The prognostic value of family history among patients with urinary bladder cancer

A history of urinary bladder cancer (UBC) in first‐degree relatives increases UBC risk by twofold. The influence of positive family history on UBC prognosis is unknown. Here, we investigated association of first‐degree UBC family history with clinicopathological characteristics and prognosis of UBC patients. Detailed clinical data of 1,465 non‐muscle‐invasive bladder cancer (NMIBC) and 250 muscle‐invasive or metastatic bladder cancer (MIBC) patients, diagnosed from 1995 to 2010, were collected through medical file review. Competing risk analyses were used to compare recurrence‐free survival (RFS) and progression‐free survival (PFS) of NMIBC patients according to self‐reported UBC family history. Overall survival in MIBC patients was estimated using Kaplan‐Meier analysis. The added value of family history in prediction of NMIBC prognosis was quantified with Harrell's concordance‐index. Hundred (6.8%) NMIBC and 14 (5.6%) MIBC patients reported UBC in first‐degree relatives. Positive family history was statistically significantly associated with smaller tumor size and non‐significantly with more favorable distribution of other tumor characteristics. In univariable analyses, positive family history correlated with longer RFS (p = 0.11) and PFS (p = 0.04). Hazard ratios for positive vs. negative family history after adjustment for clinicopathological characteristics were 0.75 (95% CI = 0.53–1.07) and 0.45 (95% CI = 0.18–1.12) for RFS and PFS, respectively. Five familial and 48 sporadic MIBC patients (Kaplan‐Meier 10‐year risk: 41% and 25%) died within 10 years. Family history did not improve the c‐index of prediction models. This study shows that a first‐degree family history of UBC is not clearly associated with NMIBC prognosis. Family history does not aid in prediction of NMIBC recurrence or progression.     

Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion

Background

Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC)/invasive have different gene profile and clinical course. NMIBC prognosis is not completely predictable, since the relapse rate is higher than 20%, even in the form of MIBC. The aim of this study is to evaluate if UTR expression can discriminate between NMIBC and MIBC and predict the risk of relapses in NMIBCs.

Methods

We have investigated upon urotensin-II (UII) receptor (UTR) expression in vivo in 159 patients affected by NMIBC. The biological role of UTR was also investigated in vitro. UTR expression was evaluated in a tissue-micro-array, consisting of normal, NMIBC and invasive bTCC samples.

Results

UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC. The superagonist UPG84 induced growth suppression at nM concentrations on 3/4 cell lines. Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells.

Conclusions

The evaluation of UTR expression can discriminate between NMIBC at high and low risk of relapse. Moreover, our data suggest that UTR is involved in the regulation of motility, invasion and proliferation of bladder cancer cells. High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.     

History of Non–Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy

Purpose

To investigate whether a history of non–muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC.

Nested quantitative PCR approach for urinary cell‐free EZH2 mRNA and its potential clinical application in bladder cancer

EZH2 is overexpressed in bladder cancer (BC) and plays important roles in tumor development and progression. Recent studies show cell free (cf) RNAs released from cancer cells can reflect tissues changes and are stable and detectable in urine. Although conventional quantitative real‐time PCR (qPCR) is highly sensitive, low abundances of urinary cf‐RNAs usually result in false‐negatives. Thus, this study develops a nested qPCR (nqPCR) approach to quantify cf‐EZH2 mRNA in urine and further assess its clinical significance for BC. Forty urine samples were first selected to evaluate feasibility of nqPCR. Then, levels of urinary cf‐EZH2 mRNA were detected using developed method in an independent cohort of subjects with 91 healthy, 81 cystitis, 169 nonmuscle invasive BC (NMIBC) and 103 muscle‐invasive BC (MIBC). In cf‐EZH2 mRNA detection, nqPCR method was significantly associated with qPCR, but it could detect more urine samples and increase detection limit three orders of magnitude. Based on nqPCR method, cf‐EZH2 mRNA levels have been found to be increased in urine of NMIBC and MIBC patients (p < 0.001). Compared with cytology, cf‐EZH2 mRNA showed higher diagnostic ability for MIBC (p < 0.001) while not for NMIBC (p > 0.05). Moreover, it also could distinguish MIBC from NMIBC, with AUC of 0.787. For MIBC patients, high expression of cf‐EZH2 mRNA associated with advanced stage and was an independent predictor of reduced disease free survival or overall survival. In conclusion, detection of cf‐EZH2 mRNA in urine by nqPCR is a sensitive and noninvasive approach and may be used for diagnosis and prognosis prediction of MIBC.     

