Prognostic models for upper urinary tract urothelial carcinoma patients after radical nephroureterectomy based on a novel systemic immune-inflammation score with machine learning.

PURPOSE: This study aimed to evaluate the clinical significance of a novel systemic immune-inflammation score (SIIS) to predict oncological outcomes in upper urinary tract urothelial carcinoma(UTUC) after radical nephroureterectomy(RNU). METHOD: The clinical data of 483 patients with nonmetastatic UTUC underwent surgery in our center were analyzed. Five inflammation-related biomarkers were screened in the Lasso-Cox model and then aggregated to generate the SIIS based on the regression coefficients. Overall survival (OS) was assessed using Kaplan-Meier analyses. The Cox proportional hazards regression and random survival forest model were adopted to build the prognostic model. Then we established an effective nomogram for UTUC after RNU based on SIIS. The discrimination and calibration of the nomogram were evaluated using the concordance index (C-index), area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration curves. Decision curve analysis (DCA) was used to assess the net benefits of the nomogram at different threshold probabilities. RESULT: According to the median value SIIS computed by the lasso Cox model, the high-risk group had worse OS (p<0.0001) than low risk-group. Variables with a minimum depth greater than the depth threshold or negative variable importance were excluded, and the remaining six variables were included in the model. The area under the ROC curve (AUROC) of the Cox and random survival forest models were 0.801 and 0.872 for OS at five years, respectively. Multivariate Cox analysis showed that elevated SIIS was significantly associated with poorer OS (p<0.001). In terms of predicting overall survival, a nomogram that considered the SIIS and clinical prognostic factors performed better than the AJCC staging. CONCLUSION: The pretreatment levels of SIIS were an independent predictor of prognosis in upper urinary tract urothelial carcinoma after RNU. Therefore, incorporating SIIS into currently available clinical parameters helps predict the long-term survival of UTUC.

Empagliflozin improves renal ischemia-reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK-OPA1 pathway promotion.

BACKGROUND: Renal ischemia-reperfusion injury (IRI) is one reason for renal transplantation failure. Recent studies have shown that mitochondrial dynamics is closely related to IRI, and that inhibition or reversal of mitochondrial division protects organs against IRI. Optic atrophy protein 1 (OPA1), an important factor in mitochondrial fusion, has been shown to be upregulated by sodium-glucose cotransporter 2 inhibitor (SGLT2i). Also, the antiinflammatory effects of SGLT2i have been demonstrated in renal cells. Thus, we hypothesized that empagliflozin could prevent IRI through inhibiting mitochondrial division and reducing inflammation. METHODS: Using hematoxylin-eosin staining, enzyme linked immunosorbent assay (ELISA), flow cytometry, immunofluorescent staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, real-time PCR, RNA-sequencing, and western blot, we analyzed renal tubular tissue from in vivo and in vitro experiments. RESULTS: Through animal experiments and sequencing analysis, we first confirmed the protection against IRI and the regulation of mitochondrial dynamics-related factors and inflammatory factors by empagliflozin pretreatment. Then, through hypoxia/reoxygenation (H/R) cellular experiments, we confirmed that empagliflozin could inhibit mitochondrial shortening and division and upregulate OPA1 in human renal tubular epithelial cell line (HK-2) cells. Subsequently, we knocked down OPA1, and mitochondrial division and shortening were observed, which could be alleviated by empagliflozin treatment. Combined with the previous results, we concluded that OPA1 downregulation leads to mitochondrial division and shortening, and empagliflozin can alleviate the condition by upregulating OPA1. We further explored the pathway through which empagliflozin functions. Related studies have shown the activation of AMPK pathway by empagliflozin and the close correlation between the AMPK pathway and OPA1. In our study, we blocked the AMPK pathway, and OPA1 upregulation by empagliflozin was not observed, thus demonstrating the dependence of empagliflozin on the AMPK pathway. CONCLUSION: The results indicated that empagliflozin could prevent or alleviate renal IRI through antiinflammatory effects and the AMPK-OPA1 pathway. Ischemia-reperfusion injury is an inevitable challenge in organ transplantation. It is necessary to develop a new therapeutic strategy for IRI prevention in addition to refining the transplantation process. In this study, we confirmed the preventive and protective effects of empagliflozin in renal ischemia-reperfusion injury. Based on these findings, empagliflozin is promising to be a preventive agent for renal ischemia-reperfusion injury and can be applied for preemptive administration in kidney transplantation.

Effect of subsequent bladder cancer on survival in upper tract urothelial carcinoma patients post-radical nephroureterectomy: a systematic review and meta-analysis.

