Role of clinicopathological variables in predicting recurrence and survival outcomes after surgery for non-metastatic renal cell carcinoma: Systematic review and meta-analysis.

Renal cell carcinoma (RCC) represents 2% of all diagnosed malignancies worldwide, with disease recurrence affecting 20% to 40% of patients. Existing prognostic recurrence models based on clinicopathological features continue to be a subject of controversy. In this meta-analysis, we summarized research findings that explored the correlation between clinicopathological characteristics and post-surgery survival outcomes in non-metastatic RCC patients. Our analysis incorporates 99 publications spanning 140 568 patients. The study's main findings indicate that the following clinicopathological characteristics were associated with unfavorable survival outcomes: T stage, tumor grade, tumor size, lymph node involvement, tumor necrosis, sarcomatoid features, positive surgical margins (PSM), lymphovascular invasion (LVI), early recurrence, constitutional symptoms, poor performance status (PS), low hemoglobin level, high body-mass index (BMI), diabetes mellitus (DM) and hypertension. All of which emerged as predictors for poor recurrence-free survival (RFS) and cancer-specific survival. Clear cell (CC) subtype, urinary collecting system invasion (UCSI), capsular penetration, perinephric fat invasion, renal vein invasion (RVI) and increased C-reactive protein (CRP) were all associated with poor RFS. In contrast, age, sex, tumor laterality, nephrectomy type and approach had no impact on survival outcomes. As part of an additional analysis, we attempted to assess the association between these characteristics and late recurrences (relapses occurring more than 5 years after surgery). Nevertheless, we did not find any prediction capabilities for late disease recurrences among any of the features examined. Our findings highlight the prognostic significance of various clinicopathological characteristics potentially aiding in the identification of high-risk RCC patients and enhancing the development of more precise prediction models.

Urinary function in female patients after traditional, organ-sparing and nerve-sparing radical cystectomy for bladder cancer: a systematic review and pooled analysis.

OBJECTIVES: To determine and summarize the available data on urinary, sexual, and health-related quality-of-life (HRQOL) outcomes after traditional radical cystectomy (RC), reproductive organ-preserving RC (ROPRC) and nerve-sparing RC (NSRC) for bladder cancer (BCa) in female patients. METHODS: The PubMed, SCOPUS and Web of Science databases were searched to identify studies reporting functional outcomes in female patients undergoing RC and urinary diversion for the treatment of BCa. The outcomes of interest were voiding function (for orthotopic neobladder [ONB]), sexual function and HRQOL. The following independent variables were derived and included in the meta-analysis: pooled rate of daytime and nighttime continence/incontinence, and intermittent self-catheterization (ISC) rates. Analyses were performed separately for traditional, organ- and/or nerve-sparing surgical approaches. RESULTS: Fifty-three studies comprising 2740 female patients (1201 traditional RC and 1539 organ-/nerve-sparing RC, and 264 nerve-sparing-alone RC) were eligible for qualitative synthesis; 44 studies comprising 2418 female patients were included in the quantitative synthesis. In women with ONB diversion, the pooled rates of daytime continence after traditional RC, ROPRC and NSRC were 75.2%, 79.3% and 71.2%, respectively. The pooled rate of nighttime continence after traditional RC was 59.5%; this rate increased to 70.7% and 71.7% in women who underwent ROPRC and NSRC, respectively. The pooled rate of ISC after traditional RC with ONB diversion in female patients was 27.6% and decreased to 20.6% and 16.8% in patients undergoing ROPRC and NSRC, respectively. The use of different definitions and questionnaires in the assessment of postoperative sexual and HRQOL outcomes did not allow a systematic comparison. CONCLUSIONS: Female organ- and nerve-sparing surgical approaches during RC seem to result in improved voiding function. There is a significant need for well-designed studies exploring sexual and HRQOL outcomes to establish evidence-based management strategies to support a shared decision-making process tailored towards patient expectations and satisfaction. Understanding expected functional, sexual and quality-of-life outcomes is necessary to allow individualized pre- and postoperative counselling and care delivery in female patients planned to undergo RC.

Efficacy and safety of desmopressin in nocturia and nocturnal polyuria control of neurological patients: A systematic review and meta-analysis.