BCG Administration after Prior Radiation Treatment for Prostate Cancer

IntroductionProstate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. The underlying mechanism is incompletely understood but is thought to be related to an altered microenvironment promoting tumorigenesis. However, there is a gap in the literature regarding how the effect of BCG varies according to prior radiotherapy in patients with non–muscle invasive bladder cancer (NMIBC). In this context, we sought to evaluate oncologic outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy.MethodsThis is a retrospective cohort study that includes all patients who received intravesical for NMIBC at our institution from 2001 to 2019. Patients were stratified into 3 cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). The outcomes of interest were recurrence at 1-year, progression to muscle-invasive bladder cancer (MIBC), and progression to metastatic disease. Comparisons were also made between cohorts with respect to elapsed time from radiation therapy. Wilcoxon rank-sum test was used for comparing continuous variables, while χ² and Fischer's exact tests were used to examine categorical variables.ResultsIn 199 total patients who underwent BCG for NMIBC, 23 had a prior history of prostate radiotherapy treatment, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at 1 year. There was no difference in the number of induction or maintenance BCG administrations received between the cohorts within the first year. There was no significant difference in recurrence at 1 year between the 3 cohorts (P = .56). There was also no difference in progression to MIBC or progression to metastatic disease with P = .50 and 0.89, respectively.ConclusionThe risk of recurrence after induction BCG treatment for high-grade NMIBC does not vary according to prior radiation treatment for prostate cancer.     

Effects of Bladder Cancer on UK Healthcare Costs and Patient Health-Related Quality of Life: Evidence From the BOXIT Trial

BackgroundLimited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non–muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial.Material and MethodsThe costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification.ResultsCases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (−0.08; 95% confidence interval [CI], −0.13 to −0.03; and −0.10; 95% CI, −0.17 to −0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152).ConclusionEvidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC.     

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study

Introduction

There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown.

Objective

The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study.

Methods

728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake.

Results

During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78–1.47, p?=?0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90–1.15, p?=?0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42–1.01, p?=?0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85–1.18, p?=?1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence.

Conclusion

Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.

     

Prognostic Value of Pretreatment Albumin-to-Globulin Ratio in Patients With Non–Muscle-Invasive Bladder Cancer

Purpose

To investigate the relationship between albumin-to-globulin ratio (AGR) and oncologic outcomes in patients with non–muscle-invasive bladder cancer (NMIBC).

Hedgehog pathway activation in human transitional cell carcinoma of the bladder

Background:

The Hedgehog (Hh) signalling pathway functions as an organiser in embryonic development. Recent studies have shown constitutive activation of this pathway in various malignancies, but its role in bladder cancer remains poorly studied.

Methods:

Expression levels of 31 genes and 9 microRNAs (miRNAs) involved in the Hh pathway were determined by quantitative real-time RT–PCR in 71 bladder tumour samples (21 muscle-invasive (MIBC) and 50 non-muscle-invasive (NMIBC) bladder cancers), as well as in 6 bladder cancer cell lines.

Results:

The SHH ligand gene and Gli-inducible target genes (FOXM1, IGF2, OSF2, H19, and SPP1) were overexpressed in tumour samples as compared with normal bladder tissue. SHH overexpression was found in 96% of NMIBC and 52% of MIBC samples, as well as in two bladder cancer cell lines. Altered expression of miRNAs supported their oncogene or tumour-suppressor gene status. In univariate analysis, high expression levels of PTCH2, miRNA-92A, miRNA-19A, and miRNA-20A were associated with poorer overall survival in MIBC (P=0.02, P=0.012, P=0.047, and P=0.036, respectively).

Conclusion:

We observed constitutive activation of the Hh pathway in most NMIBC and about 50% of MIBC. We also found that some protein-coding genes and miRNAs involved in the Hh pathway may have prognostic value at the individual level.     