BACKGROUND: Radical nephroureterectomy (RNU) is the primary treatment strategy for upper tract urothelial carcinoma (UTUC). However, the intravesical recurrence occurs in 20-50% of all patients. The specific effect of subsequent bladder cancer (SBCa) on survival remains unclear. Therefore, we investigated the effect of SBCa following RNU in patients with UTUC. METHODS: PubMed, EMBASE, and Cochrane Library were exhaustively searched for studies comparing oncological outcomes between SBCa and without SBCa. Standard cumulative analyses using hazard ratios (HR) with 95% confidence intervals (CI) were performed using Review Manager (version 5.3). RESULTS: Five studies involving 2057 patients were selected according to the predefined eligibility criteria. Meta-analysis of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences between the SBCa and non-SBCa groups. However, subgroup analysis of pT0-3N0M0 patients suggested that people with SBCa had worse CSS (HR = 5.13, 95%CI 2.39-10.98, p < 0.0001) and OS (HR = 4.00, 95%CI 2.19-7.31, p < 0.00001). CONCLUSIONS: SBCa appears to be associated with worse OS in patients with early stage UTUC. However, caution must be taken before recommendations are made because this interpretation is based on very few clinical studies and a small sample size. Research sharing more detailed surgical site descriptions, as well as enhanced outcome data collection and improved reporting, is required to further investigate these nuances.

Clinicopathological and Prognostic Significance of Preoperative Prognostic Nutritional Index in Patients with Upper Urinary Tract Urothelial Carcinoma.

To investigate the prognostic value of preoperative prognostic nutritional index (PNI) to predict oncological outcome and intravesical recurrence (IVR) in upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU).This study involved the clinical data of 255 patients with UTUC who had undergone RNU from 2004 to 2019 at our institution. Patients were grouped according to an optimal value of preoperative PNI. Kaplan-Meier analyses and Cox proportional hazards models were used to analyze the associations of preoperative PNI with progression-free survival (PFS), cancer-specific survival (CSS), overall survival (OS), and IVR.Patients with low PNI were more likely to be older, have higher tumor stage, higher eGFR, and multifocal lesions. No significant association was found between PNI and CSS, IVR. In subgroup analysis according to the risk stratification, low PNI was associated with worse PFS, CSS, and OS for patients with higher risk. Multivariate analyses showed that elevated PNI was an independent prognostic indicator for PFS (P = 0.014) and OS (P = 0.048).A low PNI is an independent predictor of PFS and OS in patients with UTUC after RNU. By subgroup analysis, the prognostic value of PNI was limited to patients with higher risk. PNI may become a useful biomarker to predict oncological outcomes in patients with UTUC after RNU.

Presence of secondary bladder cancer following radical nephroureterectomy for upper tract urothelial carcinoma: characteristics, risk factors, and predictive value.

BACKGROUND: To assess the characteristics, predictive risk factors, and prognostic effect of secondary bladder cancer (SBCa) following radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). METHODS: Using the Surveillance, Epidemiology, and End Results database, the authors analyzed clinicopathologic characteristics and survival data from 472 UTUC patients with SBCa after RNU, between 2004 and 2017. Cox's proportional hazard regression model was implemented to identify independent predictors associated with post-recurrence outcomes. The threshold for statistical significance was p < 0.05. RESULTS: In total, 200 Ta-3N0M0 localized UTUC patients with complete data were finally included. With a median follow-up of 71.0 months (interquartile ranges [IQR] 36.0 -103.8 months), 52.5% (n = 105) had died, with 30.5% (n = 61) dying of UTUC. The median time interval from UTUC to SBCa was 13.5 months (IQR 6.0-40.8 months). According to multivariable Cox regression analysis, patients with SBCa located at multiple sites, advanced SBCa stage, higher SBCa grade, elderly age and a shorter recurrence time, encountered worse cancer-specific survival (CSS), all p < 0.05. CONCLUSION: For primary UTUC patients with SBCa after radical surgery, advanced age, multiple SBCa sites, shorter recurrence time, higher SBCa stage, and grade proved to be significant independent prognostic factors of CSS. We ought to pay more attention to SBCa prevention as well as to earlier signs which may increase the likelihood of early detection. Having the ability to manage what may be seen as the superficial SBCa signs may enable us to improve survival but further research is required.

Does Xylinas' nomogram accurately predict intravesical recurrence risk after radical nephroureterectomy for primary upper urinary tract urothelial carcinoma when applied to Asian populations?

