomy biopsy of the prostatic urethra in males and the bladder neck in females, at our institution between April 1986 and December 2017. RESULTS: Pre-cystectomy biopsies were negative in 755 of the 803 patients (94%) (group 1) and positive in 48 (6%) (group 2). Biopsies in group 2 revealed carcinoma in situ in 35 of the 48 cases (73%), pTaG1/G2 in 5 (10%) and pTaG3/pT1G3 in 8 (17%). Median followup was 64 months (IQR 21-128). At a median followup of 56 months (IQR 18-127) urethral recurrence developed in 45 of the 803 patients (5.6%), including 30 of the 755 (4%) in group 1 and 15 of the 48 (31.3%) in group 2 (p <0.001). Only 10 of the 45 patients (22%) with urethral recurrence required salvage urethrectomy while locally conservative treatment was successful in 27 (60%). Of the remaining 8 patients 6 of 45 (13%) underwent synchronous palliative chemotherapy and 2 of 45 (4%) refused treatment. Multivariate regression analysis revealed a higher risk of urethral recurrence if patients had positive pre-cystectomy biopsies (group 2 HR 6.49, 95% CI 3.33-12.62, p <0.001) or received neoadjuvant or adjuvant chemotherapy (HR 3.05, 95% CI 1.66-5.59, p <0.001). Cancer specific and overall survival as well as functional outcomes were similar in the 2 groups. CONCLUSIONS: Positive pre-cystectomy biopsies prior to orthotopic bladder substitution increased the urethral recurrence rate but did not lower cancer specific or overall survival. Most urethral recurrences were managed successfully by local treatment. Orthotopic bladder substitution is an option in highly selected patients with positive, noninvasive pre-cystectomy biopsies, provided that they undergo regular followup including urethral cytology.

Effect of Thoracic Epidural Ropivacaine versus Bupivacaine on Lower Urinary Tract Function: A Randomized Clinical Trial.

BACKGROUND: Thoracic epidural analgesia with bupivacaine resulted in clinically relevant postvoid residuals due to detrusor underactivity. This study aimed to compare the risk of bladder dysfunction with ropivacaine versus bupivacaine using postvoid residuals and maximum flow rates. Our hypothesis was that ropivacaine would result in lower postvoid residuals, because ropivacaine has been shown to have less effect on motor blockade. METHODS: In this single-center, parallel-group, randomized, double-blind superiority trial, 42 patients undergoing open renal surgery were equally allocated to receive epidural bupivacaine 0.125% or ropivacaine 0.2%, and 36 were finally included. Inclusion criterion was normal bladder function. Patients underwent urodynamic investigations preoperatively and during thoracic epidural analgesia. Primary outcome was the difference in postvoid residual preoperatively and during thoracic epidural analgesia postoperatively. Secondary outcomes were changes in maximum flow rate between and within the groups. RESULTS: Median difference in postvoid residual (ml) from baseline to postoperatively was 300 (range, 30 to 510; P < 0.001) for bupivacaine and 125 (range, -30 to 350; P = 0.011) for ropivacaine, with a significant mean difference between groups (-175; 95% CI, -295 to -40; P = 0.012). Median difference in maximum flow rate (ml/s) was more pronounced with bupivacaine (-12; range, -28 to 3; P < 0.001) than with ropivacaine (-4; range, -16 to 7; P = 0.025) with a significant mean difference between groups (7; 95% CI, 0 to 12; P = 0.028). Pain scores were similar. No adverse events occurred. CONCLUSIONS: Postvoid residuals were significantly lower using ropivacaine compared to bupivacaine for thoracic epidural analgesia reflecting less impairment of detrusor function with ropivacaine.

More extended lymph node dissection template at radical prostatectomy detects metastases in the common iliac region and in the fossa of Marcille.

