Dawei Tian

Metastasis-associated in colon cancer 1 is a novel survival-related biomarker for human patients with renal pelvis carcinoma.

Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.

Human telomerase reverse-transcriptase promoter-controlled and herpes simplex virus thymidine kinase-armed adenoviruses for renal cell carcinoma treatment

New treatment strategies are required for renal cell carcinoma (RCC) due to its relative insensitivity to conventional radio- and chemotherapies. The promising strategy of tumor inhibition using human telomerase reverse transcriptase (hTERT)-controlled herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) in the hTERT promoter-driven HSV-TK/GCV suicide gene system was investigated. Tumor volume, weight, relative proliferation rate, and cell-apoptosis levels were examined in mice injected with adenovirus (Ad)-hTERT-HSV-TK and GCV. Increased cell death occurred following treatment with Ads carrying hTERT-HSV-TK/GCV or cytomegalovirus promoter-controlled (CMV)-HSV-TK/GCV for human RCC 786-0 and fibroblast MRC-5 cells. In mice, Ad-hTERT-HSV-TK/GCV more specifically inhibited tumor and RCC xenograft growth than Ad-CMV-HSV-TK/GCV (P < 0.05). Furthermore, Ad-hTERT-HSV-TK/GCV did not significantly damage normal fibroblasts or organ systems (heart, lung, liver, brain, kidney, and spleen). Thus, Ad-hTERT-HSV-TK/GCV is an effective RCC inhibitor in human cells in vitro and in vivo mouse models, indicating potential usefulness in RCC-targeted gene therapy.

The evaluation of the association between the metabolic syndrome and tumor grade and stage of bladder cancer in a Chinese population

Objective The objective of this article was to summarize the relationship between some components of metabolic syndrome (MetS) and the histopathologic findings in bladder cancer in a Chinese population. Methods We retrospectively analyzed data of 323 patients from the Department of Urology, Second Hospital of Tianjin Medical University between January 2012 and January 2014. All the patients were diagnosed with bladder cancer for the first time. Age, height, weight, histologic stage, grade, the presence of hypertension, diabetes mellitus, and body mass index were evaluated. The 2009 American Joint Committee on Cancer TNM staging system was used, with Ta and T1 tumors accepted as lower stage and T2, T3, and T4 tumors as higher stage bladder cancers. Also, pathologists assigned tumor grade according to the 1973 World Health Organization grading system. Noninvasive papillary urothelial neoplasms of low malignant potential were regarded as low grade. Analyses were completed using chi-square tests and logistic regression analysis. Results Of the 323 patients, 164 had hypertension, 151 had diabetes mellitus, and 213 had a body mass index ≥25 kg/m2. MetS was significantly associated with histologic grade (P<0.001) and stage (P=0.006) of bladder cancer. Adjusted for age in binary logistic regression analysis, the presence of MetS predicts the risk of higher T stage (odds ratio =4.029, P<0.001) and grade (odds ratio =3.870, P<0.001) of bladder cancer. Conclusion The patients with MetS in the People’s Republic of China were found to have statistically significant higher T stage and grade of bladder cancer.

Association between MDM2 SNP309 T>G polymorphism and the risk of bladder cancer: new data in a Chinese population and an updated meta-analysis

Objective Human murine double minute 2 protein (MDM2) is mainly a negative regulator of p53 tumor suppressor pathway. We aimed to investigate the association between MDM2 SNP309 polymorphism and bladder cancer risk. Methods A total of 535 bladder cancer patients and 649 health controls were recruited for our study. MDM2 SNP309 T>G polymorphism was genotyped by polymerase chain reaction-ligase detection reaction method. Logistic regression was used to analyze the relationship between the genotype and susceptibility of bladder cancer. Kaplan–Meier estimates and log-rank test were obtained to analyze the association between the genotype and risk of recrudesce in nonmuscle-invasive bladder cancer patients. A multivariable Cox proportional hazards model was fitted to identify independent prognostic factors. To further investigate the association, we conducted a meta-analysis including six studies. Results The frequency of the MDM2 SNP309 T>G polymorphism showed no significant difference between cases and controls (all P>0.05). In the stratification analysis, the results showed that G allele carriers were prone to have a significant decrease in risk of low-grade bladder cancer (adjusted odds ratio: 0.613, 95% confidence interval: 0.427–0.881), and G variant was associated with a significantly reduced risk of recurrence in nonmuscle-invasive bladder cancer patients with or without chemotherapy (P<0.05). The results of the meta-analysis showed that G allele and GG genotype of MDM2 SNP309 polymorphism were significantly associated with increased risk of bladder cancer in Caucasians (both P<0.05), and no association was observed in total populations and Asians (P>0.05). Conclusion MDM2 SNP309 T>G polymorphism has no influence on bladder cancer risk in Asians, but this single nucleotide polymorphism may be associated with genetic susceptibility of bladder cancer among Caucasians.