PURPOSE: Evidence on the efficacy of desmopressin in nocturia in patients with neurological diseases is still very limited except for multiple sclerosis (MS). Our aim was to evaluate the efficacy and safety of desmopressin treatment on nocturia in patients with underlying neurological diseases. METHODS: Studies were identified by electronic search of PubMed, Embase, Cochrane, CINAHL, and Google Scholar databases. Studies were considered if they provided information on the effectiveness and safety of desmopressin (1-desamino-8-d-arginine vasopressin, or DDAVP) in the treatment of nocturia and their participants had acquired neurological pathology. Two researchers independently extracted the articles using specified datasets, such as quality-of-study indicators. Statistical meta-analysis was carried out using Review Manager (RevMan) 5.4 statistical software (Cochrane Collaboration). RESULTS: Of a total of 1042 articles in the initial search, 14 studies were included. Most of the published papers were related to MS (n = 7), two were on spinal cord injury, and other conditions were neural tube defect, myelodysplasia, Parkinson's disease, stroke, and multiple system atrophy. Overall, a total of 200 patients (mostly females) were enrolled. Thirteen studies evaluated the intranasal formulation of desmopressin and one study evaluated oral desmopressin. A significant decrease in nocturia episodes was reported in seven studies evaluating this topic. An increase in the maximum hours of uninterrupted sleep was reported in the three studies in which this outcome was assessed. A significant reduction in the volume of nocturnal incontinence was found in one study. Three studies were eligible to include in the meta-analysis. The results showed that desmopressin compared to placebo, significantly reduced nighttime urination (mean difference: -0.75, 95% CI: -1.10 to -0.41; p < 0.00001). The rate of adverse events ranged from 0% to 68.42%. The critical appraisal results for all trials showed that most of the studies had low or moderate quality. CONCLUSIONS: Our results emphasized desmopressin's safety and efficacy in reducing nocturia episodes, with transient adverse effects on neurological patients. However, the data were achieved from low or medium-quality trials, and further well-designed randomized controlled trials are needed.

Genitourinary Fistula: 5 Years' Experience of Five Referral Centers in Iran.

INTRODUCTION AND HYPOTHESIS: Genitourinary fistula is a devastating ailment that has an impact on women's physical health, mental health, emotional health, and financial security. The management of genitourinary fistula depends on the type, size, and duration of fistula formation. The purpose of this study is to report the features of genitourinary fistula in Iranian women and our experience in the management of fistula. METHODS: Retrospective chart reviews of 283 patients were performed to determine the cause of the fistula, prior repairs, tissue interposition, and the success rate. The operation was considered successful if the patient did not have any urine leakage during the observation time. RESULTS: The mean (SD) age of women was 49.51 (19.39; range: 21-70) years, Of these, 137 (52.9%) had a history of previous genitourinary fistula surgery. The average fistula was 1.53 (0.041) cm in size. The median (interquartile range) operation lasted 70 (15) min. The success rate after fistula repair was 91.5%. The typical follow-up period lasted 13.26 (range: 1-88) months. Forty-three (15.2%) patients had a big fistula (>2.5 cm) and 4 patients (1.4%) had a history of pelvic radiation therapy, among other reasons for failure. After a second repair, all patients' initial failures were resolved. There were no significant complications, as classified by Clavien-Dindo class 2 or greater. Additionally, there were no bowel, ureteral, or nerve injuries. CONCLUSIONS: Our patients with genitourinary fistula had a successful outcome following repair techniques, without any significant morbidity or mortality.

Iatrogenic ureteric injury during abdominal or pelvic surgery: a meta-analysis.

OBJECTIVE: To assess the incidence of ureteric injuries, clinical value of prophylactic ureteric stenting and impact of intra- or postoperative detection of ureteric injuries in patients treated with gynaecological or colorectal surgery. METHODS: Multiple databases were searched for articles published before September 2021 according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Studies were deemed eligible if they evaluated the differences in the rate of ureteric injuries between laparoscopic and open surgery, prophylactic ureteric stenting or not, and those of final treatment success between intra- and postoperative detection in patients who underwent gynaecological or colorectal surgery. RESULTS: Overall, 46 studies were eligible for this meta-analysis. Compared to open surgery, laparoscopic hysterectomy was associated with a higher incidence of ureteric injuries (pooled odds ratio [OR] 2.12, 95% confidence interval [CI] 1.71-2.62), but there was no statistically significant difference in colectomy (pooled OR 0.89, 95% CI 0.77-1.03). Prophylactic ureteric stenting was associated with a lower incidence of ureteric injuries during gynaecological surgery (pooled OR 0.61, 95% CI 0.39-0.96). The number needed to perform ureteric stenting to prevent one ureteric injury was 224 in gynaecological surgery. On the other hand, prophylactic ureteric stenting did not reduce the risk of ureteric injuries during colorectal surgery. Intraoperative detection of a ureteric injury was associated with a lower rate of complication management failure compared to postoperative detection (pooled OR 0.22, 95% CI 0.12-0.41). CONCLUSIONS: Laparoscopic hysterectomy seems to be associated with a higher rate of ureteric injuries compared to an open approach. Prophylactic ureteric stenting seems to reduce this risk during gynaecological surgery. Intraoperative detection of a ureteric injury during abdominal/pelvic surgery improves outcomes, suggesting the need for awareness and proactive problem identification. Further well-designed studies assessing the candidates who are more likely to benefit from prophylactic ureteric stenting including cost analysis are needed.