OBJECTIVE: To validate a prognostic nomogram (Xylinas' nomogram) for intravesical recurrence after radical nephroureterectomy for primary upper urinary tract urothelial carcinoma patients of Asian descent. METHODS: Clinicopathological and survival data from 243 primary urinary tract urothelial carcinoma patients who underwent radical nephroureterectomy with bladder cuff excision between January 2004 and May 2017 were collated. Univariate and multivariable Cox regression analyses were performed to identify independent risk factors associated with intravesical recurrence-free survival. External validation was determined using regression coefficients abstracted from previously published data. Performance was then quantified through calibration and discrimination, according to concordance indexes (c-index) in receiver operating characteristic curves. RESULTS: 163 patients met our eligibility criteria and were finally included in this study. At a median follow-up of 60 months, intravesical recurrence occurred in 29.4% (n = 48). Multivariable analysis revealed that being male, ureteral tumor location, tumor multifocality and previous bladder cancer were independent prognostic factors of intravesical recurrence-free survival. When Xylinas' nomogram was applied to our cohort, the discriminatory power was found to be roughly equivalent with a c-index of 68.3% for the reduced model and 68.4% for the full model. Calibration plots also revealed intravesical recurrence predictions at 3, 6, 12, 18, 24 and 36 months had relative concordance. Contrasting the respective performances of the reduced and full model suggests there is no significant difference between the two (all P > 0.05). CONCLUSIONS: This nomogram appears accurate at predicting intravesical recurrence after radical nephroureterectomy for primary urinary tract urothelial carcinoma in Asian populations. However, it remains necessary to data mine for unknown prognostic factors for optimization. Further external validation is required across larger, ethically diverse populations before applying this nomogram in clinical practice.

Developing a nomogram for predicting intravesical recurrence after radical nephroureterectomy: a retrospective cohort study of mainland Chinese patients.

OBJECTIVE: To evaluate the role of Ki-67 in predicting subsequent intravesical recurrence following radical nephroureterectomy and to develop a predictive nomogram for upper tract urothelial carcinoma patients. METHODS: This retrospective analysis involved 489 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy with bladder cuff excision. The data set was randomly split into a training cohort of 293 patients and a validation cohort of 196 patients. Immunohistochemical analysis was used to assess the immunoreactivity of the biomarker Ki-67 in the tumor tissues. A multivariable Cox regression model was utilized to identify independent intravesical recurrence predictors after radical nephroureterectomy before constructing a nomographic model. Predictive accuracy was quantified using time-dependent receiver operating characteristic curve. Decision curve analysis was performed to evaluate the clinical benefit of models. RESULTS: With a median follow-up of 54 months, intravesical recurrence developed in 28.2% of this sample (n = 137). Tumor location, multifocality, pathological T stage, surgical approach, bladder cancer history and Ki-67 expression levels were independently associated with intravesical recurrence (all P < 0.05). The full model, which intercalated Ki-67 with traditional clinicopathological parameters, outperformed both the basic model and Xylinas' model in terms of discriminative capacity (all P < 0.05). Decision-making analysis suggests that the more comprehensive model can also improve patients' net benefit. CONCLUSIONS: This new model, which intercalates the Ki-67 biomarker with traditional clinicopathological factors, appears to be more sensitive than nomograms previously tested across mainland Chinese populations. The findings suggest that Ki-67 could be useful for determining risk-stratified surveillance protocols following radical nephroureterectomy and in generating an individualized strategy based around intravesical recurrence predictions.

Sexual Functions in Women With Stress Urinary Incontinence After Mid-Urethral Sling Surgery: A Systematic Review and Meta-Analysis of Prospective Randomized and Non-Randomized Studies.