Risk Factors Predictive of Recurrence and Progression for Patients Who Suffered Initial Recurrence After Transurethral Resection of Stage pT1 Bladder Tumor in Chinese Population: A Retrospective Study

Abstract Bladder cancer is one of the most common malignancies worldwide and the stage pT1nonmuscle invasive bladder cancer (NMIBC) has a high probability of recurrence after initial diagnosis and treatment. However, risk factors predictive of repeated recurrence and progression of pT1 bladder tumors after primary relapse have not been uncovered. Thus, we conducted the retrospective study. A total of 418 patients who suffered initial recurrence after transurethral resection (TUR) of pT1 bladder tumor were selected for the analyses. Clinic information of the patients was retrieved from their medical records. Recurrence-free survival (RFS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. The probability of recurrence and progression by multivariate analyses was used as a surrogate marker to construct receiver operating curve (ROC). Results showed that variables including time to prior recurrence time, prior treatment, number of tumor, tumor size, tumor grade, and time of instillation after surgery were associated with the repeated recurrence of pT1 bladder tumor (P < 0.05). The variables including time to prior recurrence time, tumor size, tumor grade, carcinoma in situ (CIS), and time of instillation after surgery were associated with progression of pT1 bladder tumor (P < 0.05). In the present study, the multivariate model showed an area under ROC (AUC) value of 0.754 and 0.798 for tumor recurrence and progression, respectively, which was more effective in prediction than a single risk factor. In conclusion, we have identified several risk factors relevant to RFS and PFS for patients who have had a history of recurrence of pT1 bladder tumor after TUR. These predictive factors may help urologists to stratify patients into distinct risk groups of recurrence and progression, which probably contributes to the individualized treatment for patients.

Expression of brain‑specific angiogenesis inhibitor‑1 and association with p53, microvessel density and vascular endothelial growth factor in the tissue of human bladder transitional cell carcinoma

The aim of the present study was to investigate the expression levels of brain‑specific angiogenesis inhibitor‑1 (BAI‑1) in bladder transitional cell carcinoma (BTCC) at different stages and the mechanism by which it inhibits tumor endothelial cell proliferation. Normal bladder mucosa biopsy specimens were obtained as the control group, and human BTCC biopsy specimens were used as the study group. Immunohistochemical assays were used to detect the expression levels of BAI‑1, vascular endothelial growth factor (VEGF) and mutant p53, in addition to microvessel density (MVD) in the tissues. Western blotting was used to analyze the differential expression of BAI‑1 in the two samples. Statistical analysis was performed, which indicated that BAI‑1 expression levels in the normal bladder mucosa group were significantly higher than those in the BTCC group and were associated with clinical staging. BAI‑1 levels in the T1 stage BTCC tissues were higher than those in the T2‑4 stage BTCC tissues (P<0.05). BAI‑1 expression levels were negatively correlated with those of VEGF (r=‑0.661, P<0.001), mutant p53 (r=‑0.406, P=0.002) and with the MVD (r=‑0.675, P<0.001). BAI‑1 may be involved in the negative regulation of BTCC microvascular proliferation, and its expression may be associated with a reduction in p53 mutations.

Prognostic significance of urothelial carcinoma with divergent differentiation in upper urinary tract after radical nephroureterectomy without metastatic diseases: A retrospective cohort study

Abstract To evaluate the impact of urothelial carcinoma with divergent differentiation (UCDD) on the prognosis of patients for primary upper urinary tract urothelial carcinoma (UTUC) with pN0/x status treated with radical nephroureterectomy (RNU) and to evaluate the prognostic value of UCDD in different tumor locations (renal pelvis and ureter). Data from a total of 346 patients with UTUC who received RNU between January 2012 and March 2016 in the institution were retrospectively analyzed. Clinicopathological features and prognostic factors age, sex, complaint, height, weight, blood pressure, tumor grade, stage, smoking status, history of adjuvant chemotherapy, tumor location, history of bladder cancer, tumor necrosis, degree of hydronephrosis, tumor size, tumor focality, and preoperative anemia were compared between patients with pure UTUC and patients with UCDD. The endpoints were cancer-specific survival (CSS), overall survival (OS), and intraluminal recurrence-free survival (IRFS). Overall, divergent differentiation was present in 50 patients (14.5%). UCDD was related to different tumor location (P = .01), smoking (P = .04), higher body mass index (P = .02), and advanced tumor grade (P = .01). By Kaplan–Meier analysis, UCDD was found to be significantly correlated with worse IRFS, CSS, and OS (all P < .01). Multivariate analysis demonstrated that UCDD was an independent predictor of IRFS (P < .01), CSS (P = .01), and OS (P = .01). However, 40 patients died for various reasons and the 5-year OS rates were 91.9% in UCDD− group and 68.0% in UCDD+ group, respectively. In patients with ureteral tumors, UCDD was the significant predictor for IRFS, CSS, and OS. However, the prognostic value of UCDD was not observed in pyelocaliceal tumors. The presence of divergent differentiation is associated with inferior survival. UCDD may identify patients at high risks for poor prognosis especially in patients with ureteral tumors. As a result, more attention and follow-up should be given to patients with ureteric urothelial carcinoma.

