Higher genetically predicted triglyceride level increases the bladder cancer risk independent of LDL and HDL levels.

The causal relationship between lipid levels and bladder cancer is still inconclusive currently. We aimed to reveal the causal relationship between triglycerides, HDL, and LDL and the risk of bladder cancer by univariable and multivariable Mendelian randomization (MR) analysis. The single nucleotide polymorphisms (SNPs) of exposure (triglycerides: 441,016 samples; HDL: 403,943 samples; LDL: 440,546 samples) were obtained from UK Biobank. The Genetic variation related to bladder cancer included 1554 cases and 359,640 controls. Univariable and multivariable MR methods were conducted with subsequent analysis, and smoking was regarded as a confounder. The inverse-variance weighted (IVW), MR-Egger, weighted-median method, Cochran's Q test, and MR-PRESSO were considered the main MR analysis and sensitivity analysis methods. Univariable MR analysis results suggested the triglycerides level (P = 0.011, OR = 1.001, 95% CI = 1.000-1.002) was causally associated with increased risk of bladder cancer. Multivariable MR results indicated that higher triglyceride levels could still increase the risk of bladder cancer after adjusting the effects of HDL, LDL, and smoking (P = 0.042, OR = 1.001, 95% CI = 1.000-1.002). Our findings supported that triglyceride level is causally associated with an increased risk of bladder cancer independent of LDL and HDL at the genetic level. Timely attention to changes in blood lipid levels might reduce the risk of bladder cancer.

Association of interleukin6 rs1800796 gene polymorphism and serum level with bladder cancer in Egyptian population.

BACKGROUND: Urinary bladder cancer (UBC)is a common tumor of the urinary tract. OBJECTIVES: To assess the diagnostic significance of IL6 rs1800796 gene polymorphism and IL6 serum level among Egyptian patients with UBC. DESIGN AND METHODS: One hundred patients with UBC were selected from the Mansoura Urology and Nephrology Center, in addition to 100 healthy control subjects; using PCR and ELISA techniques for IL6 detection. RESULTS: The rs1800796 GC, CC genotypes, and C allele were significantly more prevalent in the cases with bladder cancer compared to the healthy group (p < 0.001, = 0.021, < 0.001 respectively). There was a clear association between elevated levels of IL6 and bladder cancer versus the control group (median = 4.2, 0.89 respectively, p < 0.001). Serum IL6 levels showed significantly higher levels in patients carrying CC, followed by GC then GG genotypes. No significant association was found between IL6 rs1800796 gene polymorphism or serum level with demographic or laboratory data. CONCLUSION: It is suggested that there is a clear link between elevated IL6 levels as well as IL6 rs1800796 gene polymorphism with bladder cancer, suggesting their potential utility as biomarkers for the disease.

Preoperative blood-based nutritional biomarkers as significant prognostic factors after intravesical BCG therapy in patients with non-muscle-invasive bladder cancer.

The aim of this study was to investigate the prognostic role of blood-based nutritional biomarkers, including red blood cell (RBC count), hemoglobin (Hb), total protein (TP), albumin, the serum albumin to globulin ratio (AGR) and the prognostic nutritional index (PNI) in patients who underwent intravesical treatment for non-muscle invasive bladder cancer (NMIBC). A total of 501 NMIBC patients who received intravesical Bacillus Calmette-Guerin (BCG) treatment following transurethral resection of bladder tumor (TURBT) were included. The optimal cutoff values for these nutrition-based indicators were determined using receiver operating characteristic curve analysis. We observed a significantly higher recurrence-free survival (RFS) rate in patients with elevated levels of RBC count, Hb, TP, and albumin. Cox univariate and multivariate Cox regression analyses demonstrated that serum albumin (P = 0.002, HR = 0.51, 95%CI: 0.33-0.78), RBC count (P = 0.002, HR = 0.50, 95%CI: 0.32-0.77), TP (P = 0.028, HR = 0.62, 95%CI: 0.41-0.95), Hb (P = 0.004, HR = 0.53, 95%CI: 0.33-0.84), AGR (P = 0.003, HR = 0.46, 95%CI: 0.27-0.76) and PNI (P = 0.019, HR = 0.56, 95%CI: 0.35-0.91) were significant independent factors predicting RFS. These cost-effective and convenient blood-based nutritional biomarkers have the potential to serve as valuable prognostic indicators for predicting recurrence in NMIBC patients undergoing BCG-immunotherapy.

