Diagnostic Value of Urine Cytology in Pharmacologically Forced Diuresis for Upper Tract Urothelial Carcinoma Diagnosis and Follow-Up.

We performed a urine cytology analysis of a pharmacologically induced diuresis for the diagnosis of upper tract urothelial carcinoma. To evaluate the diagnostic value of cytology of pharmacologically forced diuresis, an initial cohort of 77 consecutive patients with primary upper tract urothelial carcinoma treated via radical surgery was enrolled. To evaluate pharmacologically forced diuresis cytology as a follow-up procedure, a second cohort of 1250 patients who underwent a radical cystectomy for bladder cancer was selected. In the first cohort, the sensitivity of cytology of pharmacologically forced diuresis in patients with invasive, high-grade, low-grade, and concomitant carcinoma in situ was 8%, 9%, 0%, and 14%, respectively. In the second cohort, cytology of pharmacologically forced diuresis was positive in 30/689 (4.3%) patients, in whom upper urinary tract recurrence was present in 21/30 (70%) of cases, and urethral recurrence was present in 8/30 (26%) of cases. As a follow-up tool, cytology of pharmacologically forced diuresis showed a sensitivity, specificity, and positive and negative predictive values of 60%, 99%, 70%, and 98%, respectively. Overall, as a diagnostic tool, the sensitivity of cytology of pharmacologically forced diuresis is slightly better in patients with invasive upper tract urothelial carcinoma and concomitant carcinoma in situ. As a follow-up method, positive cytology of pharmacologically forced diuresis is strongly related to cancer recurrence and can reveal urethral recurrence. Cytology of pharmacologically forced diuresis might be useful in cases with contraindications for imaging or when achieving endoscopic access to the upper urinary tract is difficult.

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.

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.

Sex Does Not Affect Survival: A Propensity Score-Matched Comparison in a Homogenous Contemporary Radical Cystectomy Cohort.

OBJECTIVES: To determine whether biological sex affects oncological outcome after extended pelvic lymph node dissection, radical cystectomy, and urinary diversion for muscle-invasive bladder cancer, and to identify risk factors impacting outcome. PATIENTS AND METHODS: We performed a single-center, retrospective observational cohort study with prospective data collection with a propensity score matched population. A total of 1165 consecutive patients from 2000 to 2020, (317 women and 848 men) scheduled for open extended pelvic lymph node dissection, radical cystectomy, and urinary diversion for urothelial bladder cancer were included in the final analysis. Overall Survival (OS), Cancer-Specific-Survival (CSS), and Recurrence-Free-survival (RFS) were assessed with multivariable weighted Cox regression analysis as well as with propensity score matched Cox-Regression. RESULTS: No significant difference was found between sexes regarding OS (HR 1.18, [0.93-1.49], P = .16), CSS (HR 0.87, [0.64-1.18], P = .38), or RFS (HR 0.80, [0.59-1.07], P = .13). These results were confirmed after propensity score matching: female sex was not associated with inferior OS (HR 1.20, [0.91-1.60], P = .19), CSS (HR 1.01, [0.75-1.35], P = .97) or RFS (HR 0.98, [0.75-1.27], P = .86). CONCLUSIONS: We did not find a significant difference in cancer-related outcomes or overall survival after extended pelvic lymph node dissection, open radical cystectomy, and urinary diversion for urothelial cancer between males and females even after adjustment with propensity matching score for multiple factors including oncological parameters, smoking status, and renal function.

Impact of Intraoperative Fluid Balance and Norepinephrine on Postoperative Acute Kidney Injury after Cystectomy and Urinary Diversion over Two Decades: A Retrospective Observational Cohort Study.