BACKGROUND: Stress urinary incontinence (SUI) is a common, distressing health issue which affects many women. Mid-urethral sling (MUS) surgeries are recommended as gold standard interventions, although evidence regarding their impact on female sexual function remains controversial. AIM: To provide high-quality evidence of the impact of MUS surgeries on sexual functions in women with SUI. METHODS: A systematic search of PubMed, Embase, and the Cochrane Library was conducted to identify studies assessing the effect of MUS treatments on sexual functions in women with SUI. The included studies were prospective randomized or non-randomized trials which assessed patients using 2 validated questionnaires, the Female Sexual Function Index (FSFI) and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). Pre- and postoperative data regarding sexual function were extracted. Meta-analysis of comparable data was performed using Review Manager (version 5.3) software. MAIN OUTCOME MEASURES: The relationship between MUS interventions and sexual functions was analyzed by pooling weighted mean differences (WMD) with 95% CI from studies which used either the FSFI or PISQ-12 questionnaires, before and after receiving surgical interventions. RESULTS: Of the 22 eligible studies, 13 utilized FSFI and 9 adopted the PISQ-12. Pooled analysis indicates that 6-month postoperative PISQ-12 scores were significantly higher than preoperative scores (WMD -3.31 points; 95% CI -5.32 to -1.30; P = .001). Similar results were found at the 12-month juncture (WMD -3.30 points; 95% CI -6.01 to -0.58; P = .02) and at 24 months (WMD -4.44 points; 95% CI -5.45 to -3.44; P < .00001). Likewise, pooled postoperative FSFI total scores were significantly higher than preoperative scores at 6 months (WMD -2.22 points; 95% CI -3.36 to -1.08; P = .00001) and 12 months (WMD -3.49 points; 95% CI -5.96 to -1.02; P = .006). Postoperative FSFI sub-scores also suggest that desire, arousal, orgasm, lubrication, satisfaction, and pain during sexual intercourse significantly improved postoperatively (all P < .05). Moreover, combined evidence highlighted a significant reduction in coital incontinence postoperatively (risk ratio 5.78; 95% CI 3.16-10.58; P < .00001). CLINICAL IMPLICATIONS: These assessment tools might be more appropriately used to create opportunities for counseling. STRENGTHS & LIMITATIONS: We encountered substantial heterogeneity and insufficient long term follow-up data. There is also a distinct lack of standards, in terms of data recording and reporting across this evidence base which adds to the problems with the PISQ-12 and FSFI which, even though validated, appear unsophisticated and not necessarily fit-for-purpose. CONCLUSION: This meta-analysis confirms that sexual functions do improve after MUS surgeries for women with SUI. Lai S, Diao T, Zhang W, et al. Sexual Functions in Women With Stress Urinary Incontinence After Mid-Urethral Sling Surgery: A Systematic Review and Meta-Analysis of Prospective Randomized and Non-Randomized Studies. J Sex Med 2020;17:1956-1970.

Contasure-needleless single incision slings versus transobturator slings (TOT/TVT-O) for female patients with stress urinary incontinence: a systematic review and meta-analysis.

BACKGROUND: To assess the current evidence on the effectiveness and safety of Contasure-Needleless (C-NDL) versus transobturator slings (TOT/TVT-O) in the management of female stress urinary incontinence (SUI). METHODS: A comprehensive literature review of articles that investigated the efficacy and safety of C-NDL and TOT/TVT-O was performed based on studies published before June 2019 and retrieved from PubMed, Embase, CNKI and the Cochrane Library. Two reviewers searched the literature, independently extracted the data and evaluated the quality of the data according to the inclusion and exclusion criteria. A meta-analysis was performed by using Review Manager 5.3 software. RESULTS: Seven studies with 1188 SUI female patients without intrinsic sphincter deficiency (ISD) or mixed urinary incontinence were included. Our meta-analysis showed that the clinical efficacy of C-NDL is statistically non-inferior to that of TOT / TVT-O in terms of subjective cure rate [OR = 0.77, 95% confidence interval (CI) (0.53 to 1.10), p = 0.15] and objective cure rate [OR = 0.78, 95% CI (0.53 to 1.13), p = 0.19]. In addition, operating times were statistically shorter with C-NDL compared to TOT / TVT-O [mean difference (MD) = - 7.38, 95% CI (- 10.73 to - 4.04), p < 0.0001]. In terms of the postoperative visual analogue scale (VAS) and the incidence of postoperative pain, C-NDL has a greater advantage [MD = - 1.71, 95% CI (- 2.91 to - 0.50), p = 0.005]; [OR = 0.21, 95% CI (0.05 to 0.96), p = 0.04]. Complication rates were statistically similar between the groups, except for groin pain which was higher in TOT / TVT-O. CONCLUSION: Our data suggest that C-NDL slings have similar short-term efficacy as TOT/TVT-O in curing SUI patients. Compared with TOT/TVT-O, C-NDL is associated with a shorter operative time, and the incidence of postoperative pain is decreased. Nevertheless, these findings should be further confirmed through large-volume, well-designed prospective randomized controlled trials (RCTs) with long-term follow-up.