Role of pelvic drain and timing of urethral catheter removal following RARP: a systematic review and meta-analysis.

OBJECTIVES: To assess the clinical value of routine pelvic drain (PD) placement and early removal of urethral catheter (UC) in patients undergoing robot-assisted radical prostatectomy (RARP), as perioperative management such as the necessity of PD or optimal timing for UC removal remains highly variable. METHODS: Multiple databases were searched for articles published before March 2022 according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. Studies were deemed eligible if they investigated the differential rate of postoperative complications between patients with/without routine PD placement and with/without early UC removal, defined as UC removal at 2-4 days after RARP. RESULTS: Overall, eight studies comprising 5112 patients were eligible for the analysis of PD placement, and six studies comprising 2598 patients were eligible for the analysis of UC removal. There were no differences in the rate of any complications (pooled odds ratio [OR] 0.89, 95% confidence interval [CI] 0.78-1.00), severe complications (Clavien-Dindo Grade ≥III; pooled OR 0.95, 95% CI 0.54-1.69), all and/or symptomatic lymphocele (pooled OR 0.82, 95% CI 0.50-1.33; and pooled OR 0.58, 95% CI 0.26-1.29, respectively) between patients with or without routine PD placement. Furthermore, avoiding PD placement decreased the rate of postoperative ileus (pooled OR 0.70, 95% CI 0.51-0.91). Early removal of UC resulted in an increased likelihood of urinary retention (OR 6.21, 95% CI 3.54-10.9) in retrospective, but not in prospective studies. There were no differences in anastomosis leakage and early continence rates between patients with or those without early removal of UC. CONCLUSIONS: There is no benefit for routine PD placement after standard RARP in the published articles. Early removal of UC seems possible with the caveat of the increased risk of urinary retention, while the effect on medium-term continence is still unclear. These data may help guide the standardisation of postoperative procedures by avoiding unnecessary interventions, thereby reducing potential complications and associated costs.

Oncological impact of cystoscopic findings in non-muscle-invasive bladder cancer: a meta-analysis.

OBJECTIVE: To assess the association between cystoscopic findings and oncological outcomes in patients with non-muscle-invasive bladder cancer (NMIBC) given that the oncological impact of quantity and quality assessment of tumours with cystoscopy has not been well verified. METHODS: Multiple databases were queried in May 2022 for studies investigating the association of oncological outcomes, such as recurrence-free (RFS), progression-free (PFS), and cancer-specific survival (CSS), with cystoscopic findings, including multiplicity, size, and gross appearance of tumours in patients with NMIBC. RESULTS: Overall, 73 studies comprising 28 139 patients were eligible for the meta-analysis. Tumour multiplicity was associated with worse RFS (pooled hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.48-1.74) and PFS (pooled HR 1.44, 95% CI 1.18-1.76) in NMIBC patients (including both Ta and T1). Tumour size (≥3 cm) was associated with worse RFS (pooled HR 1.97, 95% CI 1.69-2.30) and PFS (pooled HR 1.81, 95% CI 1.52-2.15) in NMIBC patients. In patients with T1 bladder cancer (BCa), tumour multiplicity and size (≥3 cm) were also associated with worse RFS, PFS and CSS. By contrast, among patients treated with bacillus Calmette-Guérin (BCG), tumour multiplicity was not associated with worse RFS, and tumour size (≥3 cm) was not associated with worse PFS. Sessile tumours were associated with worse RFS (pooled HR 2.14, 95% CI 1.52-3.01) and PFS (pooled HR 2.17, 95% CI 1.42-3.32) compared to pedunculated tumours. Compared to papillary tumours, solid tumours were associated with worse RFS (pooled HR 1.84, 95% CI 1.25-2.72) and PFS (pooled HR 3.06, 95% CI 2.31-4.07) in NMIBC patients, and CSS in T1 BCa patients (pooled HR 2.32, 95% CI 1.63-3.30). CONCLUSIONS: Cystoscopic findings, including tumour multiplicity, size, and gross appearance, strongly predict oncological outcomes in NMIBC patients. Cystoscopic visual features can help in the decision-making process regarding the timeliness and extent of tumour resection as well as future management such as intravesical therapy.