LncRNA BCYRN1 as a Potential Therapeutic Target and Diagnostic Marker in Serum Exosomes in Bladder Cancer.

Bladder cancer (BC) is a common genitourinary malignancy that exhibits silent morbidity and high mortality rates because of a lack of diagnostic markers and limited effective treatments. Here, we evaluated the role of the lncRNA brain cytoplasmic RNA 1 (BCYRN1) in BC. We performed loss-of-function assays to examine the effects of BCYRN1 downregulation in T24 and BOY BC cells. We found that BCYRN1 downregulation significantly inhibited the proliferation, migration, invasion, and three-dimensional spheroid formation ability and induced apoptosis in BC cells. Additionally, gene set enrichment analysis (GSEA) using RNA sequences from tumor fractions showed that BCYRN1 downregulation decreased the expression of mRNAs associated with the cell cycle. These findings were supported by observations of G2/M arrest in flow cytometry assays. Finally, we examined the expression of serum exosomal BCYRN1 as a biomarker. Clinically, BCYRN1 expression in serum exosomes from patients with BC (n = 31) was significantly higher than that in healthy donors (n = 19; mean difference: 4.1-fold higher, p < 0.01). Moreover, in patients who had undergone complete resection of BC, serum exosomal BCYRN1 levels were significantly decreased (n = 8). Thus, serum exosomal BCYRN1 may be a promising diagnostic marker and therapeutic target in patients with BC.

Investigating angiogenin/ribonuclease 5 as a diagnostic biomarker for bladder cancer: In-depth analysis from a systematic review and meta-analysis.

Bladder cancer (BC) represents a prevalent malignancy in North America and Europe, posing significant health burdens. The identification of a reliable biomarker for early BC detection is imperative to enhance prognostic outcomes. Our aim for this study is to determine the diagnostic accuracy and potential clinical utility of Angiogenin/Ribonuclease 5 (ANG/RNase 5) as a biomarker for detection of BC. A systematic literature search across multiple databases up to March 20, 2024, was conducted. CMA 3.7 and Meta-disk 1.4 were used to analyze specificity, sensitivity, AUC, DOR, LR+, LR-, Q*index, and SROC for ANG as a urinary biomarker in BC patients. Publication bias was assessed using Egger's regression asymmetry and Begg's rank correlation tests. Additional diagnosing analyses were performed using Python programming language version 3.12.1. In this meta-analysis of seven case-control studies comprising 1,051 participants (576 cases and 481 controls), pooled sensitivity was 0.701 (95 % CI: 0.662-0.738), specificity was 0.787 (95 % CI: 0.752-0.819), LR + was 3.582 (95 % CI: 2.260-5.676), LR- was 0.398 (95 % CI: 0.327-0.485), and DOR was 10.637 (95 % CI: 6.106-18.529). The AUC and Q* index values were 0.823 and 0.756, respectively. Both Begg and Mazumdar Rank Correlation Test (p = 0.229) and Egger's Test of the Intercept (p = 0.135) revealed no significant evidence of publication bias. Our meta-analysis confirms ANG/RNase 5 as a reliable biomarker for early bladder cancer detection, showing strong diagnostic accuracy and no publication bias.

Genetically predicted 91 circulating inflammatory proteins in relation to risk of urological malignancies: a Mendelian randomization study.

BACKGROUND: Urological malignancies, including kidney, bladder, and prostate cancer, are major health concerns worldwide. Inflammation has been implicated in the pathogenesis of these cancers, and circulating inflammatory proteins may play a role in their development. However, the causal relationship between specific plasma proteins and urological malignancies remains unclear. METHODS: We performed a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS). Instrumental variables representing genetic variants associated with circulating inflammatory proteins were used to infer causality on the risk of kidney, bladder, and prostate cancer. Four MR methods were utilized to provide robust effect estimates. RESULTS: Our analysis identified several plasma proteins associated with a lower risk of kidney and bladder cancer, including Eukaryotic translation initiation factor 4E-binding protein 1, Caspase 8, Natural killer cell receptor 2B4, and Tumor necrosis factor ligand superfamily member 12. However, after adjusting for multiple testing, these associations did not remain statistically significant. For prostate cancer, CUB domain-containing protein 1 and Interleukin-10 receptor subunit beta were found to be protective, while Glial cell line-derived neurotrophic factor and SIR2-like protein 2 were identified as risk factors. After FDR adjustment, none of the inflammatory proteins were found to be significantly associated with a lower risk of prostate cancer. CONCLUSION: Our findings suggest that certain plasma proteins may be involved in the development of urological malignancies. Mendelian randomization provides a useful framework for investigating causal relationships between inflammatory proteins and urological cancers, offering potential insights into their underlying biology and therapeutic targets.

