Preoperative Serum Gamma-Glutamyltransferase as a Prognostic Biomarker in Patients Undergoing Radical Cystectomy for Bladder Cancer.

BACKGROUND: Serum gamma-glutamyltransferase (GGT) has been reported to be correlated with survival in a variety of malignancies. However, its effect on patients with bladder cancer (BC) treated by radical cystectomy has never been evaluated. PATIENTS AND METHODS: We retrospectively evaluated 263 patients who underwent radical surgery in our center. Baseline features, hematologic variables, and follow-up data were obtained. The endpoints included overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). The relationship between GGT and survival were evaluated. RESULTS: The median follow-up period for all patients was 34.7 (22.9-45.9) months. At the last follow-up, 67 patients died, 51 patients died of cancer, 92 patients experienced disease recurrence. Patients with an elevated serum GGT had a higher rate of pT3-T4 tumors. Patients with a higher preoperative serum GGT had a lower rate of OS, CSS and DFS (P < 0.001 for all). Multivariate analysis identified that preoperative serum GGT was independent predictor of OS (HR: 3.027, 95% CI: 1.716-5.338; P < 0.001), CSS (HR: 2.115, 95% CI: 1.093-4.090; P = 0.026), DFS (HR: 2.584, 95% CI: 1.569-4.255; P < 0.001). Age, diabetes history, pathologic T stage, and lymph node status also were independent predictors of prognosis for BC patients. CONCLUSIONS: Our results indicated that preoperative serum GGT was an independent prognosis predictor for survival of BC patients after radical cystectomy, and can be included in the prognostic models.

Prognostic Role of Pretreatment De Ritis Ratio (Aspartate Transaminase/Alanine Transaminase Ratio) in Urological Cancers: A Systematic Review and Meta-Analysis.

Background: To examine the potential prognostic significance of pretreatment De Ritis ratio (aspartate transaminase/alanine transaminase ratio) in urological cancers, including upper tract urothelial cancer (UTUC), renal cell carcinoma (RCC), prostate cancer (PCa), bladder cancer (BCa). Methods: Potential literatures were searched with PubMed, Embase, Cochrane Library, and Web of Science in December 2019. Merged hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate the associations. Results: Totally, 15 studies with 8,565 patients were included. Merged results showed that an elevated pretreatment De Ritis ratio was correlated with poorer OS (HR 1.80, 95% CI 1.61-2.01), CSS (HR 2.15, 95% CI 1.80-2.56), PFS (HR 1.57, 95% CI 1.34-1.85), BRFS (HR 1.67, 95% CI 1.11-2.53) for urological cancers. Subgroup analyses by cancer type for OS found that De Ritis ratio can be a predictor in UTUC (HR 1.91, 95% CI 1.57-2.33), RCC (HR 1.74, 95% CI 1.47-2.07), and BCa (HR 1.80, 95% CI 1.43-2.27). Similar results could be found for CSS (UTUC: HR 2.46, 95% CI 1.93-3.13; RCC: HR 1.90, 95% CI 1.46-2.47; BCa: HR 2.71, 95% CI 1.39-5.31) and PFS (UTUC: HR 1.59, 95% CI 1.15-2.20; RCC: HR 1.52, 95% CI 1.26-1.83; BCa: HR 1.79, 95% CI 1.18-2.72). There was no publication bias among these included studies. Conclusions: Pretreatment De Ritis ratio was a significant predictor for OS, CSS, PFS and BRFS in urological cancers, indicating that it could be a promising prognostic factor during clinical practice.

Prognostic significance of serum lactate dehydrogenase in patients undergoing radical cystectomy for bladder cancer.