Impact of performance status on efficacy of systemic therapy for prostate cancer: a meta-analysis.

OBJECTIVE: To evaluate the efficacy of systemic therapies in patients with worse performance status (PS) treated for high-risk non-metastatic prostate cancer (PCa), metastatic hormone-sensitive PCa (mHSPC), and non-metastatic/metastatic castration-resistant PCa (nmCRPC/mCRPC), as there is sparse pooled data showing the effect of PS on oncological outcomes in patients with PCa. METHODS: Three databases were queried in June 2022 for randomised controlled trials (RCTs) analysing patients with PCa treated with systemic therapy (i.e., adding androgen receptor signalling inhibitor [ARSI] or docetaxel [DOC] to androgen-deprivation therapy [ADT]). We analysed the oncological outcomes of patients with PCa with worse PS, defined as Eastern Cooperative Oncology Group PS ≥ 1, treated with combination therapies and compared these to patients with good PS. The main outcomes of interest were overall survival (OS), metastasis-free survival (MFS), and progression-free survival. RESULTS: Overall, 25 and 18 RCTs were included for systematic review and meta-analyses/network meta-analyses, respectively. In all clinical settings, combination systemic therapies significantly improved OS in patients with worse PS as well as in those with good PS, while the MFS benefit from ARSI in the nmCRPC setting was more pronounced in patients with good PS than in those with worse PS (P = 0.002). Analysis of treatment ranking in patients with mHSPC revealed that triplet therapy had the highest likelihood of improved OS irrespective of PS; specifically, adding darolutamide to DOC + ADT had the highest likelihood of improved OS in patients with worse PS. Analyses were limited by the small proportion of patients with a PS ≥ 1 (19%-28%) and that the number of PS 2 was rarely reported. CONCLUSIONS: Among RCTs, novel systemic therapies seem to benefit the OS of patients with PCa irrespective of PS. Our findings suggest that worse PS should not discourage treatment intensification across all disease stages.

Impact of sex on outcomes after surgery for non-muscle-invasive and muscle-invasive bladder urothelial carcinoma: a systematic review and meta-analysis.

PURPOSE: To assess the prognostic value of sex for non-muscle-invasive/muscle-invasive bladder urothelial carcinoma (NMIBC/MIBC) treated with radical surgery. METHODS: The PubMed, Web of Science, and Scopus databases were searched in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they involved the comparison of the overall, cancer-specific, progression, and recurrence-free survival of patients with NMIBC/MIBC. Formal sex-stratified meta-analyses of these outcomes were performed. RESULTS: Thirty-one studies, which included 32,525 patients with NMIBC, and 63 studies, which included 85,132 patients with MIBC, were eligible for review and meta-analysis. Female sex was associated with worse cancer-specific survival (pooled hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.11-1.31) and overall survival (pooled HR, 1.02; 95% CI, 1.00-1.05) in patients with MIBC. In contrast, however, sex was not associated with cancer-specific survival (pooled HR, 1.01; 95% CI, 0.70-1.46), progression-free survival (pooled HR, 1.04; 95% CI, 0.88-1.24), and recurrence-free survival (pooled HR, 1.06; 95% CI, 0.98-1.16) in patients with NMIBC. CONCLUSIONS: Sex is associated with an increased risk of worse survival outcomes in patients with MIBC but not in those with NMIBC. Given the genetic and social differences between sexes, sex may represent a key factor in the clinical decision-making process.

Impact of preoperative plasma levels of interleukin 6 and interleukin 6 soluble receptor on disease outcomes after radical cystectomy for bladder cancer.

BACKGROUND: Preoperative plasma levels of Interleukin 6 (IL6) and its soluble receptor (IL6sR) have previously been associated with oncologic outcomes in urothelial carcinoma of the bladder (UCB); however, external validation in patients treated with radical cystectomy (RC) for UCB is missing. PATIENTS/METHODS: We prospectively collected preoperative plasma from 1,036 consecutive patients at two institutes. These plasma specimens were assessed for levels of IL6 and IL6sR. Logistic and Cox regression analyses were used to assess the correlation of plasma levels with pathologic and survival outcomes. The additional clinical net benefits of preoperative IL6 and IL6sR were evaluated using decision curve analysis (DCA). RESULTS: Median IL6 and IL6sR plasma levels were significantly higher in patients with adverse pathologic features. Elevated biomarker levels were independently associated with an increased risk for lymph node metastasis and ≥ pT3 disease. Both biomarkers were independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The addition to, respectively, fitted pre- and postoperative prognostic models improved the predictive accuracy for lymph node metastasis, ≥ pT3 disease, RFS and CSS on DCA. INTERPRETATION: We confirmed that elevated preoperative plasma levels of IL6 and IL6sR levels are associated with worse oncological disease survival in patients treated with RC for UCB in a large multicenter study. Both biomarkers hold potential in identifying patients with adverse pathological features that may benefit from intensified/multimodal therapy and warrant inclusion into predictive/prognostic models. They demonstrated the ability to improve the discriminatory power of such models and thus guide clinical decision making.