Testing the accuracy of a four serum microRNA panel for the detection of primary bladder cancer: a discovery and validation study.

BACKGROUND: Bladder cancer (BC) is one of the ten most common cancers worldwide with late detection and early age of diagnosis. There is abundant evidence that early detection and timely intervention can lead to a better prognosis of BC. Substantial evidence has indicated that microRNAs (miRNAs) are specific to different tumour types and are remarkably stable, indicating that serum miRNAs may serve as potential cancer diagnostic markers. This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary BC. METHODS: In this study, 18 miRNAs that were differentially expressed in BC were obtained from the PubMed or Gene Expression Omnibus database. Then, 18 BC-related-miRNAs were verified in screening and validation sets created using 56 (28 primary BC vs. 28 NCs) and 168 (84 primary BC vs. 84 NCs) serum samples, respectively. Quantitative reverse transcription-PCR (qRT-PCR) was performed to verify the identity of the differential miRNAs. A multi-miRNA panel with superior diagnostic performance was constructed. TCGA and KEGG databases were used to conduct the survival analysis and bioinformatics analysis, respectively. RESULTS: Six serum miRNAs (miR-221-5p, miR-181a-5p, miR-98-5p, miR-15a-5p, miR-222-3p, and miR-197-3p) were significantly aberrantly expressed in the BC patients, while four miRNAs from among them (miR-221-5p, miR-181a-5p, miR-15a-5p, miR-222-3p) were assembled into a panel that showed high diagnostic value (AUC = 0.875, 95% CI: 0.815 - 0.921; sensitivity: 82.14%; and specificity: 85.71%) based on the logistic regression analysis. The survival analysis showed that miR-181a-5p was closely associated with BC prognosis (Log-rank p-value < 0.05). CONCLUSION: The combination of the four miRNAs (miR-221-5p, miR-181a-5p, miR-15a-5p and miR-222-3p) may be a novel non-invasive serological biomarker for BC screening.

Early detection and timely intervention can lead to a better prognosis of bladder cancer.This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary bladder cancer.

A panel of four plasma amino acids is a promising biomarker for newly diagnosed bladder cancer.

BACKGROUND: Metastasis and recurrence are the main causes of death in post-operative bladder cancer (BC), emphasizing the importance of exploring early-stage diagnostic markers. Serum biomarkers constitute a promising diagnostic approach for asymptomatic stage cancer as they are non-invasive, have high accuracy and low cost. AIMS: To correlate concentrations of plasma amino acids with BC progression to assess their utility as an early-stage diagnostic. METHODS: Newly diagnosed BC patients (n = 95) and normal controls (n = 96) were recruited during the period from 1 December 2018 to 30 December 2020. General and food frequency questionnaires established their basic information and dietary intake data. Venous blood samples were collected from fasting subjects and used to detect levels of plasma amino acids by liquid chromatography-mass spectrometry. Verification was performed on the GSE13507 transcriptome gene expression matrix of BC from Gene Expression Omnibus (GEO) database. RESULTS: Eleven amino acids have been identified as altered in the plasma of newly diagnosed BC patients compared to controls (P < 0.05). Adjusted by gender, education, smoking and other factors, plasma ornithine level (OR = 0.256, 95% CI: 0.104-0.630) is a protective factor for BC, plasma levels of methionine (OR = 3.460, 95% CI: 1.384-8.651), arginine (OR = 3.851, 95% CI: 1.542-9.616), and glutamate (OR = 3.813, 95% CI: 1.543-9.419) are all risk factors for BC. ROC analysis demonstrated that the combination of plasma ornithine, methionine, arginine and glutamate could accurately diagnose BC (AUC = 0.84, 95% CI: 0.747-0.833). In addition, the mRNA level of arginase 1 was decreased (P < 0.05), while the inducible nitric oxide synthase was increased significantly, which may be linked with the disturbance of arginine metabolism in BC patients. Further analysis of GEO database confirmed the role of arginine metabolism. CONCLUSION: A biomarker panel containing four amino acids may provide a feasible strategy for the early diagnosis of BC. However, further validation is required through prospective studies.