Sacral Neuromodulation for Lower Urinary Tract Dysfunction in Spinal Cord Injury: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the intervention effect of sacral neuromodulation (SNM) in the treatment of lower urinary tract dysfunction after spinal cord injury (SCI). METHODS: We selected relevant studies published between January 1, 1971 and November 15, 2018 by searching the PubMed, EMBASE, Cochrane databases. The outcome was assessed as follows: patients who had at least 50% improvement in bladder diary variables (number of leakages, pad use, number of voids, number of catheterizations, and so on). All analyses were performed with R software (version 3.5.1). We used Cochran's Q test and I2 statistics to evaluate the heterogeneity. RESULTS: A total of 8 articles met all inclusion criteria for the systematic review. According to the Oxford Centre for Evidence-Based Medicine hierarchy, the evidence levels ranged from 2b to 4. During the test phase of SNM, we considered 108 patients. During the test phase, the merged success rate was 45% (95% CI 36-55%, p = 0.23, I2 = 31%). Overall, 99 patients were considered during the permanent implantation phase of SNM; the mean follow-up time ranged from 8.4 to 61.3 months, and the merged success rate of the permanent SNM phase was 75% (95% CI 64-83%, p = 0.46, I2 = 0%). All the reported adverse events were resolved. CONCLUSIONS: Based on current evidence, the success rate of the test phase of SNM for LTUD in SCI patients was low, but in the permanent phase, the success rate of SNM was optimistic. In the future, well-designed randomized controlled trial with adequate sample sizes and power are necessary to validate the efficacy and safety of SNM.

A Systematic Review and Meta-Analysis of the Effects on Dutasteride Treatment for Reducing Surgical Blood Loss during Transurethral Resection of the Prostate.

OBJECTIVE: This systematic review and meta-analysis were performed to evaluate the efficacy of preoperative dutasteride treatment for reducing surgical blood loss in patients undergoing transurethral resection of the prostate (TURP). METHODS: A systematic search was performed from the electronic databases including PubMed, EMBASE, and Cochrane Library by May 2016. We followed the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analysis statement when examining the literature. Identified articles were strictly appraised for quality and relevance. RESULTS: Five randomized controlled trials (RCTs) and 5 retrospective cohort studies involving 1,022 patients with benign prostate hyperplasia were analyzed based on the inclusion criteria. Pooled analysis revealed that preoperative treatment with dutasteride had a significantly smaller decrease in hemoglobin (weighted mean difference [WMD] -0.47, 95% CI -0.70 to -0.24, p < 0.0001) and hematocrit levels (WMD -1.03, 95% CI -1.73 to -0.33, p = 0.004); However, no significant difference has been found in terms of the total blood loss during TURP and blood loos per gram of resected prostatic tissue, the weight of resected prostate tissue, the microvessel density of the prostate, and the transfusion rate between the dutasteride and the control group. CONCLUSIONS: This systematic review and meta-analysis indicate that preoperative treatment with dutasteride could reduce surgical bleeding during TURP, but the findings of this study should be further confirmed by well-designed prospective RCTs with a larger patient series.

Prognostic variations between 'primary' and 'progressive' muscle-invasive bladder cancer following radical cystectomy: a novel propensity score-based multicenter cohort study.

OBJECTIVE: To assess prognostic differences between primary and progressive muscle-invasive bladder cancer (MIBC) following radical cystectomy. MATERIAL AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to abstract MIBC data following radical cystectomy from 2000 to 2019. Patients were classified as either 'Primary' MIBC (defined as the presentation of muscle-invasive disease at initial diagnosis) or 'Progressive' MIBC (defined as a non-muscle invasive disease that later progressed to MIBC). Baseline characteristics for the two groups were balanced using a propensity score overlap weight (PSOW) technique. Survival differences between the two groups were analyzed using Kaplan-Meier's plots and log-rank tests. Cox's proportional hazard regression was used to assess risk factors associated with overall survival (OS) and cancer-specific survival (CSS). RESULTS: Six thousand six hundred thirty-two MIBC patients were identified in the SEER database. Among them, 83.3% ( n =5658) were considered primary MIBC patients, and 16.7% ( n =974) were categorized as progressive MIBC patients. Distribution of baseline covariates, including age, sex, race, T stage, N stage, tumour grade, marital status, and chemotherapy, were well-balanced after PSOWs were applied. After stable PSOW adjustments, Kaplan-Meier survival analysis showed that the CSS for progressive MIBC [hazard ratio (HR)=1.25, 95% confidence interval (CI): 1.12-1.38, P <0.001) was poorer than the primary MIBC group. However, the difference in OS (HR=1.08, 95% CI: 0.99-1.18) was not significant ( P =0.073). Multivariate analysis also suggested that patients with progressive MIBC have significantly poorer CSS (HR=1.24, 95% CI: 1.19-1.38, P <0.001) but not OS (HR=1.08, 95% CI: 0.99-1.18, P =0.089). CONCLUSION: CSS for progressive MIBC patients appears worse than for those with primary MIBC. This highlights the need to direct more resources for this patient population and particularly for high-risk cases of non-MIBC, where timely radical surgery will improve patients prognoses.