Preoperative plasma level of endoglin as a predictor for disease outcomes after radical cystectomy for nonmetastatic urothelial carcinoma of the bladder.

Elevated preoperative plasma level of endoglin has been associated with worse oncologic outcomes in various malignancies. The present large-scale study aimed to determine the predictive and prognostic values of preoperative endoglin with regard to clinicopathologic and survival outcomes in patients treated with radical cystectomy (RC) for nonmetastatic urothelial carcinoma of the bladder (UCB). We prospectively collected preoperative blood samples from 1036 consecutive patients treated with RC for UCB. Logistic and Cox regression analyses were undertaken to assess the correlation of endoglin levels with pathologic and survival outcomes, respectively. The AUC and C-index were used to assess the discrimination. Patients with adverse pathologic features had significantly higher median preoperative endoglin plasma levels than their counterparts. Higher preoperative endoglin level was independently associated with an increased risk for lymph node metastasis, ≥pT3 disease, and nonorgan confined disease (NOCD; all p < 0.001). Plasma endoglin level was also independently associated with cancer-specific and overall survival in both pre- and postoperative models (all p < 0.05), as well as with recurrence-free survival (RFS) in the preoperative model (p < 0.001). The addition of endoglin to the preoperative standard model improved its discrimination for prediction of lymph node metastasis, ≥pT3 disease, NOCD, and RFS (differential increases in C-indices: 10%, 5%, 5.8%, and 4%, respectively). Preoperative plasma endoglin is associated with features of biologically and clinically aggressive UCB as well as survival outcomes. Therefore, it seems to hold the potential of identifying UCB patients who may benefit from intensified therapy in addition to RC such as extended lymphadenectomy or/and preoperative systemic therapy.

En Bloc Resection for Bladder Tumors: An Updated Systematic Review and Meta-Analysis of Its Differential Effect on Safety, Recurrence and Histopathology.

PURPOSE: En bloc resection for bladder tumors has been developed to overcome shortcomings of conventional transurethral resection of bladder tumors with regard to safety, pathological evaluation and oncologic outcomes. However, the potential benefits and utility compared to conventional transurethral resection of bladder tumors have not been conclusively demonstrated. We aimed to update the current evidence with focus on the pathological benefits of en bloc resection for nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: The PubMed®, Web of Science™ and Scopus® databases were searched in August 2021 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they compared safety, and pathological and clinical outcomes in patients who underwent en bloc resection with conventional transurethral resection of bladder tumors. RESULTS: Overall, 29 studies comprising 4,484 patients were eligible for this meta-analysis. Among 13 randomized controlled trials, the pooled 12- and 24-month recurrence risk ratios were not statistically different between the 2 surgical techniques (0.96, 95% CI 0.74-1.23 and 0.83, 95% CI 0.55-1.23, respectively). The pooled risk ratio for bladder perforation was 0.13 (95% CI 0.05-0.34) in favor of en bloc resection. In randomized controlled trials, the differential rates of detrusor muscle presence (pooled RR 1.31, 95% CI 1.19-1.43) and of detectable muscularis mucosae (pooled RR 2.69, 95% CI 1.81-3.97) were more likely in patients receiving en bloc resection. Patients who underwent en bloc resection had a lower rate of residual tumor at repeat transurethral resection than those treated with conventional transurethral resection of bladder tumors in 1 randomized controlled trial and 3 observational studies (pooled RR 0.47, 95% CI 0.31-0.71). CONCLUSIONS: En bloc resection for bladder tumors seems to be safer, and to yield superior histopathological information and performance compared to conventional transurethral resection of bladder tumors. Despite the failure to improve the recurrence rate, the more accurate histopathological analysis is likely to improve clinical decision making and care delivery in nonmuscle-invasive bladder cancer.

Prognostic Role of Preoperative Vascular Cell Adhesion Molecule-1 Plasma Levels in Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy.