OBJECTIVES: To assess the effect of adding lymph nodes (LNs) located along the common iliac vessels and in the fossa of Marcille to the extended pelvic LN dissection (PLND) template at radical prostatectomy (RP). PATIENTS AND METHODS: A total of 485 patients underwent RP and PLND at a referral centre between 2000 and 2008 (historical cohort: classic extended PLND template) and a total of 268 patients between 2010 and 2015 (contemporary cohort: extended PLND template including LNs located along the common iliac vessels and in the fossa of Marcille). Descriptive analyses were used to compare baseline, pathological, complication and functional data between the two cohorts. A logistic regression model was used to assess the template's effect on the probability of detecting LN metastases. RESULTS: Of 80 patients in the historical cohort with pN+ disease, the sole location of metastasis was the external iliac/obturator fossa in 23 (29%), and the internal iliac in 18 (23%), while 39 patients (49%) had metastases in both locations. Of 72 patients in the contemporary cohort with pN+ disease, the sole location of metastasis was the external iliac/obturator fossa in 17 patients (24%), the internal iliac in 24 patients (33%), and the common iliac in one patient (1%), while 30 patients (42%) had metastases in >1 location (including fossa of Marcille in five patients). Among all 46 patients in the contemporary cohort with ≤2 metastases, three had one or both metastases in the common iliac region or the fossa of Marcille. The adjusted probability of detecting LN metastases was higher, but not significantly so, in the contemporary cohort. There were no differences between the two cohorts in complication rates and functional outcomes. CONCLUSION: A more extended template detects LN metastases in the common iliac region and the fossa of Marcille and is not associated with a higher risk of complications; however, the overall probability of detecting LN metastases was not significantly higher.

Nerve-sparing radical cystectomy has a beneficial impact on urinary continence after orthotopic bladder substitution, which becomes even more apparent over time.

OBJECTIVE: To analyse urinary continence in long-term survivors after radical cystectomy (RC) and orthotopic bladder substitution (OBS) according to attempted nerve-sparing (NS) status. PATIENTS AND METHODS: We analysed 180 consecutive patients treated at our department between 1985 and 2007, who underwent RC with OBS, and survived ≥10 years after RC. We stratified patients by attempted NS status and evaluated continence outcomes using descriptive statistics and Cox proportional hazards regression models. A secondary analysis evaluated erectile function as a quality control for attempted NS. RESULTS: The median (interquartile range [IQR]) age at RC was 62 (57-71) years. Of 180 patients, attempted NS status was none in 24 (13%), unilateral in 100 (56%), and bilateral in 56 (31%). After a median (IQR) follow-up of 169 (147-210) months, 160 (89%) patients were continent during daytime and 124 (69%) during night-time. In multivariable analysis, any degree of attempted NS was significantly associated with daytime continence (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.05-4.11; P = 0.04). Correspondingly, any attempted NS was significantly associated with night-time continence (OR 2.51, 95% CI 1.08-5.85; P = 0.03). Recovery of erectile function at 5 years was also significantly associated with attempted NS (P < 0.001). CONCLUSION: Nerve-sparing during RC and OBS was associated with better long-term continence outcomes. This becomes more apparent as the patients age with their OBS. We advocate a NS RC whenever an OBS is considered.

Reproductive organ-sparing cystectomy significantly improves continence in women after orthotopic bladder substitution without affecting oncological outcome.

OBJECTIVES: To compare functional and oncological outcomes of reproductive organ-sparing cystectomy (ROSC) compared with standard cystectomy (SC) in women undergoing orthotopic bladder substitution (OBS). PATIENTS AND METHODS: Between 1995 and 2016, 121 consecutive women undergoing OBS were prospectively included in this single-centre non-randomized clinical follow-up study comprising an ROSC and an SC group. Urinary continence, the need for intermittent self-catheterization (ISC), lateral standing micturition cystourethrogram (MCUG), urethral pressure profile findings, if available, and oncological outcomes were assessed and compared between ROSC and SC. RESULTS: After 12 months, patients who had undergone ROSC with OBS had significantly higher daytime and nighttime continence rates than patients who had undergone SC with OBS (87.5% vs 63.5%; P = 0.027 and 87.5% vs 57.7%; P = 0.008), whereas no significant differences were found between groups in ISC rates (12.5% vs 12.94%; P > 0.99). The degree of attempted nerve-sparing (none, unilateral, bilateral) positively affected continence rates in both groups. No significant differences were found in local recurrence rates (0% vs 9.4%; P = 0.126), 5- and 10-year overall survival rates (80.9% and 80.9% vs 64.9% and 55.7%; P = 0.443) or 5- and 10-year cancer-specific survival rates (84.3% and 84.3% vs 73% and 66.2%; P = 0.431). CONCLUSION: Superior continence rates were found for ROSC with an OBS compared with SC, without a negative impact on oncological outcome. ROSC should, therefore, be offered to women receiving an OBS whenever justifiable.