A novel model of urosepsis in mice developed by ureteral ligation and injection of Escherichia coli into the renal pelvis.

Despite extensive investigations, urosepsis remains a life-threatening and high-mortality illness. The absence of widely acknowledged animal models for urosepsis prompted this investigation with the objective of formulating a replicable murine model. Eighty-four adult male C57BL/6J mice were arbitrarily distributed into three cohorts based on the concentration of the Escherichia coli (E. coli) solution administered into the renal pelvis: Sham, Low-grade sepsis (1.0 × 108 cfu/mL), and High-grade sepsis (1.0 × 109 cfu/mL). By fabricating a glass needle with a 100 µm outer diameter, bacterial leakage during renal pelvic injection was minimized. After the ureteral ligation, the mice were injected with this needle into the right renal pelvis (normal saline or E. coli solution, 1 ml/kg). Ten days post after E. coli injection, the mortality rates for the Low-grade sepsis and High-grade sepsis groups stood at 30 % and 100 %, respectively. Post-successful modeling, mice in the urosepsis cohort exhibited a noteworthy reduction in activity, body temperature, and white blood cell count within a 2-h timeframe. At the 24-h mark post-modeling, mice afflicted with urosepsis displayed compromised coagulation functionality. Concurrently, multiple organ dysfunction was confirmed as evidenced by markedly elevated levels of inflammatory factors (IL-6 and TNF-α) in four distinct organs (heart, lung, liver, and kidney). This study confirmed the feasibility of establishing a standardized mouse model of urosepsis by ureteral ligation and E. coli injection into the renal pelvis. A primary drawback of this model resides in the mice's diminished blood volume, rendering continuous blood extraction at multiple intervals challenging.

Efficacy of cytoreductive surgery for metastatic upper tract urothelial carcinoma: a Surveillance, Epidemiology and End Results (SEER) study of 508 patients.

Background: Cisplatin-based combination chemotherapy alone is currently considered the standard of care for patients with metastatic upper tract urothelial carcinoma (mUTUC). However, less research has been done on the efficacy of other combinations. In this study, we explored the role of cytoreductive surgery in patients with mUTUC receiving different types of systemic therapy. Methods: Data from 9,436 anonymized records were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2008-2018. Of these, 508 individuals received systemic therapy subsequent to being diagnosed with mUTUC. These patients had all been treated with systemic therapies such as chemotherapy and/or radiotherapy. Patients were stratified into either a non-surgical or surgical group based on cytoreductive surgery status before systemic therapeutics commenced. Kaplan-Meier curves were used to compare overall survival (OS) and cancer-specific survival (CSS). Cox's proportional hazard models were then used to analyze prognostic factors related to OS and CSS. Results: Of the 508 cases, 36.8% (n=187) had received cytoreductive surgery with systemic treatments. The remaining 63.2% (n=321) received either chemotherapy and/or radiotherapy alone. Kaplan-Meier curves showed that 11.6% had 3-year OS [95% confidential interval (CI): 7.1-17.3] for cytoreductive surgery with systemic treatment and 4.9% (95% CI: 2.7-8.0) for systemic treatment alone (P=0.001). The 3-year CSS was 14.9% for cytoreductive surgery plus systemic treatment (95% CI: 9.4-21.7%) and 6.0% (95% CI: 3.4-9.8%) for systemic treatments alone (P=0.003). Under multivariate regression analysis, primary ureter site OS had a hazard ratio (HR) of 0.74 (95% CI: 0.58-0.95, P=0.02) and a CSS HR of 0.72 (95% CI: 0.56-0.94, P=0.01). The cytoreductive surgery OS HR was 0.79 (95% CI: 0.65-0.95, P=0.02) and the CSS HR was 0.75 (95% CI: 0.61-0.92, P=0.006). Additionally, chemotherapy had an OS HR of 0.46 (95% CI: 0.33-0.0.65, P<0.001) and a CSS HR of 0.44 (95% CI: 0.31-0.63, P<0.001). Bones and liver metastases were also indicative of poorer prognosis. Validation was conducted through subgroup analysis which suggested cytoreductive surgery was effective only for patients who received chemotherapy or combined chemo-radiotherapy but not for radiotherapy alone. Conclusions: Cytoreductive surgery provided significantly increased OS and CSS for mUTUC patients who received chemotherapy or combined chemo-radiotherapy in this study. In addition, the primary tumor and metastatic sites were shown to be related to improved patient survival although this was a small and relatively homogeneous cohort of study, sample therefore, further research is required.