BACKGROUND: Angiogenesis-related marker vascular cell adhesion molecule-1 (VCAM-1) has been shown to be elevated in urothelial carcinoma of the bladder (UCB), but its predictive/prognostic role has not been determined. Thus, this study aimed to investigate the predictive/prognostic role of VCAM-1 for patients who have UCB treated with radical cystectomy (RC). METHODS: The study enrolled 1036 patients with clinically non-metastatic advanced UCB who underwent RC, and plasma VCAM-1 was evaluated preoperatively. The correlation of plasma VCAM-1 with pathologic and survival outcomes was assessed using binominal logistic regression and multivariable Cox regression analyses. Discrimination was assessed using the area under the curve and concordance indices. The clinical net benefit was evaluated using decision curve analysis (DCA). RESULTS: Preoperative VCAM-1 was significantly elevated in patients with adverse pathologic features. Higher VCAM-1 levels were independently associated with increased risk of lymph-node-metastasis (LNM), ≥pT3 disease, and non-organ-confined disease (NOCD (p < 0.001 for each). Preoperative plasma VCAM-1 was independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in pre- and postoperative multivariable models. Adding VCAM-1 to these predictive models improved their discriminatory ability to predict all outcomes by a significant margin. In the DCA, VCAM-1 addition to the reference models for prediction of LNM, NOCD, RFS, and CSS resulted in relevant improvement. CONCLUSIONS: Elevated plasma VCAM-1 was associated with biologically and clinically aggressive UCB disease features. After validation, preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from intensified/multimodal therapy. In addition, VCAM-1 improved the discriminatory power of predictive/prognostic models and can be used to refine personalized clinical decision-making.

Systemic therapies for metastatic hormone-sensitive prostate cancer: network meta-analysis.

OBJECTIVES: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel. METHODS: Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible. RESULTS: Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS. CONCLUSIONS: All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials.

A panel of systemic inflammatory response biomarkers for outcome prediction in patients treated with radical cystectomy for urothelial carcinoma.

OBJECTIVES: To determine the predictive and prognostic value of a panel of systemic inflammatory response (SIR) biomarkers relative to established clinicopathological variables in order to improve patient selection and facilitate more efficient delivery of peri-operative systemic therapy. MATERIALS AND METHODS: The preoperative serum levels of a panel of SIR biomarkers, including albumin-globulin ratio, neutrophil-lymphocyte ratio, De Ritis ratio, monocyte-lymphocyte ratio and modified Glasgow prognostic score were assessed in 4199 patients treated with radical cystectomy for clinically non-metastatic urothelial carcinoma of the bladder. Patients were randomly divided into a training and a testing cohort. A machine-learning-based variable selection approach (least absolute shrinkage and selection operator regression) was used for the fitting of several multivariable predictive and prognostic models. The outcomes of interest included prediction of upstaging to carcinoma invading bladder muscle (MIBC), lymph node involvement, pT3/4 disease, cancer-specific survival (CSS) and recurrence-free survival (RFS). The discriminatory ability of each model was either quantified by area under the receiver-operating curves or by the C-index. After validation and calibration of each model, a nomogram was created and decision-curve analysis was used to evaluate the clinical net benefit. RESULTS: For all outcome variables, at least one SIR biomarker was selected by the machine-learning process to be of high discriminative power during the fitting of the models. In the testing cohort, model performance evaluation for preoperative prediction of lymph node metastasis, ≥pT3 disease and upstaging to MIBC showed a 200-fold bootstrap-corrected area under the curve of 67.3%, 73% and 65.8%, respectively. For postoperative prognosis of CSS and RFS, a 200-fold bootstrap corrected C-index of 73.3% and 72.2%, respectively, was found. However, even the most predictive combinations of SIR biomarkers only marginally increased the discriminative ability of the respective model in comparison to established clinicopathological variables. CONCLUSION: While our machine-learning approach for fitting of the models with the highest discriminative ability incorporated several previously validated SIR biomarkers, these failed to improve the discriminative ability of the models to a clinically meaningful degree. While the prognostic and predictive value of such cheap and readily available biomarkers warrants further evaluation in the age of immunotherapy, additional novel biomarkers are still needed to improve risk stratification.

Selection and evaluation of preoperative systemic inflammatory response biomarkers model prior to cytoreductive nephrectomy using a machine-learning approach.