C-reactive protein (CRP) as a prognostic biomarker in patients with urothelial carcinoma: A systematic review and meta-analysis.

C-reactive protein (CRP) may reflect a pro-inflammatory tumor microenvironment and could represent a biomarker to select patients with urothelial carcinoma more likely to benefit from therapies directed at modulating tumor-promoting inflammation. We performed a systematic review to evaluate survival outcomes based on pre-treatment CRP values in urothelial carcinoma. The hazard ratios (HRs) of survival such as overall survival (OS) and progression-free survival (PFS) between groups with high versus low CRP values were pooled by the random-effect model meta-analyses. Overall, 28 studies comprising 6789 patients were identified for meta-analyses. High CRP levels were associated with shorter OS (HR=1.96 [95% CI: 1.64-2.33], p < 0.01), particularly in advanced disease treated with immune checkpoint blockade (ICB, HR=1.78 [1.47-2.15], p < 0.01). Similar findings were observed in ICB-treated patients with PFS. These findings suggest that CRP could be an attractive biomarker to select patients with urothelial carcinoma for strategies seeking to modulate tumor-promoting inflammation.

Prognostic significance of circulating tumor DNA in urothelial carcinoma: a systematic review and meta-analysis.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a noninvasive technique that provides valuable insights into molecular profiles and tumor disease management. This study aimed to evaluate the prognostic significance of circulating tumor DNA (ctDNA) in urothelial carcinoma (UC) through a systematic review and meta-analysis. METHODS: A comprehensive search was conducted in MEDLINE, EMBASE, and the Cochrane Library from the inception to December 2023. Studies investigating the prognostic value of ctDNA in UC were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted. Overall meta-analysis and subgroup exploration stratified by metastatic status, ctDNA sampling time, treatment type, and detection method was performed using the R software (version 4.2.2). RESULTS: A total of 16 studies with 1725 patients were included. Fourteen studies assessed the association between baseline ctDNA status and patient outcomes. Patients with elevated ctDNA levels exhibited significantly worse DFS (HR=6.26; 95% CI: 3.71-10.58, P <0.001) and OS (HR=4.23; 95% CI: 2.72-6.57, P <0.001) regardless of metastatic status, ctDNA sampling time, treatment type, and detection methods. Six studies evaluated the prognostic value of ctDNA dynamics in UC. Patients who showed a decrease or clearance in ctDNA levels during treatment or observation demonstrated more favorable DFS (HR=0.26, 95% CI: 0.17-0.41, P <0.001) and OS (HR=0.21, 95% CI: 0.11-0.38, P <0.001) compared to those who did not. The association remained consistent across the subgroup analysis based on metastatic status and detection methods. In the immune checkpoint inhibitor-treated setting, both lower baseline ctDNA level and ctDNA decrease during the treatment were significantly associated with more favorable oncologic outcomes. Furthermore, specific gene mutations such as FGFR3 identified in ctDNA also demonstrated predictive value in UC patients. CONCLUSION: This meta-analysis demonstrates a strong association of ctDNA status and its dynamic change with survival outcomes in UC, suggesting substantial clinical utility of ctDNA testing in prognosis prediction and decision making in this setting.

Beyond basics: Key mutation selection features for successful tumor-informed ctDNA detection.