The expression of vasohibin‑1 and its prognostic significance in bladder cancer

Angiogenesis is important in the development of solid tumors. Vasohibin-1 (VASH-1) is an endothelium-derived protein that acts as an inhibitor of angiogenesis in many different types of cancer. However, the expression of VASH-1 and its clinical value in bladder cancer remain unknown. The current study analyzed the expression of VASH-1, as well as the expression of the angiogenesis-related factors vascular endothelial growth factor-A, hypoxia inducible factor-1α and cluster of differentiation 34 in bladder cancer tissues from 50 patients using immunohistochemistry. The associations between the expression of these factors and the clinicopathological characteristics of the patients were assessed. The current study demonstrated that VASH-1 is primarily expressed in the cytoplasm of bladder cancer cells and in a fraction of vascular endothelial cells. Furthermore, the expression of VASH-1 was positively associated with the tumor stage (P<0.01), pathological grade (P<0.01) and distant metastasis (P<0.05) but not with patient age or sex (P>0.05). Spearman rank correlation tests indicated that levels of those four factors were positively correlated with each other. Kaplan-Meier analysis indicated that high expression of these four factors was significantly associated with lower 5-year overall survival and progression-free survival rates. Collectively, the results of the current study suggest that VASH-1 is clinically significant in bladder cancer and its high expression may predict the progression and prognosis of patients with bladder cancer. The present study also implies that VASH-1 may be a novel target for vascular targeting therapy.

AB176. Impact of squamous and/or glandular differentiation on recurrence and progression after transurethral resection for non-muscle invasive urothelial carcinoma of bladder

Objective To investigate the impact of squamous and/or glandular differentiation on recurrence and progression in patients with non-muscle-invasive urothelial carcinoma of bladder (NMIUCB) following transurethral resection (TURBT). Methods A total of 869 patients with NMIUCB treated with TURBT at our institution from January 2006 to January 2011 were selected retrospectively for the analysis. Correlations among squamous and/or glandular differentiation with other clinical and pathological features were assessed by chi-square. Recurrence-free survival (RFS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed through a Cox proportional hazards regression model. Results Among 869 consecutive patients, 232 (26.7%) patients had squamous and/or glandular differentiation. High grade tumors were more common in patients with squamous and/or glandular differentiation than those with pure UCB (P<0.001). Correlations between age (P=0.115), gender (P=0.184), tumor size (P=0.223), tumor multiplicity (P=0.108), pathological tumor stage (P=0.909) and squamous and/or glandular differentiation were not statistically significant. There was a statistically prominent tendency towards higher recurrence rate and shorter RFS time in patients with squamous and/or glandular differentiation. However, no statistically significant differences were observed in progression rate and PFS between the two groups. On multivariate Cox regression analysis, squamous and/or glandular differentiation was identified as an independent prognostic predictor of recurrence (HR 1.46, 95% CI, 1.10–1.92, P=0.008). Conclusions The presence of squamous and/or glandular differentiation could be associated with higher recurrence rate and shorter RFS time in patients with NMUCB. It is an independent prognostic predictor of recurrence.

AB175. Girdin protein is a novel prognosis predictor for patients with non-muscle invasive bladder cancer

Objective This study aimed to determine the expression status of actin-binding protein Girdin in non-muscle invasive bladder cancer (NMIBC) tissues, and to explore the relationships between Girdin expression and the clinicopathological characteristics of bladder carcinoma. Methods This study included 160 patients with NMIBC who underwent surgery from January 2006 to January 2011 at Second Hospital of Tianjin Medical University. The correlations between Girdin expression and the clinicopathological parameters were examined by Chi-square test. Recurrence-free survival (RFS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. The prognostic significance of Girdin expression was assessed using univariate and multivariate Cox regression analysis models. Results Girdin positivity was more frequently seen in high-grade tumors than in low-grade tumors (P=0.019), and in undifferentiated tumors than in differentiated tumors (P=0.028). In Kaplan-Meier analysis, expression of Girdin was significantly associated with lower RFS (P=0.007) and PFS (P=0.024) rates. The univariate analysis revealed that Girdin expression was a risk factor for both recurrence and progression of NMIBC. Further multivariate analysis identified Girdin as an independent predictor of tumor recurrence [hazard ratio (HR) 2.056, 95% CI, 1.213–3.483, P=0.007]. Conclusions The present study suggests that Girdin is differentially expressed in bladder tumors and may represent an independent predictor of prognosis for patients with NMIBC.