The use of norepinephrine and the restriction of intraoperative hydration have gained increasing acceptance over the last few decades. Recently, there have been concerns regarding the impact of this approach on renal function. The objective of this study was to examine the influence of norepinephrine, intraoperative fluid administration and their interaction on acute kidney injury (AKI) after cystectomy. In our cohort of 1488 consecutive patients scheduled for cystectomies and urinary diversions, the overall incidence of AKI was 21.6% (95%-CI: 19.6% to 23.8%) and increased by an average of 0.6% (95%-CI: 0.1% to 1.1%, p = 0.025) per year since 2000. The fluid and vasopressor regimes were characterized by an annual decrease in fluid balance (-0.24 mL·kg-1·h-1, 95%-CI: -0.26 to -0.22, p < 0.001) and an annual increase in the amount of norepinephrine of 0.002 µg·kg-1·min-1 (95%-CI: 0.0016 to 0.0024, p < 0.001). The interaction between the fluid balance and norepinephrine levels resulted in a U-shaped association with the risk of AKI; however, the magnitude and shape depended on the reference categories of confounders (age and BMI). We conclude that decreased intraoperative fluid balance combined with increased norepinephrine administration was associated with an increased risk of AKI. However, other potential drivers of the observed increase in AKI incidence need to be further investigated in the future.

Effects of Deep Brain Stimulation on Lower Urinary Tract Function in Neurological Patients.

BACKGROUND: Deep brain stimulation (DBS) has clear beneficial effects on motor signs in movement disorders, but much less is known about its impact on lower urinary tract (LUT) function. OBJECTIVE: To evaluate the effects of DBS on LUT function in patients affected by movement disorders. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 58 neurological patients affected by movement disorders, who were planned to receive DBS. INTERVENTION: DBS in the globus pallidus internus, ventral intermediate nucleus of the thalamus, or subthalamic nucleus. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subjective symptom questionnaires (International Prostate Symptom Score) and objective urodynamic studies were carried out before implantation of the DBS leads and several months after surgery. After DBS surgery, urodynamic investigations were performed with DBS ON as well as DBS OFF. RESULTS AND LIMITATIONS: We enrolled patients suffering from Parkinson's disease (n = 39), dystonia (n = 11), essential tremor (n = 5), Holmes tremor (n = 2), and multiple sclerosis with tremor (n = 1). DBS of the globus pallidus internus resulted in worsening of LUT symptoms in 25% (four of 16) of the cases. DBS of the subthalamic nucleus in patients with Parkinson's disease led to normalization of LUT function in almost 20% (six of 31 patients), while a deterioration was seen in only one (3%) patient. DBS of the ventral intermediate nucleus of the thalamus improved LUT function in two (18%) and deteriorated it in one (9%) patient with tremor. CONCLUSIONS: DBS effects on LUT varied with stimulation location, highly warranting patient counseling prior to DBS surgery. However, more well-designed, large-volume studies are needed to confirm our findings. PATIENT SUMMARY: In this report, we looked at outcomes of deep brain stimulation on lower urinary tract function. We found that outcomes varied with stimulation location, concluding that counseling of patients about the effects on lower urinary tract function is highly recommended prior to surgery.

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.

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.

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.

Predictors for Perioperative Blood Transfusion in Patients Undergoing Open Cystectomy and Urinary Diversion and Development of a Nomogram: An Observational Cohort Study.

Open radical cystectomy is associated with a substantial rate of perioperative blood transfusion. Early detection of potentially modifiable perioperative factors could reduce the need for perioperative blood transfusion and thus positively impact the outcome. We conducted an observational, single-center cohort study of 1168 patients undergoing cystectomy. Perioperative blood transfusion was defined as the need for packed red blood cells and/or fresh frozen plasma units within the first 24 h after the initiation of surgery. Multiple logistic regression analysis was performed to model the association between risk factors and blood transfusion, and a nomogram was developed. Blood transfusion occurred in 370/1168 patients (31.7%). Significant predictors were age (OR: 1.678, (95% CI: 1.379-2.042); p < 0.001), blood loss ratio (6.572, (4.878-8.853); p < 0.001), preoperative hemoglobin (0.316, (0.255-0.391); p < 0.001), tumor stage (2.067, (1.317-3.244); p = 0.002), use of oral anticoagulants (2.70, (1.163-6.270), p = 0.021), and interaction between female sex and blood loss ratio (1.344, (1.011-1.787); p = 0.042). Of the major predictors found to affect perioperative blood transfusion, two can be influenced: blood loss ratio by meticulous surgery and hemoglobin by preoperative optimization. Others such as age or advanced disease are not modifiable. This emphasizes the importance of optimal management of patients prior to surgery.