Tumor-informed mutation-based approaches are frequently used for detection of circulating tumor DNA (ctDNA). Not all mutations make equally effective ctDNA markers. The objective was to explore if prioritizing mutations using mutational features-such as cancer cell fraction (CCF), multiplicity, and error rate-would improve the success rate of tumor-informed ctDNA analysis. Additionally, we aimed to develop a practical and easily implementable analysis pipeline for identifying and prioritizing candidate mutations from whole-exome sequencing (WES) data. We analyzed WES and ctDNA data from three tumor-informed ctDNA studies, one on bladder cancer (Cohort A) and two on colorectal cancer (Cohorts I and N). The studies included 390 patients. For each patient, a unique set of mutations (median mutations/patient: 6, interquartile 13, range: 1-46, total n = 4023) were used as markers of ctDNA. The tool PureCN was used to assess the CCF and multiplicity of each mutation. High-CCF mutations were detected more frequently than low-CCF mutations (Cohort A: odds ratio [OR] 20.6, 95% confidence interval [CI] 5.72-173, p = 1.73e-12; Cohort I: OR 2.24, 95% CI 1.44-3.52, p = 1.66e-04; and Cohort N: OR 1.78, 95% CI 1.14-2.79, p = 7.86e-03). The detection-likelihood was additionally improved by selecting mutations with multiplicity of two or above (Cohort A: OR 1.55, 95% CI 1. 14-2.11, p = 3.85e-03; Cohort I: OR 1.78, 95% CI 1.23-2.56, p = 1.34e-03; and Cohort N: OR 1.94, 95% CI 1.63-2.31, p = 2.83e-14). Furthermore, selecting the mutations for which the ctDNA detection method had the lowest error rates, additionally improved the detection-likelihood, particularly evident when plasma cell-free DNA tumor fractions were below 0.1% (p = 2.1e-07). Selecting mutational markers with high CCF, high multiplicity, and low error rate significantly improve ctDNA detection likelihood. We provide free access to the analysis pipeline enabling others to perform qualified prioritization of mutations for tumor-informed ctDNA analysis.

Impact of Preoperative Plasma Potassium Levels on Oncological Outcomes, Major Complications, and 30-Day Mortality in Bladder Cancer Patients Undergoing Radical Cystectomy.

INTRODUCTION AND OBJECTIVES: We examined the impact of preoperative plasma potassium levels (PPLs) on outcomes in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB), hypothesizing that potassium imbalances might influence outcomes. PATIENTS AND METHODS: In this retrospective study, 501 UCB patients undergoing RC from 2009 to 2017 at a tertiary center were analyzed. Blood samples collected a week prior to surgery defined normal and abnormal PPL based on institutional standards. We assessed overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), postoperative complications, 30-day mortality, and non-organ confined disease. Kaplan-Meier estimates, Cox proportional hazards, logistic regression, and decision curve analyses (DCA) were employed. RESULTS: 63 (13%) patients had abnormal preoperative PPLs, with 50 (10%) elevated and 13 (2.5%) decreased. In a 59 months median follow-up, 152 (31%) had disease recurrence, 197 (39%) died from any cause, and 119 (24%) from UCB. Multivariable cox regression analyses adjusting for perioperative parameters demonstrated abnormal PPL was associated with worse OS (HR=1.9, P=0.009), CSS (HR=2.8, P<0.001) and RFS (HR=2.1; P=0.007). Elevated preoperative PPLs also demonstrated significant associations with adverse outcomes in OS, CSS, and RFS (all P<0.05). In multivariable logistic regression analyses, abnormal and elevated PPLs were not associated with 30-day mortality, major 30-day postoperative complications, positive nodal disease, pT3/4 stage, and non-organ confined disease (all P>0.05). CONCLUSION: Abnormal and elevated preoperative PPLs correlate with adverse oncologic outcomes in UCB patients treated with RC. Pending external validation, preoperative PPLs might be a cost-effective, easily obtainable supplemental biomarker for enriching accuracy of outcome prediction in this highly variable maladie.

Honing the Hunt: A Comprehensive Review of Cell-free Tumor DNA to Predict Neoadjuvant Therapy Efficacy in Bladder Cancer.

OBJECTIVE: To provide an updated view on the role of cell-free DNA as a predictor of pathological response to neoadjuvant therapy in patients with muscle-invasive bladder cancer. METHODS: A systematic review was conducted from September 2023 to October 2023. Selected studies from the MEDLINE and clinical trial databases were critically analyzed regarding the clinical efficacy of cell-free DNA as a predictive instrument after neoadjuvant therapy in bladder cancer. The methodological quality assessment was based on the QUADAS-2 tool. RESULTS: In this systematic review, we analyzed 5 studies encompassing a cumulative patient cohort of 780 individuals diagnosed with muscle-invasive bladder cancer, with a median follow-up ranging from 6 to 23 months. Among these studies, 4 primarily focused on detecting and analyzing circulating tumor DNA in plasma, while 1 study uniquely utilized cell-free tumor DNA in urine samples. The diagnostic accuracy of cell-free DNA in plasma ranges from 79% to 100%, indicating a variable yet significant predictive capability. In contrast, the study utilizing urinary cell-free DNA demonstrated an accuracy of 81% in predicting treatment response post-neoadjuvant chemotherapy. CONCLUSION: Cell-free DNA is emerging as a valuable biomarker for predicting response to neoadjuvant chemotherapy in patients with muscle-invasive bladder tumors.