Correlation of IL-31 gene polymorphisms with susceptibility and clinical recurrence of bladder cancer

Interleukin-31 is a crucial cytokine triggering inflammation which could be one of the risk factors of tumors. However, data for correlation between IL-31 and tumors are limited. The purpose of our study was to discuss whether genetic polymorphisms of IL-31 were associated with the susceptibility and clinical outcomes of bladder cancer. Our study enrolled 478 controls, 156 non-muscle-invasive bladder cancer (NMIBC) and 138 muscle-invasive bladder cancer (MIBC) patients. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping two single nucleotide polymorphisms (SNPs) of IL-31 gene including rs7977932 and rs4758680. Our results showed that A allele and CA/AA genotypes of rs4758680 were associated with susceptibility to bladder cancer (P?=?0.04, OR 1.32, 95% CI 1.01–1.72, and P?=?0.02, OR 1.43, 95% CI 1.05–1.96, respectively), and G allele of rs7977932 might be a protect factor for tobacco smoking patients compared with non-smoking patients (P?=?0.005, OR 0.42, 95% CI 0.23–0.76). Furthermore, CA/AA genotypes of rs4758680 might be the independent risk factors for the decreased recurrence-free survival of the patients with MIBC (P?=?0.03, OR 2.02, 95% CI 1.06–3.85. Our data indicated that polymorphisms of IL-31 are associated with bladder cancer, and rs4758680 could be an independent prediction for MIBC patients with a high risk of recurrence.     

microRNA expression profile in a large series of bladder tumors: Identification of a 3‐miRNA signature associated with aggressiveness of muscle‐invasive bladder cancer

The aim of this study was to evaluate the expression levels of microRNAs (miRNAs) in bladder tumors in order to identify miRNAs involved in bladder carcinogenesis with potential prognostic implications. Expression levels of miRNAs were assessed by quantitative real‐time RT‐PCR in 11 human normal bladder and 166 bladder tumor samples (86 non‐muscle‐invasive bladder cancer (NMIBC) and 80 muscle‐invasive bladder cancer (MIBC)). The expression level of 804 miRNAs was initially measured in a well‐defined series of seven NMIBC, MIBC and normal bladder samples (screening set). The most strongly deregulated miRNAs in tumor samples compared to normal bladder tissue were then selected for RT‐PCR validation in a well‐characterized independent series of 152 bladder tumors (validation set), and in six bladder cancer cell lines. Expression levels of these miRNAs were tested for their association with clinical outcome. A robust group of 15 miRNAs was found to be significantly deregulated in bladder cancer. Except for two miRNAs, miR‐146b and miR‐9, which were specifically upregulated in MIBC, the majority of miRNAs (n = 13) were deregulated in the same way in the two types of bladder tumors, irrespective of pathological stage : three miRNAs were upregulated (miR‐200b, miR‐182 and miR‐138) and the other 10 miRNAs were downregulated (miR‐1, miR‐133a, miR‐133b, miR‐145, miR‐143, miR‐204, miR‐921, miR‐1281, miR‐199a and miR‐199b). A 3‐miRNA signature (miR‐9, miR‐182 and miR‐200b) was found to be related to MIBC tumor aggressiveness and was associated with both recurrence‐free and overall survival in univariate analysis with a trend to significance in the multivariate analysis (p = 0.05). Our results suggested a promising individual prognostic value of these new markers.     

Identification of novel potential genetic predictors of urothelial bladder carcinoma susceptibility in Pakistani population

Urothelial bladder carcinoma (UBC) is the most common among urinary bladder neoplasms. We carried out a preliminary study to determine the genetic etiology of UBC in Pakistani population, for this 25 sequence variants from 17 candidate genes were studied in 400 individuals by using polymerase chain reaction-based techniques. Multivariate logistic regression analysis was performed for association analysis of the overall data as well as the data stratified by smoking status, tumor grade and tumor stage. Variants of GSTM1, IGFBP3, LEPR and ACE were found to be associated with altered UBC risk in the overall comparison. CYP1B1 and CDKN1A variants displayed a risk modulation among smokers; IGFBP3 and LEPR variants among non­smokers while GSTM1 polymorphism exhibited association with both. GSTM1 and LEPR variants conferred an altered susceptibility to low grade UBC; GSTT1, IGFBP3 and PPARG variants to high grade UBC while ACE polymorphism to both grades. GSTM1 and LEPR variants exhibited risk modulation for non-muscle-invasive bladder cancer (NMIBC); GSTT1 and PPARG variants for muscle-invasive bladder cancer (MIBC), and ACE variant for NMIBC as well as MIBC. In general, the susceptibility markers were common for low grade and NMIBC; and distinct from those for high grade and MIBC indicating the distinct pathologies of both groups. In brief, our results conform to reports of previously associated variants in addition to identifying novel potential genetic predictors of UBC susceptibility.     

Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non-muscle invasive bladder cancer

Background

PCDH8 is a novel tumor suppressor gene, and frequently inactivated by promoter methylation in human cancers. However, there is little information regarding PCDH8 methylation in non-muscle invasive bladder cancer (NMIBC). The aim of this study was to investigate the methylation status of PCDH8 in NMIBC and its clinical significance.