Urinary miRNA profiles discriminate between obstruction-induced bladder dysfunction and healthy controls.

Urgency, frequency and incomplete emptying are the troublesome symptoms often shared between benign prostatic obstruction-induced (BLUTD) and neurogenic (NLUTD) lower urinary tract dysfunction. Previously, using bladder biopsies, we suggested a panel of miRNA biomarkers for different functional phenotypes of the bladder. Urine is a good source of circulating miRNAs, but sex- and age-matched controls are important for urinary metabolite comparison. In two groups of healthy subjects (average age 32 and 57 years old, respectively) the total protein and RNA content was very similar between age groups, but the number of secreted extracellular vesicles (uEVs) and expression of several miRNAs were higher in the young healthy male volunteers. Timing of urine collection was not important for these parameters. We also evaluated the suitability of urinary miRNAs for non-invasive diagnosis of bladder outlet obstruction (BOO). A three urinary miRNA signature (miR-10a-5p, miR-301b-3p and miR-363-3p) could discriminate between controls and patients with LUTD (BLUTD and NLUTD). This panel of representative miRNAs can be further explored to develop a non-invasive diagnostic test for BOO. The age-related discrepancy in the urinary miRNA content observed in this study points to the importance of selecting appropriate, age-matched controls.

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.

Long-term Outcomes of Cystectomy and Crossfolded Ileal Reservoir Combined with an Afferent Tubular Segment for Heterotopic Continent Urinary Diversion: A Longitudinal Single-centre Study.

BACKGROUND: The crossfolded ileal reservoir combined with an afferent tubular isoperistaltic segment for heterotopic continent urinary diversion has been performed on a regular basis for over 20 years. Yet data on long-term-outcomes remain sparse. OBJECTIVE: To report long-term functional and oncological outcomes, gastrointestinal and metabolic disturbances, urinary tract infections (UTIs), and quality of life. DESIGN, SETTING, AND PARTICIPANTS: Long-term functional and oncological outcomes of a consecutive series of 118 patients undergoing cystectomy and construction of a continent cutaneous crossfolded ileal reservoir from 2000 to 2018 were evaluated. INTERVENTION: Patients underwent cystectomy and construction of a continent cutaneous crossfolded ileal reservoir according to the Studer technique for bladder reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pre- and postoperative data until last follow-up appointment were entered prospectively in the departmental database. Self-reported questionnaires regarding quality of life, patient satisfaction, and difficulty in catheterisation were sent to patients preoperatively; after 3, 6, 12, and 24 mo; and at last follow-up, and were then manually entered in the departmental database. RESULTS AND LIMITATIONS: The median follow-up was 7.8 (interquartile range 3-12.7) yr. Patient satisfaction was high in 77.4% and moderate in 16.9%. Serum creatinine and estimated glomerular filtration rate remained stable during follow-up. Of all patients, 81% (96/118) had at least one UTI during follow-up. Recurrent UTIs occurred in 67% (79/118) of patients. Urolithiasis was found in 12% (14/118), with 6% (7/118) having a single and 6% a recurrent event. Of all stone formers, 79% (11/14) had recurrent UTIs. In oncological patients, 12.5% (10/79) developed a local recurrence. Cancer-specific survival and overall survival were 90% and 88%, and 68% and 56% after 1 and 10 yr, respectively. A limitations is the retrospective analysis from prospectively assessed data. CONCLUSIONS: A high satisfaction level, stability of kidney function, and low rates of urolithiasis in patients with a heterotopic continent ileal reservoir can be achieved, provided that close attention is paid to intra- and postoperative details. Regular lifelong follow-up is essential for timely detection and treatment of complications. Oncological outcome is not affected by the urinary diversion. PATIENT SUMMARY: In patients with a continent cutaneous ileal reservoir, good quality of life and a high satisfaction rate are possible provided that patients adhere to regular lifelong follow-up.

Functional Results, Complications Associated with the Serosa-lined Tunnel, and Quality of Life with a Cross-folded Ileal Reservoir Combined with an Afferent Tubular Isoperistaltic Segment for Heterotopic Continent Urinary Diversion: An Observational Long-term Cohort Analysis.