BACKGROUND: To investigate the prognostic significance of preoperative serum lactate dehydrogenase (LDH) in patients undergoing radical cystectomy for bladder cancer (BCa). PATIENTS AND METHODS: A cohort of 263 patients undergoing open or laparoscopic radical cystectomy between 2011 and 2016 was studied. Baseline characteristics, hematological variables, follow-up data were collected. Kaplan-Meier curves and Cox proportional hazard regression model were applied to assess the relationship between LDH and overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). RESULTS: After a median 34.2 (22.9-45.8) months follow-up, all-cause death, cancer-specific death, and disease recurrence occurred in 66 patients, 50 patients, and 91 patients. The elevation of serum LDH was associated with several unfavorable parameters, including advanced age, continent cutaneous urinary diversion, increased neutrophil-to-lymphocyte ratio, decreased lymphocyte-to-monocyte ratio. Patients with a higher serum LDH (> 220 U/L) had a worse OS (P < 0.001), CSS (P < 0.001) and DFS (P < 0.001). Multivariate Cox analysis suggested that elevated LDH was an independent predictor for OS (hazard ratio [HR]: 3.113, 95% confidence interval [CI]: 1.524-6.358; P = 0.002), CSS (HR: 4.564, 95% CI: 2.008-10.373; P < 0.001), DFS (HR: 2.051, 95% CI: 1.125-3.739; P = 0.019). Medical history of diabetes, high pT stage, and positive lymph node also were adverse predictors for oncological outcomes of BCa patients in multivariate analysis. CONCLUSIONS: Preoperative serum LDH is an independent prognostic biomarker for OS, CSS, and DFS in patients undergoing radical cystectomy for BCa, which can be incorporated into prognostic models.

Prognostic role of pretreatment derived neutrophil to lymphocyte ratio in urological cancers: A systematic review and meta-analysis.

BACKGROUND: To investigate the possible prognostic role of pretreatment derived neutrophil-lymphocyte ratio (dNLR) in urological cancers, including renal cell carcinoma (RCC), prostate cancer (PCa), and urothelial cancer (UCa). MATERIALS AND METHODS: Eligible studies were comprehensively searched from PubMed, Embase, Cochrane Library and Web of Science, up to April 2019. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the relationships. RESULTS: A total of 12 studies embracing 6585 patients were included in the meta-analysis. Our results indicated that a higher pretreatment dNLR was associated with a decreased cancer-specific survival (CSS, HR 2.67, 95% CI 1.06-6.71, P = 0.037) and disease-free survival (DFS, HR 2.02, 95% CI 1.03-3.94, P = 0.040) in RCC, but not for overall survival (OS, HR 1.05, 95% CI 0.71-1.53, P = 0.818). A higher dNLR was associated with an inferior biochemical recurrence-free survival (BRFS, HR 1.70, 95% CI 1.00-2.87, P = 0.049) and OS (HR 1.35, 95% CI 1.20-1.51, P < 0.001) in PCa. A higher dNLR was associated with a worse OS (HR 1.29, 95% CI 1.03-1.61, P = 0.029) and CSS (HR 1.51, 95% CI 1.06-2.15, P = 0.024) in UCa, but not for DFS (HR 1.44, 95% CI 0.89-2.34, P = 0.139). CONCLUSION: A higher dNLR level was negatively associated with OS, CSS, DFS and BRFS, forecasting that it could be an independent prognosis predictor in urological cancers.

Comparison of Laparoscopic and Robot-assisted Radical Cystectomy for Bladder Cancer: Perioperative and Oncologic Outcomes.