Methods

The methylation status of PCDH8 in 233 NMIBC tissues and 43 normal bladder epithelial tissues was examined by methylation-specific PCR (MSP), and then analyzed the correlations between PCDH8 methylation and clinicopatholocial features. Subsequently, Kaplan-Meier survival analysis and Multivariate Cox proportional hazard model analysis was used to investigate the correlation between PCDH8 methylation and prognosis of patients with NMIBC.

Results

PCDH8 methylation occurred frequently in NMIBC tissues than those in normal bladder epithelial tissues. In addition, PCDH8 methylation significantly correlated with advanced stage, high grade, larger tumor size, tumor recurrence and progression in NMIBC. Kaplan-Meier survival analysis revealed that patients with PCDH8 methylated have shorter recurrence-free survival, progression-free survival and five-year overall survival than patients with PCDH8 unmethylated. Multivariate analysis suggested that PCDH8 methylation was an independent prognostic biomarker for recurrence-free survival, progression-free survival and five-year overall survival simultaneously.

Conclusions

PCDH8 methylation may be associated with tumor progression and poor prognosis in NMIBC and may be used as a potential biomarker to predict the prognosis of patients with NMIBC.     

中性粒／淋巴细胞比值在正常人群及不同分期膀胱尿路上皮癌患者中的意义

目的:评估中性粒细胞与淋巴细胞比率（neutrophil-lymphocyte ratio,NLR）在膀胱尿路上皮癌（urothelial carcinoma,UC）患者及正常人群中的意义。方法:随访非肌层浸润性膀胱癌患者（non muscle-invasive bladder cancer,NMIBC）、肌层浸润性膀胱癌患者（muscle-invasive bladder cancer,MIBC）和健康体检患者。根据受试者工作曲线（receiver operator characteristic curve,ROC）确定不同类型膀胱癌患者术后是否出现复发及转移的最佳NLR值以及膀胱癌患者中NMIBC患者区别MIBC患者的最佳NLR值。收集患者T分期、G分级、肿瘤数量、复发时间、3年无复发生存率、无瘤生存率。结果:NLR值在正常健康人群及癌症患者中存在差异,在NMIBC患者及MIBC患者中存在差异（P＜0.05）。NLR值在NMIBC患者的肿瘤T分期、G分级、肿瘤大小、肿瘤数量、复发时间及无瘤生存时间中存在差异（P＜0.05）,在MIBC患者的肿瘤T分期中存在差异（P＜0.05）。结论:NLR值很可能为患者的疾病辅助诊断及预后提供一项经济可行的炎症标志物。     

Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer

BACKGROUND:

Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date.

METHODS:

In this study, the authors applied a comprehensive pathway‐based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case‐control study that included 803 bladder cancer cases and 803 controls.

RESULTS:

In total, 17 SNPs were associated significantly with altered bladder cancer risk (P < .05), of which, 7 SNPs retained noteworthiness after they were assessed with a Bayesian approach for the probability of false discovery. The most noteworthy SNP was reference SNP 11132186 (rs11132186) in the inhibitor of growth family, member 2 (ING2) gene. Compared with the major allele‐containing genotypes, the odds ratio was 0.52 (95% confidence interval, 0.32‐0.83; P = .005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene‐smoking interactions were observed for 3 of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, potential gene‐gene interactions were identified.

CONCLUSIONS:

In this a large association study of the NER pathway and the risk of bladder cancer, several novel predisposition variants were identified along with potential gene‐gene and gene‐environment interactions in modulating bladder cancer risk. The results reinforce the importance of a comprehensive, pathway‐focused, and tagging SNP‐based candidate gene approach to identify low‐penetrance cancer susceptibility loci. Cancer 2012;. © 2011 American Cancer Society.     

Dietary patterns and risk of recurrence and progression in non‐muscle‐invasive bladder cancer

The association of dietary factors with urinary bladder cancer prognosis has scarcely been investigated, and results of studies conducted to date are inconsistent. We investigated whether empirically derived dietary patterns are associated with risks of recurrence and progression in non‐muscle‐invasive bladder cancer (NMIBC) patients. Data from 595 newly diagnosed NMIBC patients from an ongoing prospective cohort study were used to derive dietary patterns using exploratory factor analysis. Factor scores were calculated and then categorized in sex‐specific tertiles. Multivariable‐adjusted proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the associations between tertiles of adherence to the dietary patterns and risks of recurrence and progression. We identified four dietary patterns: “fruits and vegetables,” “Western,” “low‐fat,” and “Tex‐Mex.” Patients in the highest tertile of adherence to the Western pattern experienced a 1.48 times higher risk of recurrence (95% CI 1.06–2.06) compared to patients in the lowest tertile. No statistically significant associations of a Western diet with risk of progression or of the other dietary patterns with risk of recurrence and progression were found. Overall, we found that adherence to a Western diet was associated with a higher risk of recurrence but further studies are needed to confirm our findings.     