BACKGROUND: In patients who do not qualify for an orthotopic urinary diversion, for example, the urethra cannot be spared or is functionally impaired, a heterotopic continent cutaneous cross-folded ileal reservoir offers a good alternative. OBJECTIVE: To describe the indication, surgical technique, and postoperative management, and to report the reservoir-related outcomes and complications associated with the serosa-lined tunnel. DESIGN, SETTING, AND PARTICIPANTS: Perioperative outcomes of 118 consecutive patients after cystectomy and a heterotopic ileal reservoir adapted from the Studer bladder substitute technique, operated between 2000 and 2018, were evaluated. The catheterisable serosa-lined tunnel was constructed from the appendix (Mitrofanoff, n = 63), an ileal segment (Yang-Monti, n = 48), or a fallopian tube (n = 7). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pre- and postoperative data until last follow-up appointment were entered prospectively in the departmental database. The chi-square test was used to compare proportions. RESULTS AND LIMITATIONS: Median follow-up was 94 (interquartile range 36-152) mo. No peri- or postoperative mortality was observed within 90 d of surgery. Patient satisfaction was high in 77.5% and moderate in 16.9%. Overall, complications associated with the serosa-lined tunnel occurred in 52% (61/118) of patients. Stenosis of the continent outlet developed in 38% (45/118) of patients: 33/45 (75%) were simply dilated/incised at the outpatient clinic, of those 24% (8/33) required additional endoscopic dilatation. Of patients with stenosis of the continent outlet, 27% (12/45) needed open revision surgery. During follow-up, 8% (nine/118) of patients required revision of the serosa-lined tunnel due to incontinence. Twelve months postoperatively, 95% (92/97) patients were continent. A limitation is the retrospective analysis from prospectively assessed data. This could limit the generalisability of these findings, as selection bias cannot be excluded. CONCLUSIONS: The heterotopic continent cutaneous cross-folded ileal reservoir achieves good functional results. Complications associated with the serosa-lined tunnel occur in about half of the patients but generally are easy to manage. As a result, patient satisfaction is high. PATIENT SUMMARY: In patients who do not qualify for an orthotopic bladder substitute, a heterotopic continent cutaneous cross-folded ileal reservoir offers a viable alternative with good postoperative functional results and high patient satisfaction.

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.

Complication reporting with the Bern Comprehensive Complication Index CCI after open radical prostatectomy: A longitudinal long-term single-center study.

OBJECTIVE: To impartially optimize complication reporting in patients after open radical prostatectomy (ORP) and pelvic lymph node dissection (PLND) by adopting the modified Bern Comprehensive Complication Index (CCI). ORP and PLND are associated with relevant postoperative morbidity. The CCI-ranging from 0 (no complications) to 100 (death)-is a tool that aims to integrate all complications occuring within 90 days postoperatively weighted by severity in a single formula. METHODS: In an observational single-center cohort, 90-day postoperative complications of 1,123 consecutive patients undergoing standardized ORP and PLND between 1996 and 2017 were evaluated. Prospectively collected complications were graded according to the Clavien-Dindo Classification. Grade I to II complications were defined as minor and grade IIIa to V as major. Finally, the recently developed modified Bern CCI using an exponential function, which transforms the sum of the weights into a value between 0 and 100 and the original CCI for each patient were extracted and compared. The correlation between the modified Bern and original CCI values was depicted graphically. RESULTS: The complication rate was 42%, with 18% minor and 24% major complications. With the original CCI, the threshold of 100 was exceeded in 1 patient who had a maximal index value of 101 within 90d postoperatively. The maximal value of the Bern CCI was 97.5. Mean Bern and original CCI scores and standard deviations were 6.2 (11.3) and 7.6 (12.2) at 30 days, and 9.3 (13.9) and 10.7 (14.2) at 90 days. CONCLUSIONS: The Bern CCI provides a more precise depiction of postoperative morbidity and represents the burden in patients with >1 complication after ORP and PLND more accurately than the original CCI allowing for a more reliable evaluation of quality of care and recovery. It therefore warrants consideration for standardized reporting of complications after ORP and PLND.

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.