Association Between Serum Magnesium Levels and Outcomes of Atezolizumab in Patients With Metastatic Urothelial Carcinoma.

BACKGROUND/AIM: Evidence suggests that serum magnesium levels are associated with outcomes of immune checkpoint inhibitors (ICIs). However, this association remains under-explored in patients with metastatic urothelial carcinoma (UC) treated with ICIs. PATIENTS AND METHODS: This prognostic study used individual participant-level data from 1,281 patients with locally advanced or metastatic UC treated with atezolizumab (N=855) or chemotherapy (N=426) who participated in the IMvigor210 and the IMvigor211 trials. Multivariable Cox proportional hazards regression and Fine-Gray subdistribution hazards regression models were used to examine the association of baseline serum magnesium levels with overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). RESULTS: No evidence of an association was found between baseline serum magnesium levels and PFS or OS in patients treated with atezolizumab [PFS, hazard ratio (HR)=1.03, 95% confidence interval (CI)=0.78-1.35; OS, HR=1.13, 95%CI=0.84-1.51] or chemotherapy (PFS, HR=0.93, 95%CI=0.62-1.40; OS, HR=0.91, 95%CI=0.59-1.40). We also found no evidence of association with irAEs (subdistribution HR=1.29, 95%CI=0.81-2.07) in patients receiving atezolizumab. CONCLUSION: This study found no evidence of an association between baseline serum magnesium levels and treatment outcomes or irAEs in patients with metastatic UC receiving atezolizumab. Contrary to previous research suggesting a role for magnesium in cancer therapy, these results indicate that serum magnesium levels may not serve as a biomarker to predict outcomes in these patients.

Preoperative low plasma creatine kinase levels predict worse survival outcomes in bladder cancer after radical cystectomy.

BACKGROUND AND AIMS: To evaluate the prognostic significance of preoperative creatine kinase (CK) levels in bladder cancer (BCa) patients who underwent radical cystectomy (RC). MATERIALS AND METHODS: 570 BCa patients with RC were identified between 2010 and 2020. 108.5 U/L of CK levels were defined as the cutoff value. Logistic regression analysis and Cox regression models were performed to evaluate the association between CK levels and oncologic outcomes. Subgroup analyses were performed to address cofounding factors. RESULTS: Preoperative low CK levels were associated with worse recurrence-free survival (RFS, log-rank P = 0.001) and overall survival (OS, log-rank P = 0.002). Multivariate analysis revealed that preoperative low CK levels were an independent predictor for worse RFS (hazard ratio [HR]: 1.683; P < 0.001) and OS (HR: 1.567; P = 0.002). CONCLUSIONS: The preoperative low CK level independently predicts worse survival outcomes in BCa after RC. Incorporating it into prediction models might be valuable to assist risk stratification.

Exosomal noncoding RNAs as noninvasive biomarkers in bladder cancer: a diagnostic meta-analysis.

BACKGROUND: In view of discordance consisting in different reports, a meta-analysis was conducted to comprehensively evaluate the diagnostic efficacy of exosomal noncoding RNAs (ncRNAs) in blood and urine in the detection of bladder cancer. METHODS: Eligible studies were acquired by systematic retrieval through PubMed, Cochrane Library, and Embase. The pooled diagnostic efficacy was appraised by reckoning the area under the summary receiver operating characteristic (SROC) curve. The latent sources of heterogeneity were probed by subgroup analyses and meta-regression. STATA 12.0, Meta-DiSc 1.4, and RevMan 5.3 were applied to carry out all statistical analyses and plots. RESULTS: A total of 46 studies from 15 articles comprising 2622 controls and 3015 bladder cancer patients were included in our meta-analysis. Exosomal ncRNAs in blood and urine represented relatively satisfactory diagnostic efficacy in detecting bladder cancer, with a pooled sensitivity of 0.75, a specificity of 0.79, and an area under the SROC curve (AUC) of 0.84. Exosomal microRNAs (miRNAs) exhibited better diagnostic value with a pooled AUC of 0.91 than that of exosomal long noncoding RNAs (lncRNAs). To some extent, the heterogeneity among studies was induced by exosomal ncRNA types (miRNA or lncRNA), exosomal ncRNA profiling (single- or multiple-ncRNA), sample size, specimen types, and ethnicity. CONCLUSION: Exosomal ncRNAs in blood and urine may play a vital role in diagnosing bladder cancer as prospective noninvasive biomarkers; nonetheless, their clinical performance needs to be confirmed by further massive proactive researches.