The Role of Prior Bladder Cancer on Recurrence in Patients Treated with Radical Nephroureterectomy

IntroductionThe prognostic role of prior history of bladder cancer (BCa) among patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) is poorly addressed. We aimed to investigate the role of prior BCa on any recurrence, distant metastases, and bladder recurrence following RNU among low-grade (LG) and high-grade (HG) UTUC patients.Patients and MethodsWe retrospectively analyzed 1,580 UTUC patients treated with RNU at 8 tertiary referral centers between 1992 and 2016. Any recurrence was defined as recurrence in the urinary tract, in the resection bed, or distant metastases (defined as disease outside the urinary tract and regional lymph nodes). Time to recurrence was computed from RNU. Multivariable Cox models were generated to predict risk of any recurrence, distant metastases, and bladder recurrence according to prior BCa history, coded as no prior BCa, non-muscle-invasive (NMIBC), and muscle-invasive BCa (MIBC).ResultsMedian follow-up for survivors was 4 years. Overall, 71%, 25%, and 4% of patients had no prior BCa, NMIBC and MIBC. 5-year any recurrence-free survival was 61%, 41%, and 19% in LG (P < .001) and 42%, 34%, and 30% in HG patients (P = .1) with no prior BCa, NMIBC, and MIBC. On multivariable models, LG patients with NMIBC and MIBC showed a significantly higher risk of any recurrence compared to no prior BCa (both p≤0.005); previous NMIBC was associated with any recurrence among HG patients (P = 0.04). 5-year distant metastases-free survival was 92%, 90%, and 87% in LG (P > .05) and 68%, 75%, and 45% in HG patients (P = .01) with no prior BCa, NMIBC, and MIBC. Previous NMIBC increased the risk of bladder recurrence among LG (P < .001) and HG (P = .003) patients.ConclusionsUTUC patients with prior history of BCa exhibit a higher risk of any recurrence after RNU. Our study provides important information which could address patient's counseling and decision-making process.     

Carbonic anhydrase 2 is a novel invasion‐associated factor in urinary bladder cancers

Rat bladder cancer is nearly always papillary non‐invasive urothelial carcinoma (UC). To establish an animal model mimicking invasive UC that arises from papillary non‐invasive UC in the bladder, male human c‐Ha‐ras proto‐oncogene transgenic rats (Hras128) were treated with 0.05% N‐butyl‐N‐(hydroxybutyl)nitrosameine (BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in their diet as follows: BBN (8 weeks)→PEITC (8 weeks); PEITC (8 weeks)→BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN→PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion‐associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non‐invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non‐invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 (CA2), an overexpressed protein, showed that the relative number of CA2‐positive UC was significantly higher for invasive UC compared to non‐invasive UC in rats. Moreover, the incidence of CA2‐positive cancers was also significantly higher for human muscle‐invasive bladder cancer (MIBC) compared to non‐MIBC (NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion‐associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers.     

Lymphovascular invasion,ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes

Purpose

To identify predictive factors underlying recurrence and survival after partial cystectomy for pelvic lymph node-negative muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) and to report the results of partial cystectomy among select patients.

Methods

We retrospectively reviewed 101 cases that received partial cystectomy for MIBC (pT_2-3N₀M₀) between 2000 and 2010. The log-rank test and a Cox regression analyses were performed to identify factors that were predictive of recurrence and survival.

Results

With a median follow-up of 53.0 months (range 9–120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively. A total of 33 patients died of bladder cancer and 52 patients survived with intact bladder.Of the 101 patients included, 55 had no recurrence, 12 had non-muscle-invasive recurrence in the bladder that was treated successfully, and 34 had recurrence with advanced disease.The multivariate analysis showed that prior history of urothelial carcinoma (PH.UC) was associated with both CSS and RFS and weakly associated with OS; lymphovascular invasion (LVI) and ureteral reimplantation (UR) were associated with OS, CSS and RFS.

Conclusions

Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered as contraindications for partial cystectomy, and LVI is predictive of poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for the treatment of MIBC with negative pelvic lymph nodes.