INTRODUCTION: This study aimed to determine the prognostic value of a panel of SIR-biomarkers, relative to standard clinicopathological variables, to improve mRCC patient selection for cytoreductive nephrectomy (CN). MATERIAL AND METHODS: A panel of preoperative SIR-biomarkers, including the albumin-globulin ratio (AGR), De Ritis ratio (DRR), and systemic immune-inflammation index (SII), was assessed in 613 patients treated with CN for mRCC. Patients were randomly divided into training and testing cohorts (65/35%). A machine learning-based variable selection approach (LASSO regression) was used for the fitting of the most informative, yet parsimonious multivariable models with respect to prognosis of cancer-specific survival (CSS). The discriminatory ability of the model was quantified using the C-index. After validation and calibration of the model, a nomogram was created, and decision curve analysis (DCA) was used to evaluate the clinical net benefit. RESULTS: SIR-biomarkers were selected by the machine-learning process to be of high discriminatory power during the fitting of the model. Low AGR remained significantly associated with CSS in both training (HR 1.40, 95% CI 1.07-1.82, p = 0.01) and testing (HR 1.78, 95% CI 1.26-2.51, p = 0.01) cohorts. High levels of SII (HR 1.51, 95% CI 1.10-2.08, p = 0.01) and DRR (HR 1.41, 95% CI 1.01-1.96, p = 0.04) were associated with CSS only in the testing cohort. The exclusion of the SIR-biomarkers for the prognosis of CSS did not result in a significant decrease in C-index (- 0.9%) for the training cohort, while the exclusion of SIR-biomarkers led to a reduction in C-index in the testing cohort (- 5.8%). However, SIR-biomarkers only marginally increased the discriminatory ability of the respective model in comparison to the standard model. CONCLUSION: Despite the high discriminatory ability during the fitting of the model with machine-learning approach, the panel of readily available blood-based SIR-biomarkers failed to add a clinical benefit beyond the standard model.

Urethrectomy at the time of radical cystectomy for non-metastatic urothelial carcinoma of the bladder: a collaborative multicenter study.

INTRODUCTION: The optimal management of the urethra in patients planned for radical cystectomy (RC) remains unclear. We sought to evaluate the impact of urethrectomy on perioperative and oncological outcomes in patients treated with RC for non-metastatic urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: We assessed the retrospective data from patients treated with RC for UCB of five European University Hospitals. Associations of urethrectomy with progression-free (PFS), cancer-free (CSS), and overall (OS) survivals were assessed in univariable and multivariable Cox regression models. We performed a subgroup analysis in patients at high risk for urethral recurrence (UR) (urethral invasion and/or bladder neck invasion and/or multifocality and/or prostatic urethra involvement). RESULTS: A total of 887 non-metastatic UCB patients were included. Among them, 146 patients underwent urethrectomy at the time of RC. Urethrectomy was performed more often in patients with urethral invasion, T3/4 tumor stage, CIS, positive frozen section analysis of the urethra, and those who received neoadjuvant chemotherapy, underwent robotic RC, and/or received an ileal conduit urinary diversion (all p < 0.001). Estimated blood loss and the postoperative complication rate were comparable between patients who received an urethrectomy and those who did not. Urethrectomy during RC was not associated with PFS (HR 0.83, p = 0.17), CSS (HR 0.93, p = 0.67), or OS (HR 1.08, p = 0.58). In the subgroup of 276 patients at high risk for UR, urethrectomy at the time of RC decreased the risk of progression (HR 0.58, p = 0.04). CONCLUSION: In our study, urethrectomy at the time of RC seems to benefit only patients at high risk for UR. Adequate risk assessment of UCB patients' history may allow for better clinical decision-making and patient counseling.

Efficacy of percutaneous and transcutaneous posterior tibial nerve stimulation on idiopathic overactive bladder and interstitial cystitis/painful bladder syndrome: A systematic review and meta-analysis.