Antibiotic use attenuates response to immune checkpoint blockade in urothelial carcinoma via inhibiting CD74-MIF/COPA: revealing cross-talk between anti-bacterial immunity and anti-tumor immunity through a tumor marker prognostic study.

BACKGROUND: Immune checkpoint blockade (ICB) has emerged as a promising therapy for both resectable urothelial carcinoma (UC) patients preparing for radical surgery and unresectable UC patients, whereas the objective response rate of ICB remains unsatisfactory due to various factors. Antibiotic (ATB) use can influence intra-tumoral bacteria, which may further reduce ICB efficacy. The study aims to evaluate the effects of ATB use on prognosis and response in UC patients undergoing ICB, and explore potential molecular mechanisms of ATBs and intra-tumoral bacteria impacting UC immune microenvironment. MATERIALS AND METHODS: Pooled analyses, synthesizing evidence from 12 studies and 3496 UC patients with ICB treatment, was conducted via a meta-analysis. In addition, single-cell RNA and single-cell microbiome data were analyzed based on eight UC samples and 63185 single cells. Bulk RNA sequencing and clinical data from a single-arm, multi-center, atezolizumab-treated, phase 2 trial, IMvigor210, were used for validation. The study is registered at PROSPERO (XXX) and at Research Registry (XXX). RESULTS: ATB use exhibited worse overall survival (HR=1.46, 95%CI=[1.20, 1.77], P<0.001, heterogeneity I²=51%) and lower objective response (OR=0.43, 95%CI=[0.27, 0.68], P<0.001, heterogeneity I²=0%) in UC patients receiving ICB. Single-cell transcriptome and single-cell microbiome analyses identified the presence of intra-tumoral bacteria was obviously related to elevated anti-bacterial immune functions; and anti-bacterial immunity was positively correlated to anti-tumor immunity in UC immune microenvironment. Intra-tumoral bacteria could up-regulate CD74-MIF/COPA signaling of immune cells and activation of CD74-MIF/COPA mediated the promotion of T cell anti-tumor function induced by anti-bacterial immune cells. UC patients with higher CD74-MIF/COPA signaling carried better overall survival (HR=1.60, 95%CI=[1.19, 2.15], P=0.002) in IMvigor210 immunotherapy cohort. CONCLUSION: ATB use reduces overall survival and objective response to ICB in UC patients. Anti-bacterial immune cell functions induced by intra-cellular bacteria in UC microenvironment might up-regulate the function of anti-tumor T immune cells via activating CD74-MIF/COPA, whereas ATB could inhibit the above process through killing intra-cellular bacteria and result in poorer clinical benefit of ICB. The use of ATB should be considered carefully during neoadjuvant immunotherapy period for resectable UC patients preparing for radical surgery and during immunotherapy period for unresectable UC patients.

Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer.

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia-primarily caused by limited oxygen penetration-has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.

Identifying possible hub genes and biological mechanisms shared between bladder cancer and inflammatory bowel disease using machine learning and integrated bioinformatics.

BACKGROUND: Recent studies have shown that inflammatory bowel disease (IBD) is associated with bladder cancer (BC) incidence. But there is still a lack of understanding regarding its pathogenesis. Thus, this study aimed to identify potential hub genes and their important pathways and pathological mechanisms of interactions between IBD and BC using bioinformatics methods. METHODS: The data from Gene Expression Omnibus (GEO) and the cancer genome atlas (TCGA) were analyzed to screen common differentially expressed genes (DEGs) between IBD and BC. The "clusterProfiler" package was used to analyze GO term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment in DEGs. After that, we conducted a weighted gene co-expression network analysis (WGCNA) on these DEGs to determine the vital modules and genes significantly related to BC. Protein-protein interaction (PPI) networks was used to identify hub genes. Further, the hub genes were used to develop a prognostic signature by Cox analysis. The validity of the ten hub DEGs was tested using three classification algorithms. Finally, we analyzed the microRNAs (miRNA)-mRNA, transcription factors (TFs)-mRNA regulatory network. RESULTS: Positive regulation of organelle fission, chromosomal region, tubulin binding, and cell cycle signaling pathway were the major enriched pathways for the common DEGs. PPI networks identified three hub proteins (AURKB, CDK1, and CCNA2) with high connectivity. Three machine-learning classification algorithms based on ten hub genes performed well for IBD and BC (accuracy > 0.80). The robust predictive model based on the ten hub genes could accurately classify BC cases with various clinical outcomes. Based on the gene-TFs and gene-miRNAs network construction, 9 TFs and 6 miRNAs were identified as potential critical TFs and miRNAs. There are 13 drugs that interact with the hub gene based on gene-drug interaction analysis. CONCLUSIONS: This study explored common gene signatures and the potential pathogenesis of IBD and BC. We revealed that an unbalanced immune response, cell cycle pathway, and neutrophil infiltration might be the common pathogenesis of IBD and BC. Molecular mechanisms for the treatment of IBD and CC still require further investigation.