Impact of intra-operative fluid and noradrenaline administration on early postoperative renal function after cystectomy and urinary diversion: A retrospective observational cohort study.

BACKGROUND: The use of noradrenaline to enable a restrictive approach to intra-operative fluid therapy to avoid salt and water overload has gained increasing acceptance. However, concerns have been raised about the impact of this approach on renal function. OBJECTIVES: To identify risk factors for acute kidney injury (AKI) in patients undergoing cystectomy with urinary diversion and determine whether administration of noradrenaline and intra-operative hydration regimens affect early postoperative renal function. DESIGN: Retrospective observational cohort study. SETTING: University hospital, from 2007 to 2016. PATIENTS: A total of 769 consecutive patients scheduled for cystectomy and urinary diversion. Those with incomplete data and having pre-operative haemodialysis were excluded. MAIN OUTCOME MEASURES: AKI was defined as a serum creatinine increase of more than 50% over 72 postoperative hours. Multiple logistic regression analysis was performed to model the association between risk factors and AKI. RESULTS: Postoperative AKI was diagnosed in 86/769 patients (11.1%). Independent predictors for AKI were the amount of crystalloid administered (odds ratio (OR) 0.79 [95% confidence interval (CI), 0.68 to 0.91], P = 0.002), antihypertensive medication (OR 2.07 [95% CI, 1.25 to 3.43], P = 0.005), pre-operative haemoglobin value (OR 1.02 [95% CI, 1.01 to 1.03], P = 0.010), duration of surgery (OR 1.01 [95% CI, 1.00 to 1.01], P = 0.002), age (OR 1.32 [95% CI, 1.44 to 1.79], P = 0.002) but not the administration of noradrenaline (OR 1.09 [95% CI, 0.94 to 1.21], P = 0.097). Postoperative AKI was associated with longer hospital stay (18 [15 to 22] vs. 16 [15 to 19] days; P = 0.035) and a higher 90-day major postoperative complication rate (41.9 vs. 27.5%; P = 0.002). CONCLUSION: Noradrenaline administration did not increase the risk for AKI. A too restrictive approach to administration of crystalloids was associated with an increased risk for AKI, particularly in older patients, those receiving antihypertensive medication, and those whose surgery was prolonged. As AKI was associated with longer hospital stay and increased postoperative morbidity, these observations should be taken into account to improve outcome when addressing peri-operative fluid management. TRIAL REGISTRATION: Not applicable.

Stenting Prior to Cystectomy is an Independent Risk Factor for Upper Urinary Tract Recurrence.

PURPOSE: Patients with bladder cancer who present with hydronephrosis may require drainage of the affected kidney before receiving further cancer treatment. Drainage can be done by retrograde stenting or percutaneously. However, retrograde stenting carries the risk of tumor cell spillage to the upper urinary tract. The aim of this study was to evaluate whether patients with bladder cancer are at higher risk for upper urinary tract recurrence if retrograde stenting has been performed prior to radical cystectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of 1,005 consecutive patients with bladder cancer who underwent radical cystectomy at our department between January 2000 and June 2016. Negative intraoperative ureteral margins were mandatory for study inclusion. Patients received regular followup according to our institutional protocol, including imaging of the upper urinary tract and urine cytology. RESULTS: Preoperative drainage of the upper urinary tract was performed in 114 of the 1,005 patients (11%), including in 53 (46%) by Double-J® stenting and in 61 (54%) by percutaneous nephrostomy. Recurrence developed in the upper urinary tract in 31 patients (3%) at a median of 17 months after cystectomy, including 7 of 53 (13%) in the Double-J group, 0% in the nephrostomy group and 24 of 891 (3%) in the no drainage group. Multivariate regression analysis revealed a higher risk of upper urinary tract recurrence if patients underwent Double-J stenting (HR 4.54, 95% CI 1.43-14.38, p = 0.01) and preoperative intravesical instillations (HR 2.94, 95% CI 1.40-6.16, p = 0.004). CONCLUSIONS: Patients who undergo Double-J stenting prior to radical cystectomy are at higher risk for upper urinary tract recurrence. If preoperative upper urinary tract drainage is required, percutaneous drainage might be recommended.