BACKGROUND: The purpose of this study was to compare perioperative and oncologic outcomes between laparoscopic radical cystectomy (LRC) and robot-assisted radical cystectomy (RARC) for bladder cancer (BCa). MATERIALS AND METHODS: Patients who underwent LRC or RARC with curative intent for BCa between January 2011 and December 2016 were included. Perioperative, pathologic oncologic data were extracted from our database. Disease-free survival, overall survival, and cancer-specific survival were analyzed using Kaplan-Meier survival curves with log-rank tests. RESULTS: A total of 126 patients underwent LRC and 189 patients underwent RARC during the study period. All the baseline variables were similar between the two groups. Patients undergoing RARC had a significant higher median estimated blood loss (300 mL vs. 200 mL; P = .005), lower rate of 90-day postoperative complications (36.5% vs. 50.0%; P = .017), and higher median direct cost ($15,306 vs. $11,131; P < .001) than LRC. Other perioperative outcomes were similar. No differences were found in pathologic T stage, positive lymph nodes, or positive surgical margin between patients who underwent LRC and RARC. The 5-year disease-free survival, overall survival, and cancer-specific survival rates were 51.9%, 61.0%, and 69.5%, respectively, for all included patients. There were no significant differences in oncologic outcomes between the 2 groups. CONCLUSION: Patients with BCa can be safely managed with LRC and RARC by experienced surgeons. RARC was associated with a reduced rate of postoperative complication but also with higher median estimated blood loss, and higher median direct cost. These findings could be used to guide patient counseling, and treatment selection.

The clinical use of the platelet to lymphocyte ratio and lymphocyte to monocyte ratio as prognostic factors in renal cell carcinoma: a systematic review and meta-analysis.

Conflicting evidence exists regarding the effect of platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) on the prognosis of renal cell carcinoma (RCC) patients. Here we quantify the prognostic impact of these biomarkers and assess their consistency in RCC. Eligible studies were retrieved from the PubMed, Embase and Web of Science databases. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Sixteen studies containing 6,223 patients met criteria for inclusion. Overall, elevated PLR was associated with poorer overall survival (OS, HR 1.76, 95% CI 1.41-2.19, P < 0.001), progression-free survival (PFS, HR 2.81, 95% CI 1.40-5.63, P = 0.004) and recurrence-free survival (RFS, HR 2.64, 95% CI 1.35-5.14, P = 0.004). Conversely, high LMR was correlated with more favorable OS (HR 0.62, 95% CI 0.51-0.77, P < 0.001) and RFS (HR 0.53, 95% CI 0.42-0.67, P < 0.001). Moreover, low LMR was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness. By these results, elevated PLR was associated with poor outcomes, while high LMR correlated with more favorable survival in RCC patients. Pretreatment PLR and LMR can serve as prognostic factors in RCC patients.

Adenovirus-delivered microRNA targeting the vitamin D receptor reduces intracellular Ca²âº concentrations by regulating the expression of Ca²âº-transport proteins in renal epithelial cells.

UNLABELLED: What's known on the subject? and What does the study add? Experimental data have shown that VDR overexpression in the duodenum and kidney cortex is a biological characteristic of genetic hypercalciuric stone-forming rats (GHS rat), and a link between idiopathic calcium stone formation and the microstatellite marker D12S339 (near the VDR locus) has been proven in humans. Our study shows that VDR can positively regulate the mRNA and protein expression of TRPV5, calbindin-D28k and PMCA1b in NRK cell lines. VDR knockdown results in a decrease in intracellular Ca²âº concentration in NRK cell lines. The effect of the elevated VDR level in the kidney on hypercalciuria and the underlying mechanisms need to be further addressed. OBJECTIVE: • To determine the effects of vitamin D receptor (VDR) on hypercalciuria and the mechanisms underlying such effects. MATERIALS AND METHODS: • The adenovirus vector-delivered microRNA targeting rat VDR was constructed. We infected the normal rat kidney epithelial cell line NRK (Cellbank, China) with the adenovirus and then collected the cells at 0, 48, 72, 96, 120 h after infection. The mRNA and protein levels of VDR and VDR-dependent epithelial Ca2+ transport proteins were detected using real-time polymerase chain reaction and Western blot assays, respectively. • Fluorescent Ca²âº indicator Fluo-4 NW (Fluo-4 NW calcium assay kit, Molecular Probes, Invitrogen, USA) and laser scanning confocal microscope (Olympus, FV500-IX71, Japan) were used to detect the cytosolic free Ca²âº concentration at different time points after infection. RESULTS: • The mRNA and protein level of VDR, transient receptor potential vanilloid receptor subtype 5 (TRPV5), calbindin-D28k and plasma membrane Ca²âº-ATPase (PMCA1b) in infected NRK cells was significantly lower at 72 and 96 h after infection than that in control cells. • There was no significant difference between the two groups in the mRNA and protein level of TRPV6 and the Na⁺/Ca²âº-exchanger (NCX1). • Furthermore, VDR knockdown results in a decrease in intracellular Ca²âº concentration ([Ca²âº]i) in NRK cell lines. CONCLUSIONS: • Our study shows that VDR can positively regulate the mRNA and protein expression of TRPV5, calbindin-D28k and PMCA1b, but not of TRPV6 or NCX1, in NRK cell lines. VDR knockdown results in a decrease in [Ca²âº]i in NRK cell lines. • The effect of the elevated VDR level in the kidney on hypercalciuria and the mechanisms underlying need to be further addressed.