OBJECTIVES: Percutaneous and transcutaneous posterior tibial nerve stimulation (PTNS and TTNS) showed a promising effect on overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome. We aimed to give a systematic review and meta-analysis on the efficacy and safety of these therapeutic methods as well. METHODS: We searched studies available on PubMed, Embase, Cochrane, Scopus, Web of Science, and ProQuest on March 31, 2021, to find both published and unpublished studies. The retrieved articles were screened by two independent researchers and then the selected studies were critically appraised by Cochrane risk-of-bias tool for randomized trials, and Joanna Briggs Institute's checklist for quasi-experimental studies. Finally, the results of studies were synthesized using Review Manager (RevMan) 5.4 statistical software when the data were homogenous. The meta-analysis was performed by calculating the effect size (mean difference) and their 95% confidence intervals (CIs). RESULTS: Of the total 3194 publications, 68 studies were included in our qualitative evaluation and 9 studies (11 trials) in the quantitative stage. When TTNS or PTNS were compared to sham, placebo, no treatment, or conservative management, a decrease in frequency of urination was observed in both TTNS (mean difference [MD]: -3.18, 95% CI: -4.42 to -1.94, and p < 0.00001), and PTNS (MD: -2.84, 95% CI: -4.22 to -1.45, and p < 0.00001), and overall TTNS or PTNS (MD: -2.95, 95% CI: -4.01 to -1.88, and p < 0.00001). Significant improvements in mean voiding volume (MVV) and decreasing nocturia were also observed. CONCLUSIONS: Nerve stimulations either PTNS or TTNS appear to be effective interventions in treating refractory idiopathic OAB in terms of daily voiding frequency, MVV, urgency episodes, and nighttime voiding frequency. However, our result did not show any improvement in terms of urinary incontinence, postvoid residual volume or urge incontinence, and maximum cystometric capacity which emphasized the efficacy of these modalities on dry-OAB rather than wet-OAB.

Clinical application of stem cell therapy in neurogenic bladder: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: This review aims to investigate the effect of stem cell (SC) therapy on the management of neurogenic bladder (NGB) in four neurological diseases, including spinal cord injury (SCI), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, in the clinical setting. METHODS: An electronic database search was conducted in the Cochrane Library, EMBASE, Proquest, Clinicaltrial.gov , WHO, Google Scholar, MEDLINE via PubMed, Ovid, Web of Science, Scopus, ongoing trial registers, and conference proceedings in June 2019 and updated by hand searching on 1 February 2021. All randomized controlled trials (RCTs), quasi RCTs, phase I/II clinical trials, case-control, retrospective cohorts, and comprehensive case series that evaluated the regenerative potential of SCs on the management of NGB were included. Cochrane appraisal risk of bias checklist and the standardized critical appraisal instrument from the JBI Meta-Analysis of Statistics, Assessment, and Review Instrument (JBI-MAStARI) were used to appraise the studies. RESULTS: Twenty-six studies among 1282 relevant publications met our inclusion criteria. Only SC therapy was applied for SCI or MS patients. Phase I/II clinical trials (without control arm) were the most conducted studies, and only four were RCTs. Four studies with 153 participants were included in the meta-analysis. The main route of transplantation was via lumbar puncture. There were no serious adverse events. Only nine studies in SCI and one in MS have used urodynamics, and the others have reported improvement based on patient satisfaction. SC therapy did not significantly improve residual urine volume, detrusor pressure, and maximum bladder capacity. Also, the quality of these publications was low or unclear. CONCLUSION: Although most clinical trials provide evidence of the safety and effectiveness of MSCs on the management of NGB, the meta-analysis results did not show a significant improvement; however, the interpretation of study results is difficult because of the lack of placebo controls.

Pretreatment clinical and hematologic prognostic factors of metastatic urothelial carcinoma treated with pembrolizumab: a systematic review and meta-analysis.

Pembrolizumab is the standard for the first and second lines in treating metastatic urothelial carcinoma (UC). This systematic review and meta-analysis aimed to assess the value of pretreatment clinical characteristics and hematologic biomarkers for prognosticating response to pembrolizumab in patients with metastatic UC. PUBMED®, Web of Science™, and Scopus® databases were searched for articles published before May 2021 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they evaluated overall survival (OS) in patients with metastatic urothelial carcinoma treated with pembrolizumab and pretreatment clinical characteristics or laboratory examination. Overall, 13 studies comprising 1311 patients were eligible for the meta-analysis. Several pretreatment patients' demographics and hematologic biomarkers were significantly associated with worse OS as follows: Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≥ 2 (Pooled hazard ratio [HR]: 3.24, 95% confidence interval [CI] 2.57-4.09), presence of visceral metastasis (Pooled HR: 1.84, 95% CI 1.42-2.38), presence of liver metastasis (Pooled HR: 4.23, 95% CI 2.18-8.20), higher neutrophil-lymphocyte ratio (NLR) (Pooled HR: 1.29, 95% CI 1.07-1.55) and, higher c-reactive protein (CRP) (Pooled HR: 2.49, 95% CI 1.52-4.07). Metastatic UC patients with poor PS, liver metastasis, higher pretreatment NLR and/or CRP have a worse survival despite pembrolizumab treatment. These findings might help to guide the prognostic tools for clinical decision-making; however, they should be interpreted carefully, owing to limitations regarding the retrospective nature of primary data.