MicroRNA MiR-199a-5p regulates smooth muscle cell proliferation and morphology by targeting WNT2 signaling pathway.

MicroRNA miR-199a-5p impairs tight junction formation, leading to increased urothelial permeability in bladder pain syndrome. Now, using transcriptome analysis in urothelial TEU-2 cells, we implicate it in the regulation of cell cycle, cytoskeleton remodeling, TGF, and WNT signaling pathways. MiR-199a-5p is highly expressed in the smooth muscle layer of the bladder, and we altered its levels in bladder smooth muscle cells (SMCs) to validate the pathway analysis. Inhibition of miR-199a-5p with antimiR increased SMC proliferation, reduced cell size, and up-regulated miR-199a-5p targets, including WNT2. Overexpression of WNT2 protein or treating SMCs with recombinant WNT2 closely mimicked the miR-199a-5p inhibition, whereas down-regulation of WNT2 in antimiR-expressing SMCs with shRNA restored cell phenotype and proliferation rates. Overexpression of miR-199a-5p in the bladder SMCs significantly increased cell size and up-regulated SM22, SM α-actin, and SM myosin heavy chain mRNA and protein levels. These changes as well as increased expression of ACTG2, TGFB1I1, and CDKN1A were mediated by up-regulation of the smooth muscle-specific transcriptional activator myocardin at mRNA and protein levels. Myocardin-related transcription factor A downstream targets Id3 and MYL9 were also induced. Up-regulation of myocardin was accompanied by down-regulation of WNT-dependent inhibitory Krüppel-like transcription factor 4 in miR-199a-5p-overexpressing cells. In contrast, Krüppel-like transcription factor 4 was induced in antimiR-expressing cells following the activation of WNT2 signaling, leading to repression of myocardin-dependent genes. MiR-199a-5p plays a critical role in the WNT2-mediated regulation of proliferative and differentiation processes in the smooth muscle and may behave as a key modulator of smooth muscle hypertrophy, which is relevant for organ remodeling.

Patients with an Orthotopic Low Pressure Bladder Substitute Enjoy Long-Term Good Function.

PURPOSE: Orthotopic bladder substitution has been performed on a regular basis for more than 30 years and yet data on long-term functional outcomes are still lacking. MATERIALS AND METHODS: We evaluated 181 men and 19 women who underwent radical cystectomy and urinary diversion with ileal orthotopic bladder substitution from 1985 to 2004 and who had 10 years or more of followup. RESULTS: Median age at radical cystectomy was 63 years (IQR 57-69). Median followup was 167 months (IQR 137-206). Daytime and nighttime continence rates peaked 24 months postoperatively and decreased slightly thereafter during almost 2 decades. At 10, 15 and 20 years daytime continence rates were 92%, 90% and 79%, and nighttime continence rates were 70%, 65% and 55%, respectively. During the day and at night fewer than 3% and 10% of patients, respectively, had urine loss 100 ml or greater at any time 10 years or longer after surgery. At 10 and 20 years 11 of 200 patients (6%) and 1 of 29 (3%), respectively, had to perform clean intermittent self-catheterization. After an initial postoperative decrease in the estimated glomerular filtration rate the subsequent decrease was less than 1 ml/minute/1.73 m(2) per year. A total of 81 complications were observed in 42 of the 200 patients (21%) 10 years or longer after radical cystectomy with pyelonephritis as the most frequent cause. CONCLUSIONS: Patients who survive up to 20 years after radical cystectomy and diversion with an ileal orthotopic bladder substitution may enjoy satisfactory urinary continence and retain the ability to void spontaneously while experiencing no more than a physiological decrease in renal function.