Characterization of circulating CD4+CD25high regulatory T cells in men with chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVES: To identify the characteristics of circulating CD4(+)CD25(high) regulatory T cells in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We sought to discover the possible mechanism underlying induction of CP/CPPS by autoimmune factors. METHODS: A total of 69 men with CP/CPPS and 25 age-matched, asymptomatic controls underwent quantification of peripheral blood CD4(+)CD25(high) regulatory T cells, using flow cytometry, followed by measurement of interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGFbeta1) in serum, and forkhead box P3 (FOXP3) mRNA level in peripheral blood mononuclear cells, using enzyme-linked immunosorbent assay and real-time quantitative reverse transcriptase-polymerase chain reaction, respectively. RESULTS: The FOXP3 gene mRNA level in CP/CPPS patients was significantly lower than that in controls. Serum TNF-alpha level increased but the TGFbeta1 level decreased in CP/CPPS patients. No change was observed in the levels of IL-6 and IL-10. However, there was normal frequency of CD4(+)CD25(high) T cells in CP/CPPS patients. No differences were observed in expression of FOXP3 and serum cytokines and population of CD4(+)CD25(high) T cells between CP/CPPS IIIA and IIIB patients. In addition, statistically significant correlation was only found between serum IL-6 production and national institutes of health-chronic prostatitis symptom index total score of CP/CPPS patients. The frequency of CD4(+)CD25(high) T cells and FOXP3 expression level did not correlate with age, duration, and total national institutes of health-chronic prostatitis symptom index score of CP/CPPS patients. CONCLUSIONS: FOXP3 and serum cytokines, such as TNF-alpha and TGFbeta1, might be important for the pathogenesis of CP/CPPS and possibly affect the suppressive function of CD4(+)CD25(high) regulatory T cells. This influence may result in the onset of CP/CPPS, but its assessment requires further study.

The expression and implication of TRPV5, Calbindin-D28k and NCX1 in idiopathic hypercalciuria.

The expression of calcium epithelium TRPV5, alcium binding protein Calbindin-D28k and Na(+)/Ca(2+) exchanger NCX1 was detected in renal distal convoluted tubule, and their effects on urine calcium reabsorption and the possible pathogenic mechanism in idiopathic hypercalciuria (IH) were investigated. Genetic hypercalciuric stone-forming (GHS) rats were chosen as animal models to study urine calcium reabsorption and IH. The cognate female and male rats that had maximal urine calcium were matched to breed next generation. Twelve GHS rats and 12 normal control (NC) SD rats were selected. Western blot and real time quantitative PCR were used to detect the protein and gene expression of TRPV5, Calbindin-D28k and NCX1 respectively. The expression levels of TRPV5 protein and mRNA in GHS rats were significantly lower than in NC rats (P<0.05). Western blot revealed that the expression levels of Calbindin-D28k in GHS rats and NC rats were 0.49+/-0.02 and 0.20+/-0.01 respectively, with the difference being significant between them (P<0.05). By using real time quantitative PCR, it was found that there was no significant difference in Calbindin-28k mRNA expression levels between GHS rats and NC rats (P>0.05). There was no significant difference in the NCX1 expression between GHS rats and NC rats (P>0.05). It was suggested that TRPV5 and Calbindin-D28k might play an important role in urine calcium reabsorption and IH, but they differently contributed to the pathogenesis: The down-regulation of TRPV5 decreases urine calcium reabsorption, directly leading to loss of the urine calcium and resulting in hypercalciuria, and the increased Calbindin-D28k expression could relieve, neutralize and decrease intracellular Ca(2+) concentration to maintain calcium balance. NCX1 is not the key protein in urine calcium reabsorption.