Serial ctDNA analysis predicts clinical progression in patients with advanced urothelial carcinoma.

BACKGROUND: Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC). METHODS: We performed targeted sequencing of 182 serial ctDNA samples from 53 patients with advanced UC. RESULTS: Serial ctDNA-derived metrics predicted the clinical outcomes in patients with advanced UC. Combining serial ctDNA aggregate VAF (aVAF) values with clinical factors, including age, sex, and liver metastasis, improved the performance of prognostic models. An increase of the ctDNA aVAF by ≥1 in serial ctDNA samples predicted disease progression within 6 months in 90% of patients. The majority of patients with aVAFs ≤0.7 in three consecutive ctDNA samples achieved durable clinical responses (≥6 months). CONCLUSIONS: Serial ctDNA analysis predicts disease progression and enables dynamic monitoring to guide precision medicine in patients with advanced UC.

Platelet-to-Lymphocyte Ratio Predicts the Efficacy of Pembrolizumab in Patients With Urothelial Carcinoma.

BACKGROUND/AIM: This study aimed to determine useful predictive factors for selecting patients with advanced urothelial carcinoma (UC) who might benefit clinically from treatment with pembrolizumab. PATIENTS AND METHODS: We retrospectively analyzed 54 patients who underwent pembrolizumab treatment for UC. The hemoglobin, albumin, lymphocyte and platelet (HALP) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated as indices of systemic inflammatory response, and the relationships between these scores and the initial tumor response or overall survival, as well as other clinicopathological factors, were assessed. RESULTS: High NLR and PLR were associated with a poor initial tumor response to pembrolizumab. A HALP score <30.05 and a PLR ≥173.73 were associated with worse overall survival. In the multivariate Cox regression analysis, a high PLR was a significant independent prognostic factor for unfavorable outcomes. CONCLUSION: A high pretreatment PLR may be a valuable indicator for choosing therapy other than pembrolizumab in patients with advanced UC.

Autophagy-associated HMGB-1 as a novel potential circulating non-invasive diagnostic marker for detection of Urothelial Carcinoma of Bladder.

Urothelial carcinoma of bladder (UBC), a highly prevalent urological malignancy associated with high mortality and recurrence rate. Standard diagnostic method currently being used is cystoscopy but its invasive nature and low sensitivity stresses for identifying predictive diagnostic marker. Autophagy, a cellular homeostasis maintaining process, is usually dysregulated in cancer and its role is still enigmatic in UBC. In this study, 30 UBC patients and healthy controls were enrolled. Histopathologically confirmed tumor and adjacent normal tissue were acquired from patients. Molecular expression and tissue localization of autophagy-associated molecules (HMGB-1, RAGE, beclin, LC-3, and p62) were investigated. Serum HMGB-1 concentration was measured in UBC patients and healthy controls. ROC curves were plotted to evaluate diagnostic potential. Transcript, protein, and IHC expression of HMGB-1, RAGE, beclin, and LC-3 displayed upregulated expression, while p62 was downregulated in bladder tumor tissue. Serum HMGB-1 levels were elevated in UBC patients. Transcript and circulatory levels of HMGB-1 showed positive correlation and displayed a positive trend with disease severity. Upon comparison with clinicopathological parameters, HMGB-1 emerged as molecule of statistical significance to exhibit association. HMGB-1 exhibited optimum sensitivity and specificity in serum. The positive correlation between tissue and serum levels of HMGB-1 showcases serum as a representation of in situ scenario, suggesting its clinical applicability for non-invasive testing. Moreover, optimum sensitivity and specificity displayed by HMGB-1 along with significant association with clinicopathological parameters makes it a potential candidate to be used as diagnostic marker for early detection of UBC but requires further validation in larger cohort.

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.