Impact of a novel immune and nutritional score on prognosis in patients with upper urinary tract urothelial carcinoma following radical nephroureterectomy.

BACKGROUND: This study aimed to evaluate the clinical significance of a novel immune and nutritional score combining prognostic values of the controlling nutritional status (CONUT) score and prognostic immune and nutritional index (PINI) on long-term outcomes in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). METHODS: This study analyzed 437 consecutive patients with UTUC treated by RNU. Restricted cubic splines were used to visualize the relation of PINI with Survival in patients with UTUC. The PINI was stratified into low- (1) and high-PINI (0) categories. The CONUT score was divided into three groups: Normal (1), Light (2), and Moderate/severe (3). Subsequently, patients were grouped according to CONUT-PINI score (CPS) (CPS group 1; CPS group 2; CPS group 3; and CPS group 4). Survival curves were plotted using the Kaplan-Meier method and log-rank test. The Cox proportional hazards regression model was used to determine the risk factors associated with overall Survival (OS) and cancer-specific Survival (CSS). By comprising independent prognostic factors, a predictive nomogram was constructed. RESULTS: PINI and CONUT score were identified as independent prognostic factors for OS and CSS. Kaplan-Meier survival analysis showed that the high CPS group was associated with worse OS and CSS than the low CPS group. Multivariate Cox regression and competing risk analyses showed that CPS, LVI, T stage, margin, and pN were independent factors associated with OS and CSS. Based on these five significant factors, we constructed a prognostic model for predicting clinical outcomes. The receiver operating characteristic curve indicated that the model had excellent predictive abilities for survival. The C-index of this model for OS and CSS were 0.773, and 0.789, respectively. The nomogram for OS and CSS showed good discrimination and calibration. Decision curve analysis (DCA) showed that this nomogram has a higher net benefit. CONCLUSION: The CPS combined the prognostic capacity of PINI and CONUT score and was able to predict patient outcomes in our cohort of UTUC patients. We have developed a nomogram to facilitate the clinical use of the CPS and provide accurate estimates of survival for individuals.

Systematic oxidative stress indices predicts prognosis in patients with urothelial carcinoma of the upper urinary tract after radical nephroureterectomy.

BACKGROUND: Oxidative stress plays an important role in the occurrence and development of malignancy. However, the relationship between oxidative stress and upper urinary tract urothelial carcinoma (UTUC) prognosis remains elusive. This study aimed to evaluate the prognostic value of systematic oxidative stress indices as a predictor of patient outcomes in UTUC after radical nephroureterectomy. METHODS: Clinical data for 483 patients with UTUC who underwent radical nephroureterectomy were analyzed. Patients were categorized according to an optimal value of systematic oxidative stress indices (SOSIs), including fibrinogen (Fib), gamma-glutamyl transpeptidase (γ-GGT), creatinine (CRE), lactate dehydrogenase (LDH) and albumin (ALB). Kaplan-Meier analyses were used to investigate associations of SOSIs with overall survival (OS) and progression-free survival (PFS). Moreover, associations between SOSIs and OS and PFS were assessed with univariate and multivariate analyses. RESULTS: High values of Fib, γ-GGT, CRE, and LDH, and low values of ALB were associated with reduced OS. SOSIs status correlated with age, tumor site, surgical approach, hydronephrosis, tumor size, T stage, and lymph node status. The Kaplan-Meier survival analysis showed a significant discriminatory ability for death and progression risks in the two groups based on SOSIs. Multivariate Cox proportional hazards models showed that SOSIs were an independent prognostic indicator for OS (p = 0.007) and PFS (p = 0.021). SOSIs and clinical variables were selected to establish a nomogram for OS. The 1-, 3-, and 5-year AUC values were 0.77, 0.78, and 0.81, respectively. Calibration curves of the nomogram showed high consistencies between the predicted and observed survival probability. Decision curve analysis curves showed that the nomogram could well predict the 1-year, 3-year, and 5-year OS. CONCLUSIONS: SOSIs are an independent unfavorable predictor of OS and PFS in patients diagnosed with UTUC undergoing RNU. Therefore, incorporating SOSIs into currently available clinical parameters may improve clinical decision-making.