[Expression of calbindin-D28k in genetic hypercalciuric stone-forming rats kidney and its role in pathogenesis of idiopathic hypercalciuria].

OBJECTIVE: To study the expression level of calbindin-D28k, a kind of calcium binding protein, in the kidneys of genetic hypercalciuric stone-forming (GHS) rats and to investigate its role in idiopathic hypercalciuria (IH). METHODS: Kidneys were taken out from 16 GHS rats and 6 normal control (NC) rats. Western blotting and real time quantitative PCR were used to detect the protein and mRNA expression levels of calbindin-D28k respectively. RESULTS: Western blotting showed that the A value of calbindin-D28k of the GHS rats was 0.49 +/- 0.02, significantly higher than that of the NC rats (0.20 +/- 0.01, P < 0.05). The 2(-(delta delta CT)) value of mRNA of calbindin-D28k of the GHS rats was 1.21, remarkably higher than that of the NC rats [with the of 2(-(delta delta CT)) value of 1.0]. There was not significant difference in the delta CT value between the two groups (P > 0.05). CONCLUSION: The up-regulation of calbindin-D28k in the GHS rats is possibly caused by hyperexpression of VDR and hypercalcinuria, and plays an important role in urine calcium reabsorption; however, it is not the key protein that results in IH.

The Expression and Implication ofTRPV5, Calbindin-D28k and NCX1 in Idiopathic Hypercalciuria / 华中科技大学学报（医学）（英德文版）

Summary: The expression of calcium epithelium TRPV5, alcium binding protein Calbindin-D28k and Na+/Ca2+ exchanger NCX1 was detected in renal distal convoluted tubule, and their effects on urine calcium reabsorption and the possible pathogenic mechanism in idiopathic hypercalciuria (IH) were investigated. Genetic hypercalciuric stone-forming (GHS) rats were chosen as animal models to study urine calcium reabsorption and IH. The cognate female and male rats that had maximal urine calcium were matched to breed next generation. Twelve GHS rats and 12 normal control (NC) SD rats were selected. Western blot and real time quantitative PCR were used to detect the protein and gene expression of TRPV5, Calbindin-D28k and NCX1 respectively. The expression levels of TRPV5 protein and mRNA in GHS rats were significantly lower than in NC rats (P<0.05). Western blot revealed that the expression levels of Caibindin-D28k in GHS rats and NC rats were 0.49±0.02 and 0.20±0.01 respectively, with the difference being significant between them (P<0.05). By using real time quantitative PCR, it was found that there was no significant difference in Calbindin-28k mRNA expression levels between GHS rats and NC rats (P0.05). There was no significant difference in the NCX1 expression between GHS rats and NC rats (P0.05). It was suggested that TRPV5 and Caibindin-D28k might play an important role in urine calcium reabsorption and IH, but they differently contributed to the pathogenesis: The down-regulation of TRPV5 decreases urine calcium reabsorption, directly leading to loss of the urine calcium and resulting in hypercalciuria, and the increased Calbindin-D28k expression could relieve, neutralize and decrease intracellular Ca2+ concentration to maintain calcium balance. NCX1 is not the key protein in urine calcium reabsorption.